Synthesis, DFT calculation, pharmacological evaluation, and catalytic application in the synthesis of diverse pyrano[2,3-c]pyrazole derivatives

Bioorganic Chemistry 114 (2021) 105136

Contents lists available at ScienceDirect

Bioorganic Chemistry

journal homepage: www.elsevier.com/locate/bioorg

Synthesis, DFT calculation, pharmacological evaluation, and catalytic

application in the synthesis of diverse pyrano[2,3-c]pyrazole derivatives

Mostafa M.K. Amer^a, Magda H. Abdellattif^b, Samar M. Mouneir^c, Wael A. Zordok^a,

,

*

Wesam S. Shehab^a

^aDepartment of Chemistry, Faculty of Science, Zagazig University, Zagazig 44519, Egypt

^bDepartment of Chemistry, College of Science, Taif University, Taif 21944, Saudi Arabia

^cDepartment of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Cairo 12211, Egypt

A R T I C L E I N F O

A B S T R A C T

Keywords:

Pyranopyrazole and its derivatives are classiﬁed to be a pharmacologically signiﬁcant active scaffold for almost

all modes of biological activities. In this work, An efﬁcient, green, and facile three-component reaction for

preparing pyrano[2,3-c]pyrazole derivatives via the condensation reaction of 5-methyl-2-phenyl-2,4-dihydro-

3H-pyrazol-3-one, ethyl acetoacetate, and malononitrile in the presence of ZnO Nanoparticle. The products

are produced with high yields and in shorter reaction times. It also is mild, safe, green, and environmentally

friendly. The geometric parameters such as dipole moment, bond length, dihedral angles, total energy, heat of

formation, atomic charges and energies at a highly accurate for prepared compounds were computed by Denisty

Functional Theory along with the B3LYP functional. The newly synthesized compounds were screened for their

anti-inﬂammatory and antioxidant activity. Some of the tested compounds displayed promising activities. The

newly prepared compounds were found to be potent towards the antioxidant activity. Results indicated that

compounds 11 and 12 exhibited signiﬁcant (p ≥ 0.05) in vitro total antioxidant activity as 44.93 ± 0.15 and

39.60 ± 0.10 U/ML, respectively higher than standard ascorbic acid (29.40 ± 0.62).

Multicomponent reaction

Pyrano[2,3-c]pyrazole

DFT/B3LYP

HOMO - LUMO

Anti-inﬂammatory

Antioxidant

1. Introduction

which improves their efﬁcacy, selectivity, and catalytic activity [5].

Recently, nano-ZnO has great utilization as an efﬁcient heterogeneous

Pollution is a signiﬁcant universal problem today, so one of the

exciting challenges for synthetic organic chemists is designing organic

reactions following eco-friendly and straightforward protocol. Green

and simple synthetic protocols are vital concerns in organic synthesis

since then, multicomponent reactions (MCRs) have identiﬁed as a

valuable synthetic approach in organic, medicinal, and combinatorial

chemistry research [1,2] because of ensuring high atom economy,

shorter reaction times, good overall yields, and high chemo and regio-

selectivity as well as minimizing waste and avoidance of expensive pu-

riﬁcation processes [3]. It has been recognized that MCRs are much

more eco-friendly and offer rapid access to the structural diversity of

resulting compounds when compared to conventional multistep syn-

thesis [4].

catalyst in organic synthesis of varied biologically active heterocycles

due to its cheap cost, non-toxicity, commercial availability, environ-

mental friendliness, efﬁcient high reactivity, and reusability beneﬁts

[6].

Pyrano[2,3-c]pyrazole motifs are a privileged structure in several

bioactive heterocyclic scaffolds possessing potential pharmacological

effects [7,8] such as compound A acting as human Chk1 kinase in-

hibitors [9], B as an antimicrobial agent [10], and C as a molluscicidal

agent [11] (Fig. 1) besides anti-inﬂammatory [12], anti-bacterial [13],

antifungal [14,15], antimalarial [16], antiproliferative [17], anti-cancer

[18], anti-depressant [19], antioxidant [20], α-glucosidase inhibitors

[21], and analgesic [22] activities. Also, pyrano[2,3-c]pyrazole frame-

works have been demonstrated to exhibit enormous application in

biodegradable agrochemicals [23-25] and treating Alzheimer’s diseases

[26,27]. Additionally, annulated pyranopyrazole systems have a broad

spectrum of biological activities, including pyrazolopyranopyrimidine

Metal oxide nanoparticles as nanocatalysts have emerged as prom-

ising heterogeneous catalysts for various organic transformations

because of affording high surface area to volume ratio in the reaction,

* Corresponding author.

E-mail address: Dr.wesamshehab@gmail.com (W.S. Shehab).

https://doi.org/10.1016/j.bioorg.2021.105136

Received 11 June 2021; Accepted 27 June 2021

Available online 1 July 2021

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 1. Examples of Pyrano[2,3-c]pyrazoles with reported human Chk1 kinase inhibitors (A), antimicrobial (B) and Molluscicidal (C) activities, and pyrazolopyr-

anopyrimidine derivative (D) with reported anti-inﬂammatory activity.

building block in compound D as an anti-inﬂammatory agent [28]

(Fig. 1).

malononitrile (0.37 g, 0.31 mL, 0.005 mol) in ethanol (10 mL), in the

presence of a catalytic amount of supported metal nanoparticle ZnO

(0.08 g, 0.0009 mol) was reﬂuxed for 2 h. After reaction completion, the

solid product was collected by ﬁltration, washed with ethanol, and

crystallized from ethanol to afford compound 1 as pale-yellow crystals:

85%, mp: 178–180 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}). 3456, 3312 (NH₂), 2210 (CN),

3H, CH₃), 5.42(s,H,CH methine), 6.92 (d, H, H-⁶5thiophene), 6.94 (d, H,

H-3thiophene),6.91–7.07 (m, 5H, ArH’s), 7.34 (2H, s, NH₂); ¹³C(125

MHz, DMSO‑d₆):160.20 (C6), 146.82, 144.74, 143.87, 183.40, 132.45,

130.60,130.19, 129.36, 127.10, 120.97, 120.73, 115.62 (CN), 58.82

(C5), 39.90 (C4), 9.73,21.56, 14.51. Anal. calcd. For C₁₈H₁₄N₄OS

(334.09): C, 64.65; H, 4.22; N, 16.75; S, 9.59%. Found: C, 64.69; H, 4.20;

N, 16.74; S, 9.57%.

Inﬂammation is a part of the complex biological response of vascular

tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.

It can be acute or chronic; acute inﬂammation is rapid in onset and of

short period, lasting from a few minutes to as long as few days, and is

characterized by ﬂuid and plasma protein exudation, whereas chronic

inﬂammation is of longer duration, typiﬁed by the inﬂux of lymphocytes

and macrophages with associated vascular proliferation and ﬁbrosis

[29].

_1

1

–

1656 (C N), 1586 (Ar) cm ; HNMR (DMSO‑d , 400 MHz(.:δ = 2.25 (s,

–

Motivated by the aforementioned subjects and continuing our efforts

in the ﬁeld of nanocatalysts and synthesis of bioactive heterocycles [30-

35], we wish to report nano-ZnO as an efﬁcient catalyst for green and

facile one-pot three-component reaction of 5-methyl-2-phenyl-2,4-dihy-

dro-3H-pyrazol-3-one, thiophene-2-carbaldehyde, and malononitrile to

produce 6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyr-

ano[2,3-c]pyrazole-5-carbonitrile furthermore our research prolonged

to the synthesis of pyrazolopyranopyrimidine analogs with theortical

investigation using DFT calculations and assessed them in vitro as anti-

inﬂammatory agents compared to the most widely used NSAIDs cele-

coxib and quercetin besides evaluating their in vitro antioxidant activity

compared to standard ascorbic acid.

2.2.2. Synthesis of 3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4

dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5-amine (2)

A mixture of compound 1 (0.5 g, 0.001 mol) and formamide (20 mL)

was reﬂuxed for 3 h. After reaction completion, the reaction mixture was

cooled and poured over ice cold water. The formed solid was ﬁltered off,

dried and recrystallized from ethanol to yield compound 2 as a gray

solid: 86.6%, mp: 250–252 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}). 3456, 3312 (NH₂),

_1

1

–

1656 (C N), 1586 (Ar) cm ; HNMR (DMSO‑d , 400 MHz(.:δ = 1.93 (s,

–

6

3H, CH₃), 5.42(s, H,CH pyrane), 6.92 (d, H, H-5thiophene), 6.94 (d, H,

H-3thiophene),6.91–7.07 (m, 5H, ArH’s), 7.44 (s, 2H, NH₂) ppm. Anal.

calcd. For C₁₉H₁₅N₅OS (361.10): C, 63.14; H, 4.18; N, 19.38; S, 8.87%.

Found: C, 63.14; H, 4.19; N, 19.39, S, 8.86%.

2. Experimental section

2.1. Materials and methods

All chemicals were purchased from Sigma-Aldrich (Taufkirchen,

Germany), and all solvents were purchased from El-Nasr Pharmaceutical

Chemicals Company (analytical reagent grade, Egypt). Thiophene-2-

carbaldehyde was purchased from the Central Laboratory of Health

Ministry. All chemicals were used as supplied without further puriﬁca-

tion. The melting points were measured by a digital Electrothermal IA

9100 Series apparatus Cole-Parmer, Beacon Road, Stone, Staffordshire,

ST15 OSA, UK) and were uncorrected. C, H, and N analyses were carried

out on a PerkinElmer CHN 2400. IR spectra were recorded on FT-IR 460

PLUS (KBr disks) in the range from 4000 to 400 cm^{ꢀ 1}. ¹H and ¹³C NMR

spectra were recorded on a Bruker 400 MHz NMR Spectrometer using

tetramethylsilane (TMS) as the internal standard, chemical shifts are

expressed in δ (ppm), and DMSO‑d₆was used as the solvent. The mass

spectrum was carried out on the direct probe controller inlet part to a

single quadrupole mass analyzer in the thermo scientiﬁc GCMS model

(ISQLT) using thermo X-Calibur software. At the Regional Centre for

Mycology & Biotechnology (RCMB) Al-Azhar University, Naser City,

Cairo.

2.2.3. Synthesis of 3-methyl-1-phenyl-4-(thiophen-2-yl)-4,6-

dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (3)

A mixture of compound 1 (0.5 g, 0.001 mol) and formic acid (20 mL)

was heated under reﬂux conditions for 8 h. After reaction completion,

the reaction mixture was cooled and poured over ice cold water. The

formed solid was ﬁltered off, dried and recrystallized from ethanol to

give compound 3 as a greenish solid: 73%, mp: 260–262 ^◦C. IR (KBr, ʋ,

cm^{ꢀ 1}). 3350–3550(NH stretch), 3103 (aromatic CH), 1649 (C

O

–

amide), 1598 (C N), 1071 (C S stretch). ¹H NMR (DMSO‑d₆, 400

–

MHz) δ = 2.49 (s, 3H, CH₃), 6.92 (d, H, H-5thiophene), 6.94 (d, H, H-

3thiophene),6.91–7.37 (m, 5H, ArH’s), 12.16 (s, H, NH exchangeable by

13

–

D₂O) ppm. C (125 MHz, DMSO‑d ): 162.31 (C O), 152.68 (C N),

6

149.16, 139.01, 134.52,134.06, 133.78, 129.71, 129.51, 127.58,

125.49, 119.24, 13,98; MS, m = z (%): 362 (M+, 30). Anal. calcd. For

C19H14N4O2S (362.08): C, 62.97; H, 3.89; N, 15.46; O, 8.83; S, 8.85%.

Found: C, 63.14; H, 4.19; N, 19.39, S, 8.86%.

2.2.4. Synthesis of 7-(chloromethyl)-3-methyl-1-phenyl-4-(thiophen-2-yl)-

4,6-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (4)

A mixture of 1 (0.5 g, 0.001 mol) and chloroacetyl chloride (0.112 g,

0.08 mL, 0.001 mol) in DMF (5 mL) was reﬂuxed for 10 h. After reaction

completion, the reaction mixture was cooled and poured over ice cold

water, and the precipitate formed was ﬁltered and crystallized from

2.2. Synthesis

2.2.1. Synthesis of 6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-

dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1)

A mixture of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1 g,

0.005 mol), thiophene-2-carbaldehyde (0.64 g, 0.53 mL, 0.005 mol) and

ethanol to produce compound

4 as brown crystals: 25%, mp:

2

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

318–320 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}). 3350–3550(NH stretch), 3103 (aromatic

(485.12): C, 61.85; H, 3.94; N, 14.42; S, 6.60%. Found: C, 61.83; H, 3.93;

N, 14.41; S, 6.59%.

CH), 1649 (C O amide), 1598 (C N), 1071 (C S stretch). ¹H NMR

–

(DMSO‑d₆, 400 MHz) δ = 2.25 (s, 3H, CH₃),4.22(s,2H,CH₂), 5.23(s,1H,

CH.pyrane) 6.92 (d, H, H-5thiophene), 6.94 (d, H, H-3thiophene),

6.91–7.37 (m, 5H, ArH’s), 12.16 (s, H, NH exchangeable by D₂O) ppm.

¹³C (125 MHz, DMSO‑d₆):162.20, 146.82, 144.74, 143.87, 183.40,

132.45, 130.60, 130.19, 129.36, 127.10, 120.97, 120.73, 98.64, 58.82,

39.90, 22.56, 19.24. Anal. calcd. For C₂₀H₁₅ClN₄O₂S (410.06): C, 58.47;

H, 3.68; N, 13.64; S,7.80%. Found: C, 58.44; H, 3.67; N, 13.64; S, 7.79%.

2.2.8. Synthesis of 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,8-

dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-b]pyridin-7(1H)-one (8)

A mixture of compound 1 (0.5 g, 0.001 mol), ethyl cyanoacetate

(0.113 g, 0.10 mL, 0.001 mol), ammonium acetate (0.07 g, 0.001 mol),

and glacial AcOH (5 mL) was heated under reﬂux for 2 h then cooled and

poured over crushed ice. The formed solid was collected by ﬁltration and

recrystallized from ethanol to produce compound 8 as brown crystals:

53%, mp 240–242 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}). 3446, 3320 (NH, NH₂) and

2.2.5. Synthesis of 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-

dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine-7-thiol (5)

1

–

1650 (C O). H NMR (DMSO‑d , 400 MHz) δ = 1.95(s, 3H,CH ), 4.95

–

3

A mixture of compound 1 (0.5 g, 0.001 mol) and thiourea (0.08 g,

0.001 mol) was fused under dry conditions in oil bath for 0.5 h, the fused

mixture was dissolved in ethanol (10 mL) and the resulting solution was

reﬂuxed for 3 h in the presence of few drops of piperidine. After reaction

completion, the reaction mixture was cooled and the precipitate formed

was collected by ﬁltration and the ﬁltrate further worked up by diluting

with cold water to give additional amount of the product which was

washed with ethanol, dried, and recrystallized from ethanol to provide

(s, 1H, CH), 6.92 (d, H, H⁶-5thiophene), 6.94 (d, H, H-3thio-

phene),6.91–8.56 (m, 5H, ArH’s), 8.89 (s, 2H, NH₂),11.30(s,1H,NH)

ppm. ¹³C (125 MHz, DMSO‑d₆):163.30, 160.86, 152.74, 150.40, 145.87,

140.39, 133.45, 130.70, 129.36, 129.00, 126.38, 125.10, 124.54,

121.42, 120.97, 120.73, 115.79, 98.64, 58.82, 45.78. Anal. calcd. For

C

₂₀H₁₆N₄O₂S (376.10): C, 63.81; H, 4.28; N, 14.88; S, 8.52%. Found: C,

63.82; H, 4.28; N, 14.80; S, 8.51%.

compound 4 as red crystals: 45%, mp: over 360 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}

)

2.2.9. Synthesis of 5-chloro-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-

dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine (9)

–

0.3389 (NH ), 3103 (aromatic CH), 1598 (C N), 1071 (C S stretch).

–

¹H NMR (D²MSO‑d₆, 400 MHz) δ = 2.25 (s, 3H, CH₃), 5.60 (s,1H,CH

purine), 6.92 (d, H, H-5thiophene), 6.94 (d, H, H-3thiophene),6.91–7.56

(m, 5H, ArH’s), 7.93 (s,1H,D₂OEXch.NH₂), 12.16 (s, H, D₂OExch.SH)

ppm. ¹³C (125 MHz, DMSO‑d₆):175.30, 173.82, 153.74, 152.45, 150.87,

143.40, 133.45, 130.70, 129.36, 127.10, 120.97, 120.73, 98.64, 58.82,

39.90, 22.56, 13.32. Anal. calcd. For C₁₉H₁₅N₅OS₂(393.07): C, 58.00;

H, 3.84; N, 17.80; S, 16.30%. Found: C, 58.04; H, 3.84; N, 17.81;

S,16.30%.

To a cold solution of compound 1 (0.5 g, 0.001 mol) in conc. HCl (2

mL), a solution of sodium nitrite (0.06 g, 0.001 mol) in 5 mL water was

added with stirring in ice bath (at 5 ^◦C). After the completion of sodium

nitrite solution addition, the product was separated, collected by

ﬁltration, and recrystallized from etanol to provide compound 9 as

reddish brown crystals: 35%, mp 298–300 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}). 3103

(aromatic CH), 1598 (C N), 1071 (C S stretch). ¹H NMR (DMSO‑d₆,

–

400 MHz) δ = 2.49 (s, 3H, CH₃), 6.92 (d, H, H-5thiophene), 6.94 (d, H,

H-3thiophene),6.91–7.37 (m, 5H, ArH’s) ppm. MS, m = z (%):380.8

(M+, 30). Anal. calcd. For C₁₉H₁₃ClN₄OS (380.85): C, 59.92; H, 3.44; N,

14.71; S, 8.42%. Found: C, 59.91; H, 3.44; N, 14.70, S, 8.41%.

2.2.6. Synthesis of ethyl 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,7-

dihydro-1H-pyrrolo[3^′,2^′:5,6]pyrano[2,3-c]pyrazole-6-carboxylate (6)

A mixture of compound 1 (0.5 g, 0.001 mol), ethyl chloroacetate

(0.25 g, 0.21 mL, 0.002 mol) and anhydrous K₂CO₃(0.13 g, 0.001 mol)

in dry acetone (10 mL) was stirred under reﬂux for 10 h. The reaction

mixture was left overnight then poured over crushed ice. The formed

precipitate was ﬁltered off, washed with water, dried, and crystallized

2.2.10. Synthesis of 7-amino-3-methyl-5-oxo-1-phenyl-4-(thiophen-2-yl)-

1,4,5,8-tetrahydropyrazolo[4^′,3^′:5,6]pyrano[2,3-b]pyridine-6-carbonitrile

(10)

A mixture of compound 1 (0.5 g, 0.001 mol), malononitrile (0.06 g,

0.001 mol) and few drops of piperidine in DMF was reﬂuxed for 12 h, the

mixture was allowed to cool down to room temperature, poured over

crushed ice acidiﬁed with HCl, the formed precipitate was collected by

ﬁltration, dried, and recrystallized from ethanol to yield compound 10

from ethanol to furnish compound 6 as dark red crystals: 70%, mp:

ꢀ 1

230–232 ^◦C. IR (KBr, ʋ, cm ). 3397 (NH), 3389 (NH ), 1705 (C

O

–

2

ester). ¹H NMR (DMSO‑d₆, 400 MHz) δ = 1.2(t, 3H, CH₃), 2.5(s, 3H,

CH₃), 4.2(q, 2H, CH₂), 5.60 (s,1H,CH purine), 6.92 (d, H, H-5thio-

phene), 6.94 (d, H, H-3thiophene),6.91–7.56 (m, 5H, ArH’s), 7.93 (s,1H,

NH₂), 11.90 (s, 1H, NH), ppm. ¹³C (125 MHz, DMSO‑d₆):165.20,

156.90, 153.74, 152.45, 150.87, 143.40, 133.45, 130.70, 129.36,

127.10, 120.97, 120.73, 98.64, 58.82, 45.78 39.90, 22.56, 13.32. Anal.

calcd. For C₂₂H₂₀N₄O₃S (420.13): C, 62.84; H, 4.79; N, 13.32; S, 7.62%.

Found: C, 62.83; H, 4.80; N, 13.30;S,7.60%.

as gray crystals: 20%, mp 284–286 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}). 3446, 3320

1

–

(NH, NH ), 3103 (aromatic CH), and 1650 (C O). and 1598 (C N). H

–

2

NMR (DMSO‑d₆, 400 MHz) δ = 2.20(s, 3H,CH₃), 4.95(s, 1H, CH), 6.92

(d, H, H-5thiophene), 6.94 (d, H, H-3thiophene), 6.91–8.56 (m, 5H,

ArH’s), 8.89 (s, 2H, NH₂),12.18 (s,1H,NH) ppm. Anal. calcd. For

C

₂₁H₁₅N₅O₂S (401.44): C, 62.83; H, 3.77; N, 17.45; S, 7.99%. Found: C,

62.82; H, 3.79; N, 17.46; S, 7.98%.

2.2.7. Synthesis of 3-methyl-7-(4-nitrophenyl)-1-phenyl-4-(thiophen-2-yl)-

4,6,7,8-tetrahydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one

(7)

2.2.11. Synthesis of 3-methyl-6-((((2R,3S,4S,5R,6R)-2,3,4,5,6-

pentahydroxytetrahydro-2H-pyran-2-yl)methyl)amino)-1-phenyl-4-

(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (11)

A mixture of compound 1 (0.5 g, 0.001 mol) and glucose (0.26 g,

0.001 mol) in tert-butanol (15 mL) was reﬂuxed for 5 h. After cooling,

the formed solid was ﬁltered off, dried, and crystallized from ethanol to

A mixture of compound 1 (0.5 g, 0.001 mol) triturated with ethanol,

p-nitrobenzaldehyde (0.15 g, 0.001 mol), and few drops of piperidine

was fused in oil bath for 1.5 h and the reaction mixture was left to cool

then the resulting solid was dissolved in ethanol. The resulting solution

was diluted with crushed ice acidiﬁed with HCl then the formed pre-

cipitate was collected by ﬁltration, dried, and recrystallized from

ethanol to give compound 7 as dark brown crystals: 93%, mp:

256–258 ^◦C. IR (KBr, ʋ, cm^{ꢀ 1}). 3350–3550(NH stretch), 3103 (aromatic

furnish compound 11 as red crystals: 50%, mp: 160–162 ^◦C. IR (KBr,

ν,

cm^ꢀ1): 3414 cm^{ꢀ 1}(NH), 3350–3560 cm^{ꢀ 1}(broad band for OH), 2916

cm^{ꢀ 1}(CH aliphatic), 2210 cm^{ꢀ 1}(CN) and 1593 cm^{ꢀ 1}(C O for amide).

–

¹H NMR (DMSO‑d₆, 400 MHz): δ = 1.91 (s,1H,CH₃), 3.07–4.30 (m, 4H,

4CH), 3.55 (s, 2H, CH₂), 3.67 (s, 1H, NH), 4.45–6.21 (m, 5H, 5OH), 5.23

(s, 1H, HC-pyrane methine), 7.37–7.45 (m, 5H, ArH), 12.29, 12.62 (s,

2H, NH exchangeable by D₂O). ¹³C NMR (DMSO‑d₆, 100 MHz): δ =

38.54, 38.75, 38.95, 40.16, 40.37, 40.58, 67.5, 69.3, 71.9, 75.8, 79.85,

1

–

CH), and 1649 (C O amidic). H NMR (DMSO‑d , 400 MHz) δ = 1.92(s,

–

6

3H,CH₃), 5.45(s, 1H, CH), 6.92 (d, H, H-5thiophene), 6.94 (d, H, H-

3thiophene),6.91–8.56 (m, 10H, ArH’s), 9.87 (s, 1H, NH) ppm. ¹³C (125

MHz, DMSO‑d₆):167.33, 162.86, 153.74, 152.45, 145.87, 143.40,

133.45, 130.70, 129.36,125.40,126.84, 127.10, 122.54,121.42, 120.97,

120.73,115.79, 98.64, 58.82, 45.78. Anal. calcd. For C₂₅H₁₉N₅O₄S

–

86.7, 114.5, 164.5 (C O), 169.23 ppm.Anal. Calcd. for C₂₄H₂₄N₄O₇S

–

(512.14): C, 56.24; H, 4.72; N, 10.93; S, 6.26; Found: C, 56.23; H, 4.71;

3

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

N, 10.92; S, 6.28%.

2.2.12. Synthesis of 3-methyl-6-(((2S,3S,4S,5R,E)-2,3,4,5,6-

pentahydroxyhexylidene)amino)-1-phenyl-4-(thiophen-2-yl)-1,4-

dihydropyrano[2,3-c]pyrazole-5-carbonitrile (12)

A mixture of 1 (0.5 g, 0.001 mol) and glucose (0.25 g, 0.001 mol) in

acetic acid/water (15/5 mL) was reﬂuxed for 8 h. After cooling, the

resulting solution was poured over cold water, the formed solid was

ﬁltered off, dried, and crystallized from ethanol to yield compound 12 as

Scheme 1. Synthesis of 6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-

dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1).

dark red crystals: 54%, mp: 148–150 ^◦C. IR (KBr,

ν

, cm^{ꢀ 1}): 3350–3500

cm^{ꢀ 1}(very broad band for OH and absence of NH₂), 3166–2923 cm^{ꢀ 1}

(CH, aromatic and aliphatic) and 2215 cm^{ꢀ 1}(CN). ¹H NMR (DMSO‑d₆,

Table 1

Optimization of the Reaction Conditions.

400 MHz):): δ = 2.21 (S,1H,CH₃), 3.38–3.82 (m, 4H, 4CH), 3.90 (s, 2H,

–

Entry

Solvent

Catalyst (base)

Temperature

Time

(h)

Yield

(%)

CH ), 4.22–5.42 (m, 5H, 5OH), 8.20 (s, 1H, CH N), 5.16 (s, 1H, HC-

–

pyr²ane methine), 7.20–7.82 (m, 5H, ArH), 11.07, 12.28 ppm (s, 2H,

2NH exchangeable by D₂O.). ¹³C NMR (DMSO‑d₆, 100 MHz): δ = 34.54,

36.75, 39.95, 40.16, 40.37, 40.58, 64.5, 65.7, 70.55, 71.42, 73.8, 115.2,

(^◦C)

1

2

3

4

5

EtOH

AcONa

reﬂux

6

5

6

2

30

45

41

54

85

Et₃N

Piperidine

AcONH₄

ZnO

–

125.7, 164.3 (C N), 162.4 (C O), and 170.3 (C O) ppm.Anal. Calcd.

–

for C₂₄H₂₄N₄O₆S (496.14): C, 58.05; H, 4.87; N, 11.28; O, 19.33; S, 6.46;

Found: C, 58.05; H, 4.88; N, 11.28; S, 6.45%.

Nanoparticles

2.3. Computational details

determine the optimum reaction conditions (Scheme 1).

To optimize the type of catalysts, AcONa, Et₃N, or piperidine,

AcONH₄and ZnO Nanoparticles were used in this experiment. The best

results were obtained when ZnO Nanoparticles were used in the reac-

tion. The results indicated low efﬁciency for AcONa. To optimize the

time, the model reaction was carried out in ethanol at reﬂuxing condi-

tions. The results illustrate that 85% yield was obtained at 2 h (Table 1).

The structure of compound 1 was elucidated with IR, ¹H NMR, and

¹³C NMR spectra, and elemental analysis data have been discussed for a

representative compound 1. The IR spectrum of 1 showed a sharp peak

at 3456, 3312 cm^{ꢀ 1}, which corresponds to the stretching frequency of

the NH₂group, and peaks at 2210 cm^{ꢀ 1}correspond to the nitrile,

respectively. The ¹H NMR spectra of 1 showed two singlets at δ 7.34 ppm

The geometric parameters and energies were computed by density

functional theory at the B3LYP/CEP-31G level of theory, using the

GAUSSIAN 98W package of the programs [36], on geometries that were

optimized at CEP-31G basis set. The high basis set was chosen to detect

the energies at a highly accurate level. The atomic charges were

computed using the natural atomic orbital populations. The B3LYP is the

key word for the hybrid functional [37], which is a linear combination of

the gradient functionals proposed by Becke [38] and Lee, Yang and Parr

[39], together with the Hartree-Fock local exchange function [40].

2.4. Pharmacology

–

for the

NH₂protons (D₂O exchangeable), clearly indicating the

In-vitro COX-1/ COX-2 inhibitory assay: This assay was investigated

using Cayman colorimetric COX (ovine) inhibitor screening assay kit

following the manufacturer’s instructions compared to standard (Cele-

incorporation of both moieties in the product. In contrast, the ¹³C NMR

–

spectrum showed a signal at (δ in ppm) 115.62 ppm due to the C

N

–

group. A possible mechanism for the reaction is carried out according to

coxib) and expressed as μM. In-vitro 5-LOX inhibitory assay: This assay

the Knoevenagels-Micheal reaction shown in (Scheme 2).

was made using a 5-Lipoxygenase Inhibitory screening Assay Kit ac-

cording to manufacturer’s instructions. It detects the hydroperoxides

produced in the lipoxygenation reaction using a puriﬁed LOX and is used

to screen for LOX enzyme inhibitors compared to standard (Quercetin)

6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano

[2,3-c]pyrazole-5-carbonitrile 1 was found to be an adequate key

starting for the creation of some other new heterocyclic compounds,

where it was heated in formamide for 3 h., to produce compound 2. The

spectral and analytical data of compound 2 conﬁrmed its structure. The

pyrimidinone derivative 3 was obtained on the one hand by reﬂuxing

compound 1 in excess formic acid. The IR spectrum substantiated the

and expressed as μM. In-vitro TAC assay: This assay was investigated

using Total Antioxidant Capacity (TAC) ELISA kit following the manu-

facturer’s instructions compared to standard (ascorbic acid) and

expressed as U/ml.

–

absorption bands pyrimidinone NH and C O respectively at their

–

perspective values. ¹H NMR, MS, and elemental analysis gave the

conﬁrmatory data for compound 3 (cf. Scheme 3 and Experimental

section). On the other hand, reﬂuxing of compound 1 with chloroacetyl

chloride in DMF resulted in the disappearance of the NH₂signals in the

IR and ¹H NMR spectra, respectively, due to the formation of 7-(chlor-

omethyl)-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,6-dihydropyrazolo

[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one 4. While, Reactions of

compound 1 with thiourea in boiling glacial acetic acid in the presence

of a catalytic amount of HCl yielded 5-amino-3-methyl-1-phenyl-4-

(thiophen-2-yl)-1,4-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimi-

dine-7-thiol 5. The reaction of compound 1 with ethyl chloroacetate in

the presence of a catalytic amount of anhydrous K₂CO₃in dry acetone

was stirred under reﬂux for 10 h provides Ethyl 5-amino-3-methyl-1-

phenyl-4-(thiophen-2-yl)-4,7-dihydro-1H-pyrrolo[3^′,2^′:5,6]pyrano[2,3-

c]pyrazole-6-carboxylate 6, respectively (Scheme 3).

2.5. Statistical analysis

The results were expressed as the mean ± S.D. and statistical com-

parisons were carried out using one-way analysis of variance (ANOVA)

followed by Duncan’s test. The minimal level of signiﬁcance was iden-

tiﬁed at P < 0.05.

3. Result and discussion

3.1. Chemistry

One-pot multicomponent cyclocondensation conventions developed

for the synthesis of 6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-

dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1). This protocol is car-

ried out by the reaction of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-

3-one, thiophene-2-carbaldehyde malononitrile in the presence of a

catalytic amount of supported metal nanoparticle ZnO as a catalyst using

reﬂuxing conditions in ethanol. Different catalysts were used to

The cyclo condensation of compound 1 with p-nitrobenzaldehyde in

the presence of a catalytic amount of piperidine yielded pyrazolopyr-

anopyrimidone 7. IR of 7 showed C N disappearance, whereas its ¹H

–

4

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Scheme 2. The plausible mechanism for the synthesis of 1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1).

Scheme 3. Synthesis of highly functionalized Pyrano[2,3-c]Pyrazoles.

NMR showed two NH signals at δ = 9.87 ppm. While, Reactions of

compound 1 with ethyl cyanoacetate with ammonium acetate afforded

5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,8-dihydropyrazolo

[4^′,3^′:5,6]pyrano[2,3-b]pyridin-7(1H)-one 8. Continuing a series of

synthesis, the pyranopyrazole derivative 1 was transformed into 5-

chloro-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo

[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine 9 by the addition of sodium nitrite

solution to a suspended solution in concentrated hydrochloric acid at

0–5 ^◦C with stirring at room temperature. While, the reaction of 1 with

malononitrile in basic medium yielded the corresponding 7-amino-3-

methyl-5-oxo-1-phenyl-4-(thiophen-2-yl)-1,4,5,8-tetrahydropyrazolo

[4^′,3^′:5,6]pyrano[2,3-b]pyridine-6-carbonitrile 10. The structure of

compounds 9 and 10 were approved by IR, ¹H NMR, and elemental

analysis (cf. Scheme 4 and Experimental section).

solvent used in the reaction, when the reaction performed in tert-butanol

followed Maillard reaction pathway giving 3-methyl-6-

((((2R,3S,4S,5R,6R)-2,3,4,5,6-pentahydroxytetrahydro-2H-pyran-yl)

methyl)amino)-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]

pyrazole-5-carbonitrile 11.whilst, when the reaction carried out in

acetic acid the main product is the Schiff base 3-methyl-6-

(((2S,3S,4S,5R,E)-2,3,4,5,6-pentahydroxyhexylidene)amino)-1-phenyl-

4-(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 12,

The ¹H NMR spectra differentiate between the two compounds, the

Schiff base compound 12 showed an oleﬁnic proton absorption at δ =

7.43 ppm; whereby compound 11 showed two signals δ = 3.35 and 7.74

ppm due to CH₂and NH groups (Scheme 5).

The reaction of glucose with compound 1 amused depending on the

5

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Scheme 4. Synthesis of fused Pyrano[2,3-c]Pyrazoles derivatives.

Scheme 5. Reactions of 6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) with glucose.

3.2. Structural parameters and models

rings attached together, two aromatic rings as fused system 1,4-dihy-

dropyrano[2,3-c]pyrazole and two separated rings, thiophen ring

attached with fused aromatic system through the C1 of 1,4-dihydro-

pyran ring and phenyl ring through the N9 of pyrazole ring. The mole-

cule is non planer, there is two plans, one plane occupied by the two

3.2.1. 6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano

[2,3-c]pyrazole-5-carbonitrile (1)

The molecule is slightly sterically-hindered, there are four aromatic

6

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 2. Optimized geometrical structure of compound (1), 6-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile by using

DFT calculations.

and ꢀ 58.41˚, respectively, while dihedral angles S18C17C1C6 and

Table 2

S18C17C1C2 are 122.45˚and ꢀ 116.08˚, respectively. These values of

Equilibrium geometric parameters bond lengths (Å), bond angles (˚),dihedral

dihedral angles conﬁrmed that the thiophen ring is lying out of the plane

angles (˚), total energy (k cal/mol), heat of formation (k cal/mol) and dipole

occupied by 1,4-dihydropyrano[2,3-c]pyrazole. The dihedral angles

moment of the compound (1) by using DFT calculations.

C16C11N9N8 and C16C11N9C5 are 59.31˚and ꢀ 111.66˚, respectively,

Bond length (Å)

while dihedral angles C12C11N9C5 and C12C11N9C8 are 6768˚and

–

C1 C2

1.535

1.366

1.369

1.361

1.369

1.531

1.419

1.353

1.362

1.343

1.345

1.343

1.342

C14 C15

1.342

1.343

1.523

1.473

1.456

1.338

1.336

1.340

1.417

1.163

1.364

1.497

ꢀ 121.39˚, respectively. These values of dihedral angles conﬁrmed that

the phenyl group is lying out of the plane occupied by 1,4-dihydropyr-

ano[2,3-c]pyrazole and the two rings, thiophen and phenyl are lying in

–

C15 C16

C2 C3

–

C3 O4

C11 C16

–

O4 C5

C1 C17

–

the same plane as seen in Fig. 2. The C N group attached directly

–

C5 C6

C17 S18

–

C1 C6

S18 C19

through C2, the bond angle C2C22N23 is 179.19˚≈ 180˚, also all bond

angles in this compound are varied from 109.64˚to 129.51˚, these values

reﬂect that the type of sp2 hybridization spreading over most atoms of

–

C19 C20

C6 C7

–

C20 C21

C7 N8

–

N8 N9

C17 C21

–

– –

C N group, the

–

the molecule except the carbon atom of cyano group

–

C5 N9

C2 C22

–

angles C2C22N23, this value reﬂects that the type of hybridization on

central carbon atom C22 of cyano group is sp [41], all bond angles and

dihedral angles are listed in Table 2. The non planarity of the molecule

play important rule in its activity and also in the biological activity,

phenyl ring can be rotated around the nitrogen atom, N9 of pyrazole ring

of the fused aromatic system out of the plane, also the thiophen ring can

be rotated around the carbon atom, C1 of 1,4-dihydropyran ring out of

the plane occupied by molecule. The value of energy of this compound is

ꢀ 196.669 k cal/mol and the heat of formation of this compound is

ꢀ 8696.662 k cal/mol. The presence of strong withdrawing groups as

N9 C11

C22 N23

–

C11 C12

C3 N24

–

C12 C13

C7 C10

–

C13 C14

Bond angle (˚)

C1C17C21

C1C17S18

C2C1C17

C17C1C6

C2C22N23

C1C2C22

C3C2C22

C2C3N24

O4C3N24

124.63

28.02

O4C5N9

128.18

122.42

127.35

119.97

119.88

128.23

123.69

129.51

C5N9C11

C11N9N8

N9C11C12

N9C11C16

C6C7C10

N8C7C10

C1C6C7

109.64

109.79

179.19

119.31

119.13

119.24

117.18

–

–C N group besides to other strong donating groups as –NH₂and –CH₃

–

groups cause generation of week dipole moment 3.775D. The all bonds

in the phenyl group from C11 till C16 with bond lengths varied between

Dihedral angles (˚)

–

1.342 and 1.343 Å [42] are the shortest C C bonds in whole molecule.

–

The C7 N8 and C5 N9 bond lengths are 1.353 and 1.343 Å [43] are

C21C17C1C2

C21C17C1C6

S18C17C1C6

S18C17C1C2

N9C5O4C3

63.06

N24C3O4C5

C10C7C6C5

C12C11N9C5

C12C11N9N8

C16C11N9N8

C16C11N9C5

ꢀ 196.669

178.68

179.89

67.68

–

ꢀ 58.41

122.45

signiﬁcantly shorter than N8 N9 bond length 1.362 Å [42], there is a

single bond characters N9 and C5 atoms [44], the bond lengths of

ꢀ 116.08

ꢀ 178.90

ꢀ 179.89

ꢀ 121.34

59.31

–

C2 C3 and C5 C6 are 1.366 and 1.369 Å, whereas these bonds have

–

double bond characters [45], while the bond lengths of C1 C2, C1 C6

C1C6C7N8

ꢀ 111.66

–

are 1.535 and 1.531 Å, also the bond lengths of C3 O4 and C5 O4 are

1.369 and 1.361 Å these values reﬂected that presence of a single bond

characters. The bond lengths between atoms are listed in the Table 2,

these values are compared nicely with crystal structure of the molecule

Total energy/ k cal/mol

Heat of formation k cal/mol

Total dipole moment/D

ꢀ 8696.662

3.775

–

has the similar structure [43]. The S18 C19 bond length is 1.456 Å

aromatic rings of the fused aromatic system, 1,4-dihydropyrano[2,3-c]

pyrazole and other plane occupied by the two separated aromatic rings,

thiophen and phenyl. The two planes are perpendicular respect to

others, the dihedral angles C21C17C1C2 and C21C17C1C6 are 63.06˚

–

[46], this bond is shorter than C17 S18 bond length is 1.473 Å [46],

these values reﬂects that there is a single bond characters between the

S18 atom and others bonded carbon atoms with it. Detailed analysis of

7

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 3. Optimized geometrical structure of compound (2), 3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5-amine by

using DFT calculations.

corresponding bond lengths in various hetero cyclic compounds were

given elsewhere [43,47]. All distances and angles between the atoms of

the ligand are given in Table 2.

bond lengths are 1.349 and 1.376 Å, respectively [49], whereas these

–

bonds have double bond characters [45] also the N23 C22 and

–

C25 N23 bond lengths are 1.340 and 1.355 Å [49], there is a single

–

bond characters N and C atoms [44]. The length of the N C bonds

3.2.2. 3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo

(1.340–1.355 Å) in the dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrim-

idine aromatic system indicate the conjugation between the lone pair of

the nitrogen atoms and p-system of the pyrimidin group [50].

[4^′,3^′:5,6]pyrano [2,3-d]pyrimidin-5-amine (2)

Fig. 3 showed the optimized geometrical structures of the com-

pounds (2). The molecule is non planer, there is two plans, one of them is

occupied by dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin aro-

matic system and the other plane is occupied by thiophen and phenyl

rings. All bond lengths of this compound is similar to the bond lengths of

compound (1). The dihedral angles of this compound as C16C11N9N8

and C16C11N9C5 are 57.75˚and ꢀ 99.01˚, respectively, also the dihedral

angles C12C11N9N8 and C12C11N9C5 are ꢀ 124.63˚ and 78.59˚,

respectively, these values conﬁrmed that phenyl group is lying out of the

plane occupied the fused aromatic rings. The dihedral angles

S18C17C1C2 and S18C17C1C6 are ꢀ 123.76˚and 116.06˚, respectively,

these values conﬁrmed that the thiophen ring is lying out of the plane

occupied by fused aromatic rings. The value of bond angles around the

carbon atoms in this compound are varied between (116.47˚ and

128.40˚). Also the angles around the nitrogen atoms in the compound are

varied between (117.53˚and 132.74˚), these values reﬂect that the type of

sp²hybridization spreading over most atoms of the this compound. The

energy of the compound (2) has lower value ꢀ 213.859 k cal/mol less

than that of the energy of compound (1), the heat of formation of

compound (2) is ꢀ 8900.158 k cal/mol. The dipole moment of com-

pound (2) is 2.095D, this value is lower than the dipole moment of

3.2.3. 3-methyl-1-phenyl-4-(thiophen-2-yl)-4,6-dihydropyrazolo

[4^′,3^′:5,6] pyrano[2,3-d]pyrimidin-5(1H)-one (3)

Fig. 4 showed the optimized geometrical structures of the compound

(3), this compound is similar to compound (2) in all parameters and

structure with replacement of –NH2 group attached with pyrimidin ring

–

with C O group in the same atom. The energy of the compound (3) has

–

lower value ꢀ 219.457 k cal/mol less than that of the energy of com-

pound (1) and higher than the energy of compound (2), the heat of

formation of compound (3) is ꢀ 8760.918 k cal/mol, the presence of

–

C

–

O group attached to pyrimidin ring instead of NH2 group causing

rising of the value of dipole moment, 5.593D more than compound (2).

3.2.4. 7-(chloromethyl)-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,6-

dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (4)

The optimized geometrical structures of the compounds (4) is shown

in Fig. 5, this compound has the same structure features of the com-

pound (3) with adding of ClCH₂- group to the pyrimidine ring in the

carbon atom C25, lying between the two nitrogen atoms N23 and N24 of

pyrimidine ring. The presence of ClCH₂- group causes lowering of the

total energy value by 22.056 k cal/mol. The energy of this compound,

ꢀ 241.974 k cal/mol is less than the energy of compound (3), also the

heat of formation of compound (4) is ꢀ 9309.978 k cal/mol. The

–

– –

C N group in com-

–

compound (1), it attributed to the absence of

–

pound (2). The C2 C3 bond with bond length of 1.381 [48] Å is the

–

longest C C bond in whole molecule [49]. The C3 N24 and C2 C22

8

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 4. Optimized geometrical structure of compound (3), 3-methyl-1-phenyl-4-(thiophen-2-yl)-4,6-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one by

using DFT calculations.

Fig. 5. Optimized geometrical structure of compound (4), 7-(chloromethyl)-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,6-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyr-

imidin-5(1H)-one by using DFT calculations.

9

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 6. Optimized geometrical structure of compound (5), 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine-7-

thiol by using DFT calculations.

–

presence of C O and Cl groups attached to pyrimidin ring causing rising

formation of compound (6) is ꢀ 921851.487 k cal/mol, the presence of

–

– – –

R COO group attached to pyrol ring with NH₂group causing

of the value of dipole moment, 5.879D more than compound (3).

slightly increasing of the value of dipole moment, 2.935D more than

3.2.5. 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo

[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine-7-thiol (5)

compound (5).

The optimized geometrical structures of the compounds (5) is shown

in Fig. 6, this compound has the same structure features of the com-

pound (3) with presence of -SH group to the pyrimidine ring in the

carbon atom C25, instead of ClCH₂-on the pyrimidine ring. The presence

of -SH group causes lowering of the total energy value by 5.174 k cal/

mol, but not less than compound (4). The energy of this compound,

ꢀ 224.631 k cal/mol is less than the energy of compound (3), also the

heat of formation of compound (5) is ꢀ 8997.226 k cal/mol. The pres-

3.2.7. 3-methyl-7-(4-nitrophenyl)-1-phenyl-4-(thiophen-2-yl)-4,6,7,8-

tetrahydro pyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one (7)

Fig. 8 showed the optimized geometrical structures of the compound

(7), this compound is similar to compounds (3) and (4) in all parameters

and structure with presence ofnitrophenyl group attached with pyrim-

idine ring in C25. The energy of the compound (7) has lower value

ꢀ 309.987 k cal/mol less than that of the energy of compounds (3) and

(4), the heat of formation of compound (7) is ꢀ 11721.494 k cal/mol, the

presence of nitrophenyl group attached to pyrimidin ring causing

increasing of the value of dipole moment, 6.976D more than compounds

(3) and (4).

–

ence of C O and -SH groups attached to pyrimidin ring causing

–

lowering of the value of dipole moment, 2.798D more than compound

(3).

3.2.6. Ethyl-5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,7-dihydro-1H

pyrrolo[3^′,2^′:5,6]pyrano[2,3-c]pyrazole-6-carboxylate (6)

3.2.8. 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,8-dihydropyrazolo

[4^′,3^′:5,6]pyrano[2,3-b]pyridin-7(1H)-one (8)

Fig. 7 showed the optimized geometrical structures of the compound

(6), this compound is similar to compound (5) in all parameters and

structure with replacement of pyrimidine ring attached with –NH₂with

pyrol group. The energy of the compound (6) has lower value ꢀ 268.019

k cal/mol less than that of the energy of compound (5), the heat of

The optimized geometrical structures of the compounds (8) is shown

in Fig. 9, this compound has the same structure features of the com-

–

pounds (2) and (5) with presence of C O group to the pyridine ring in

–

the carbon atom C25. The presence of C O group causes lowering of the

–

total energy value less than compounds (2) and (5). The energy of this

10

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 7. Optimized geometrical structure of compound (6), Ethyl 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,7-dihydro-1H-pyrrolo[3^′,2^′:5,6]pyrano[2,3-c]pyr-

azole-6-carboxylate by using DFT calculations.

compound, ꢀ 230.985 k cal/mol, also the heat of formation of compound

around the carbon atoms in this compound are varied between (111.78˚

and 129.51˚). Also the angles around the nitrogen atoms in two com-

pounds are varied between (117.53˚and 132.74˚), these values reﬂect

that the type of sp2 hybridization spreading over most atoms of the this

compound. The energy of the compound (11) has lower value ꢀ 343.876

k cal/mol less than that of the energy of compound (1), the heat of

formation of compound (11) is ꢀ 12081.936 k cal/mol. The dipole

moment of compound (11) is 5.894D, this value is higher than the dipole

–

(8) is ꢀ 9071.547 k cal/mol. The presence of C O groups attached to

–

pyridine ring causing rising of the value of dipole moment, 5.697D more

than compounds (2) and (5).

3.2.9. 5-chloro-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo

[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine (9)

Fig. 10 showed the optimized geometrical structures of the com-

pound (9), this compound is similar to compound (2) in all parameters

and structure with replacement of –NH₂group attached with pyrimidin

ring with -Cl group in the same atom. The energy of the compound (9)

has lower value ꢀ 216.878 k cal/mol less than that of the energy of

compound (2), the heat of formation of compound (3) is ꢀ 8637.846 k

–

– –

C N group

–

moment of compound (1), it attributed to the absence of

with presence of 2,3,4,5,6-pentahydroxytetrahydro-2H-pyran-2-yl ring

attached with –NH group through –CH₂in compound (11). The bond

–

lengths of the N C bonds varied between (1.346 – 1.354 Å) in the

dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin aromatic system

indicate the conjugation between the lone pair of the nitrogen atoms and

p-system of the pyrimidin group [50].

–

cal/mol, the presence of Cl group attached to pyrimidin ring instead of

NH₂group causing slightly rising of the value of dipole moment, 2.998D

more slightly higher than compound (2).

3.2.12. 3-methyl-6-(((2S,3S,4S,5R,E)-2,3,4,5,6-pentahydroxyhexylidene)

amino)-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]pyrazole-5-

carbonitrile (12)

3.2.10. 7-amino-3-methyl-5-oxo-1-phenyl-4-(thiophen-2-yl)-1,4,5,8-

tetrahydro pyrazolo[4^′,3^′:5,6]pyrano[2,3-b]pyridine-6-carbonitrile (10)

The optimized geometrical structures of the compounds (10) is

shown in Fig. 11, this compound has the same structure features of the

Fig. 13 showed the optimized geometrical structures of the com-

pound (12), this compound is similar largely to compound (11) in all

parameters and structure with replacement of 2,3,4,5,6-pentahydroxy-

tetrahydro-2H-pyran-2-yl ring with group attached with 2,3,4,5,6-pen-

tahydroxyhexylidene group in the same atom. The energy of the

compound (12) has lower value ꢀ 351.793 k cal/mol less than that of the

energy of compound (11) by 7.917 k cal/mol, the heat of formation of

compound (12) is ꢀ 12430.749 k cal/mol, the presence of 2,3,4,5,6-pen-

tahydroxytetrahydro-2H-pyran-2-yl group as open chain attached to

pyran ring instead of 2,3,4,5,6-pentahydroxytetrahydro-2H-pyran-2-yl

group causing rising of the value of dipole moment with greater value

9.498D more higher than compound (11).

–

compound (8) with presence of C N group to the pyridine ring in the

–

carbon atom C23. The presence of C N group causes lowering of the

–

total energy value less than compound (8) by 12.711 k cal/mol. The

energy of this compound, ꢀ 243.696 k cal/mol, also the heat of forma-

–

tion of compound (10) is ꢀ 9627.488 k cal/mol. The presence of C

N

–

group attached to pyridine ring causing rising of the value of dipole

moment, 12.592D more than compound (8).

3.2.11. 3-methyl-6-((((2R,3S,4S,5R,6R)-2,3,4,5,6-

pentahydroxytetrahydro-2H-pyran-2-yl)methyl)amino)-1-phenyl-4-

(thiophen-2-yl)-1,4-dihydropyrano [2,3-c]pyrazole-5-carbonitrile (11)

Fig. 12 showed the optimized geometrical structures of the com-

pounds (11). The molecule is non planer. The value of bond angles

11

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 8. Optimized geometrical structure of compound (7), 3-methyl-7-(4-nitrophenyl)-1-phenyl-4-(thiophen-2-yl)-4,6,7,8-tetrahydropyrazolo[4^′,3^′:5,6]pyrano[2,3-

d]pyrimidin-5(1H)-one by using DFT calculations.

Fig. 9. Optimized geometrical structure of compound (8), 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,8-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-b]pyridin-7(1H)-

one by using DFT calculations.

12

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 10. Optimized geometrical structure of compound (9), 5-chloro-3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine

by using DFT calculations.

Fig. 11. Optimized geometrical structure of compound (10), 7-amino-3-methyl-5-oxo-1-phenyl-4-(thiophen-2-yl)-1,4,5,8-tetrahydropyrazolo[4^′,3^′:5,6]pyrano[2,3-

b]pyridine-6-carbonitrile by using DFT calculations.

3.3. Charge distribution analysis

population analysis (NPA). The charge distribution on the hetero atoms,

nitrogen, oxygen and sulfur of the different studied compounds indicates

the presence of a net negative pole attributed to the presence of polar

atoms beside the non planarity of these molecules, as a result the

The charge distribution analysis on the optimized geometry conﬁg-

uration of the all studied compounds was made on the basis of natural

13

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 12. Optimized geometrical structure of compound (11), 3-methyl-6-((((2R,3S,4S,5R,6R)-2,3,4,5,6-pentahydroxytetrahydro-2H-pyran-2-yl)methyl)amino)-1-

phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano [2,3-c] pyrazole-5-carbonitrile by using DFT calculations.

Fig. 13. Optimized geometrical structure of compound (12), 3-methyl-6-(((2S,3S,4S,5R,E)-2,3,4,5,6-pentahydroxyhexylidene)amino)-1-phenyl-4-(thiophen-2-yl)-

1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile by using DFT calculations.

14

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

–

– –

molecules are a slightly high dipole for the

C

N compounds, while

oxygen atom O26 of [2,3-d]pyrimidin-5(1H)-one ring, ꢀ 0.274,

–

the –NH₂compounds have slightly weak dipole. There is building up of

charge density on the donating nitrogen, oxygen and sulfur atoms

involved in the 1,4-dihydropyrano[2,3-c]pyrazole and thiophen ring in

the compound (1), the highest charged atoms are N23 (ꢀ 0.311) of

ꢀ 0.355 and ꢀ 0.479, also the two oxygen atoms O34 and O35 of

nitrophenyl group, ꢀ 0.315 and ꢀ 0.314. The positive charge densities

spreading over most carbon atoms, as C3, C5, C22 and C25, 0.403,

0.248, 0.445 and 0.348, respectively and nitrogen atom N33 of nitro-

phenyl group, 0.235. These values of charge densities play important

rule in the generation of large dipole, specially the presence of nitro-

phenyl group in this compound.

–

– –

C

N group, N24 (ꢀ 0.364) of terminal amino group and N8 (ꢀ 0.259)

–

of 1,4-dihydropyrano[2,3-c]pyrazole ring, the charge accumulated on

N9 of 1,4-dihydropyrano[2,3-c]pyrazole ring is ꢀ 0.002, there is a small

charge accumulated on sulfur atom S18 of thiophen ring is 0.034 and the

most carbon atoms have possessed negative charge density except C1,

C3, C5 and C7 of the 1,4-dihydropyrano[2,3-c]pyrazole. The variation

on the charge accumulation on all atoms in compound (1) causes

Compound (8) has possessed slightly higher dipole moment, 5.697D.

–

The presence of strong withdrawing group as C O group in this com-

–

pound as [2,3-b]pyridin-7(1H)-one causes formation of a negative pole,

the charge density on the oxygen atom O27 is ꢀ 0.449, more negative

charge, also there is more negative charge (ꢀ 0.379) on the nitrogen

atom N26 of amino group. The more positive charge densities are

localized over most carbon atoms, as C3, C5, C22 and C25, 0.384, 0.249,

0.415 and 0.538.

–

– –

C N group.

–

generating of a negative pole on the

Also, in case of compound (2), there is a deﬁnite atoms have

possessed accumulation of charge on it more than other atoms. The

charge accumulated on oxygen atom O4 and nitrogen atom N8 are

(ꢀ 0.289 and ꢀ 0.263), while nitrogen atom N9 of 1,4-dihydropyrano

[2,3-c]pyrazole ring has lower negative charge (ꢀ 0.009). The charge

accumulated on the two nitrogen atoms of pyrimidin ring N23 and N24

are (ꢀ 0.339 and ꢀ 0.326) and nitrogen atom N26 of amino group –NH2

attached with pyrimidin ring is ꢀ 0.385, the more positive charges are

located on C3, C5, C22 and C37 (0.398, 0.289, 0.369 and 0.289,

respectively).

In compound (9), there is a weak dipole can be obtained from the

–

presence of Cl group attached with [2,3-d]pyrimidine, there is no

signiﬁcant building of charge densities on atoms, the negative charge

densities on oxygen atom O4, ꢀ 0.279 and nitrogen atom N8, ꢀ 0.258 of

1,4-dihydropyrazolo[4^′,3^′:5,6]pyran ring, also the two nitrogen atoms

N23 and N24 of the pyrimidine ring, ꢀ 0.268 and ꢀ 0.285, there is a

negative charge on the Cl26, ꢀ 0.298. The positive charge densities are

spreading over most carbon atoms specially, C22 and C25, 0.399 and

0.278. From these values of charge densities, there is no large difference

between positive and negative charges can be created to produce large

dipole value.

In compound (3), there is building up of charge density on the ox-

ygen atom O26, ꢀ 0.479 and carbon atom C22, 0.443 of pyrimidin-5

(1H)-one ring. Also, there is building up of charge density on the two

nitrogen atoms N23 and N24 of pyrimidin-5(1H)-one ring, ꢀ 0.234 and

ꢀ 0.303, while the charge density on the two nitrogen atoms N8 and N9

of 4,6-dihydropyrazolo are ꢀ 0.262 and ꢀ 0.005. the more positive

charges accumulated on carbon atoms are localized on C3, C22 and C37

as shown 0.399, 0.442 and 0.272, respectively. These values of charge

densities over atoms producing slightly large dipole 5.593.

Compound (10) has possessed greater dipole moment value

12.592D, from the studying of the charge densities over all atoms of this

compound it found that, the summation of negative charges over hetero

atoms, specially oxygen atom O26, nitrogen atoms, N24, N28 and N29 of

7-amin0-5-oxo-[2,3-b]pyridine-6-carbonitrile group are ꢀ 0.458, 0.218,

ꢀ 0.345 and ꢀ 0.359, respectively. There is small positive charge den-

sities over all atoms compared with negative charge densities, the more

positive charged atoms are C3, C5, C22 and C25, 0.333, 0.244, 0.374

and 0.351. these values reﬂects that there is a greater negative pole can

be produced on this compound with formation small positive pole. in

case of compound (11) and compound (12), they have the same struc-

ture but there is important difference, in compound (11), there is a cyclic

saturated hydrocarbon as 2,3,4,5,6-pentahydroxytetrahydro-2H-pyran

ring was used, while in compound (12), there is straight long chain of

hydrocarbon was used as 2,3,4,5,6-pentahydroxyhexylidene. This dif-

ference in the substitution effects largely on the distribution of charge

densities over all atoms of these compounds and also effects on the value

of dipole moment. In compound (11), the dipole moment value 5.894D

is lower than the value of dipole moment of compound (12), 9.498D. In

compound (11), all oxygen atoms have possessed negative charge den-

sities varied from ꢀ 0.284 on oxygen atom O4 of 1,4-dihydropyran ring

to ꢀ 0.389 on the O36 of 2,3,4,5,6- pentahydroxytetrahydro-2H-pyran-

2-yl ring, also nitrogen atoms have a negative charge densities varied

from ꢀ 0.021 on N9 of pyrazole ring to ꢀ 0.286 on N23 of cyano group.

The positive charge densities are localized on most carbon atoms

specially atoms of 2,3,4,5,6–2,3,4,5,6- pentahydroxytetrahydro-2H-

pyran-2-yl ring. In case of compound (12), there is a signiﬁcant build-

ing up of a negative charge densities spreading over all hetero atoms

specially oxygen atoms of 2,3,4,5,6-pentahydroxyhexylidene, these

values of charge densities varied from ꢀ 0.281 on O4 of 1,4-dihydro-

pyran ring to ꢀ 0.378 on the O27 of 2,3,4,5,6-pentahydroxyhexylidene

group. The positive charge densities are localized on most carbon

atoms specially atoms of 1,4-dihydropyrano[2,3-c]pyrazole-5-carbon-

itrile ring. There is large difference between the negative pole and

positive pole formed in compound (12), this difference causes gener-

ating large value of dipole moment.

In compound (4), These values of charges over all atoms produced a

slightly large dipole moment, 5.879D. The charge density on O4, N8 and

N9 of the 4,6-dihydropyrazolo[4^′,3^′:5,6]pyran ring are ꢀ 0.286, ꢀ 0.261

and ꢀ 0.004, respectively. Also the charge density on the hetero atoms of

the pyrimidin-5(1H)-one ring N23, N24 and O26 are ꢀ 0.245, ꢀ 0.317

and ꢀ 0.466, respectively, while the positive charges are localized over

carbon atoms, C3, C5, C22 and C37 as, 0.398, 248, 0.446 and 0.322,

respectively. Also there is a signiﬁcant negative charge accumulated on

the Cl28, ꢀ 0.247, so there is negative pole spreading over all hetero

atoms and positive pole over carbon atoms, these poles causing slightly

large dipole moment.

–

In the compound (5), the presence of SH group decreases the value

of dipole moment, 2.798D. the negative charge densities are localized on

the O4 and N8 of the 1,4-dihydropyrazolo[4^′,3^′:5,6]pyran, ꢀ 0.286 and

ꢀ 0.261, nitrogen atoms N23 and N24 of sulfur atom S27 of [2,3-d]

pyrimidine-7-thiol ring, (ꢀ 0.355, ꢀ 0.359 and ꢀ 0.428) respectively

and nitrogen atom, N26 of amino group attached with [2,3-d]

pyrimidine-7-thiol ring, ꢀ 0.382. The positive charge densities are

spreading over most carbon atoms, as C3, C5, C22 and C25, 0.411,

0.252, 0.383 and 0.482, respectively. There is no large difference be-

tween the two charged poles, so there is a weak dipole.

In case of compound (6), there is a small difference between the

negative chare density and positive charge density, this small value

causing lowering of dipole value. The negative charge densities are

localized on N8 of the pyrazole ring, ꢀ 0.265, N24 of the 4,7-dihydro-1H-

pyrrole ring, ꢀ 0.363 and the two oxygen atoms of the carboxylate group

– –

COO , O27 and O28, ꢀ 0.329 and ꢀ 0.461, while the positive charge

densities are spreading over most carbon atoms specially C26 of

carboxylate group, 0.498.

The dipole moment value in the compound (7) is slightly high,

6.976D. There slightly large difference between negative and positive

charge on atoms of this compound, the most negative charges are

localized over hetero atoms, as O4, N8 of 4,8-dihydropyrazolo[4^′,3^′:5,6]

pyran ring, ꢀ 0.298 and ꢀ 0.265, two nitrogen atoms N23, N24 and

15

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Fig. 14. Molecular orbital surfaces and energy levels of all studied compounds (1–12) by using DFT calculations.

Table 3

Calculated charges on donating sites and energy values (HOMO, LUMO, Energy gap ΔE/eV, hardness (

η

), global softness (S), electro negativity (

χ), absolute softness

(σ), chemical potential (Pi), global electrophilicity (ω) and additional electronic charge (ΔN_max) of the studied compounds by using DFT calculations.

Parameters

1

2

3

4

5

6

7

8

9

10

11

12

HOMO, H

LUMO, L

I = ꢀ H

ꢀ 0.332

ꢀ 0.192

0.332

0.192

0.140

0.07

ꢀ 0.348

ꢀ 0.191

0.348

0.191

0.157

0.079

0.269

12.66

6.329

ꢀ 0.269

0.458

3.405

ꢀ 0.354

ꢀ 0.193

0.354

0.193

0.161

0.081

0.274

12.35

6.173

ꢀ 0.274

0.463

3.383

ꢀ 0.354

ꢀ 0.196

0.354

0.196

0.162

0.081

0.275

12.34

6.173

ꢀ 0.275

0.467

3.395

ꢀ 0.324

ꢀ 0.192

0.324

0.192

0.132

0.066

0.258

15.15

7.576

ꢀ 0.258

0.411

3.909

ꢀ 0.329

ꢀ 0.192

0.329

0.192

0.137

0.069

0.261

14.49

7.246

ꢀ 0.261

0.494

4.378

ꢀ 0.323

ꢀ 0.193

0.323

0.193

0.130

0.066

0.258

15.15

7.576

ꢀ 0.258

0.504

3.909

ꢀ 0.343

ꢀ 0.192

0.343

0.192

0.151

0.076

0.268

13.16

6.579

ꢀ 0.268

0.473

3.526

ꢀ 0.357

ꢀ 0.193

0.357

0.193

0.164

0.082

0.275

12.19

6.098

ꢀ 0.275

0.461

3.354

ꢀ 0.342

ꢀ 0.192

0.342

0.192

0.150

0.075

0.267

13.33

6.667

ꢀ 0.267

0.475

3.560

ꢀ 0.344

ꢀ 0.194

0.344

0.194

0.150

0.075

0.269

13.33

6.667

ꢀ 0.269

0.482

3.587

ꢀ 0.347

ꢀ 0.227

0.347

0.227

0.120

0.060

0.287

16.67

8.333

ꢀ 0.287

0.686

4.783

A = ꢀ L

ΔE = L ꢀ H

η

χ

σ

= (I ꢀ A)/2

= ꢀ (H ꢀ L/2)

0.262

14.29

7.143

ꢀ 0.262

0.490

3.743

= 1/

η

S = 1/2

η

Pi = ꢀ

χ

ω

= (Pi)²/2

η

ΔN_max

= χ/

(I) is ionization energy.

(A) is an electron afﬁnity.

3.4. Molecular orbitals and frontier

studied chloro compounds are hard molecules and η varied from 0.060

for compound (12) to 0.082 for compound (9), also the electronic

transition within the compounds is easy as indicated from the ΔE. There

are some quantum chemical parameters depending upon the energy

values of HOMO and LUMO were calculated as global softness (S),

Molecular orbitals play also an important role in the electric prop-

erties, as well as in UV–Vis [51]. An electronic system with smaller

values of HOMO-LUMO gap should be more reactive than one having a

greater energy gap [44]. The energy gap is closely associated with the

reactivity and stability of the executed compounds and shows the nature

of the compound with low kinetic stability and slightly high chemical

reactivity. On the other hand, the adjacent orbitals are often closely

spaced on the frontier region. The energy gap, ΔE of the studied com-

pounds varied between 0.120 for Compound (12) which more reactive

and 0.164 eV for compound (9) which less reactive, so electron move-

ment between these orbitals could be easily occur by decreasing the

value of energy gap, so that there is a peak around 250 nm in the UV–Vis

spectra for all studied compounds.

electro negativity (

χ

), absolute softness (

σ), chemical potential (Pi),

global electrophilicity (

ω

) and additional electronic charge (ΔN_max) of

the all studied compounds. From these values, the compound (9) is

absolute soft according to the (

σ

= 12.19 eV), while the compound (12)

= 16.67 eV).

is treated as hard compounds (

σ

As seen in Fig. 14, the all compounds have the same nucleus and

different substations, so these compounds are divided into four parts, the

–

1st part is Pyrano[2,3-c]pyrazole (C1 N9), 2nd part is Thiophen ring

–

(C17 C21), the 3rd part is Phenyl ring (C11 C16), the remaining 4th

part is remaining atoms Residual atoms. The electron density of HOMO,

Ψ87 of the compound (1) is localized mainly on the all atoms of the

Pyrano[2,3-c]pyrazole ring with percent 87.6%, with small portion over

residual atoms, 12.4%. The LUMO, Ψ88, the electron density localized

over all carbon atoms of Phenyl ring in compound (1), with percent

(65.1%) and 33.2% on Pyrano[2,3-c]pyrazole, as given in Table 7. Also

the HOMO, Ψ94 of the compound (2), the electron density localized over

all atoms of Pyrano[2,3-c]pyrazole with percent 75.7% and 22.4% on

the residual atoms of the compound with small portion on the Phenyl

ring, 1.9%. The LUMO, Ψ95 of the compound (2), the electron density

localized over the phenyl ring with 83.7% and 16.3% on the Pyrano[2,3-

c]pyrazole.

The nodal properties of molecular orbitals of studied complexes in

Fig. 14 are illustrative and suggest orbital delocalization, strong orbital

overlap, and low number of nodal planes. The energy difference be-

tween HOMO and LUMO (energy gap, ΔE) for the all studied compounds

varied according to the type of substitutions as shown in Table 3. All

studied chloro compounds (4) and (9) have relatively higher energy gap

more than other compounds, so these nitro compounds less reactive.

Fig. 14 shows the isodensity surface plots of HOMO and LUMO for the

studied compounds. Hard molecules have high the HOMO-LUMO gap,

and soft molecules have smaller HOMO-LUMO gap [52]. The values of

η

and ΔE(HOMO-LUMO) are given in Table 3. It is obvious that the all

16

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Table 4

Table 4 (continued)

Computed excitation energies (eV), electronic transition conﬁgurations and

wave lengths (nm) of the obtained stable compounds; compounds (1–4) by using

B3LYP/Cep-31G for the, (f ≥ 0.001) f = oscillator strengths.

Comp.

eV

nm

Major Contributions

Assignment

3.4165

362.9

H-6 → L (24%), H-6 → L + 3 (29%),

H-6 → L + 4 (18%), H-6 → L + 6

(12%), H-6 → L + 9 (13%)

π-π*

Comp.

eV

nm

Major Contributions

Assignment

1

4.4206

280.48

H-8 → L + 5(7%), H-1 → L(10%), H

→ L(13%), H-2 → L(11%), H-1 → L

+ 3(16%), H → L + 1(24%), H → L +

3(13%), H-2 → L + 3(14%)

π

-

π

*

The HOMO of the compound (3), Ψ94, the electron density localized

–

mainly over atoms of Pyrano[2,3-c]pyrazole (C1 N9) with percent

4.2308

4.1772

3.6710

4.4201

4.3073

4.1549

293.05

296.81

337.74

280.5

H-8 → L (11%), H-8 → L + 3 (9%), H-

7 → L (12%), H-7 → L + 3 (8%), H-7

→ L + 6 (10%), H-6 → L(13%), H-6

→ L + 3(14%)

78.0.8% and 18.3% on the carbon atoms of residual atoms, also, there is

–

small portion on the phenyl ring (C11 C16) benzene ring (2.9%). The

LUMO, Ψ95, the electron density delocalized over all atoms, the most

percent (46.1%) is localized on the carbon atoms of phenyl ring

H-8 → L + 5 (12%), H-7 → L + 5

(8%), H-2 → L + 1 (11%), H-2 → L +

3(13%), H → L(24%), H → L + 1

(23%), H → L + 5(14%)

–

(C11 C16). In compound (4), the HOMO, Ψ106, the electron density

localized over atoms of the Pyrano[2,3-c]pyrazole with percent 77.9%,

while the other parts have 19.1% with 0% on thiophen ring. The LUMO,

Ψ107, the electron density delocalized over the all atoms with high

H-12 → L + 5 (11%), H-10 → L + 5

(9%), H-2 → L + 5 (13%), H → L

(21%), H → L + 2(18%), H → L + 5

(28%)

n-

π

*

–

percent 57.8% on the carbon atoms of phenyl group (C11 C16), 21.7%

–

on the Pyrano[2,3-c]pyrazole (C1 N9) and 20.5% on the remaining

2

3

4

H-9 → L (11%), H-9 → L + 4 (12%),

H-9 → L + 5 (9%), H-2 → L (17%), H

→ L (29%), H → L + 2 (14%), H → L

+ 4 (13%), H → L + 5 (14%)

H-10 → L + 2 (10%), H-7 → L (19%),

H-7 → L + 1 (27%), H-7 → L + 2

(11%), H-7 → L + 10 (9%), H-6 → L

+ 1 (11%), H-6 → L + 2 (16%)

H-10 → L (7%), H-10 → L + 4 (10%),

H-10 → L + 5 (8%), H-9 → L (12%),

H-9 → L + 1 (11%), H-9 → L + 4

(6%), H-9 → L + 5 (7%), H-9 → L + 6

(11%), H-8 → L + 4 (13%), H-8 → L

+ 5 (11%), H → L (24%), H → L + 4

(18%), H → L + 5 (14%)

π-

π

atoms of thiophen ring and residual atoms. In compound (5), the elec-

tron density of HOMO, Ψ102 is localized mainly on the hetro atoms,

–

oxygen and nitrogen atoms of the Pyrano[2,3-c]pyrazole (C1 N9) with

287.85

298.4

66.5% and 23.7% on the residual atoms. The LUMO, Ψ103, the electron

density localized mainly over all carbon atoms of the phenyl ring

–

(C11 C16) with percent (73.8%) and 26.2% is delocalized on remain-

ing three parts of molecule.

In compound (6), the electron density of HOMO, Ψ110 is localized

mainly on the carbon and nitrogen atoms of the residual atoms espe-

cially on 4,7-dihydro-1H-pyrrol group with percent 79.4%, with small

–

percent 16.9% on the Pyrano[2,3-c]pyrazole (C1 N9). The LUMO,

Ψ111, the electron density localized over all carbon atoms of the phenyl

3.9942

4.4459

310.41

280.01

H-10 → L (6%), H-10 → L + 10 (8%),

H-7 → L (11%), H-7 → L + 1 (9%), H-

7 → L + 2 (10%), H-7 → L + 4 (6%),

H-6 → L (13%), H-6 → L + 1 (12%),

H-6 → L + 4 (14%)

n-

π

*

–

group (C11 C16) with the most percent (87.8%) and 12.2% is localized

–

on the Pyrano[2,3-c]pyrazole (C1 N9). Also the HOMO, Ψ125 of the

compound (7), the electron density delocalized over all atoms, the most

–

percent (69.8%) is localized on the Pyrano[2,3-c]pyrazole (C1 N9)

H-9 → L (6%), H-9 → L + 1 (11%), H-

9 → L + 3 (13%), H-9 → L + 4 (10%),

H-9 → L + 5 (9%), H-9 → L + 6

(12%), H-8 → L (11%), H-8 → L + 1

(23%), H-8 → L + 3 (21%), H-8 → L

+ 4 (21%), H-8 → L + 5 (9%), H-7 →

L + 1 (11%)

π

-

π

*

ring, with small portions on phenyl ring 22.9% and 7.3% on the residual

atoms. The LUMO, Ψ126, the electron density 86.2% localized mainly

with high percent over all atoms of residual atoms with small portion

–

(13.8%) is localized on the Pyrano[2,3-c]pyrazole (C1 N9) ring.

The HOMO of the compound (8), Ψ98, the electron density localized

–

mainly over all atoms of Pyrano[2,3-c]pyrazole (C1 N9) group with

4.3821

4.2592

282.94

291.1

H-10 → L (8%), H-3 → L (13%), H-2

→ L (11%), H-2 → L + 1 (9%), H-1 →

L (25%), H-1 → L + 1 (21%), H-1 →

L + 3 (18%), H → L (29%), H → L + 1

(18%), H → L + 3 (19%)

π

*

percent (78.5%), with 21.5% spreading over phenyl ring and residual

atoms. The LUMO, Ψ99, the electron density localized mainly over all

–

carbon atoms of phenyl ring (C11 C16) with 88.3% and 11.7% local-

ized on Pyrano[2,3-c]pyrazole (C1 N9) ring. In compound (9), the

H-12 → L (14%), H-9 → L (11%), H-9

→ L + 3 (12%), H-8 → L (6%), H-8 →

L + 3 (29%), H-7 → L (19%)

H-2 → L (24%), H-1 → L (28%), H →

L (34%)

n-

π

*

HOMO, Ψ98, the electron density delocalized over all atoms of the

compound, the most percent (53.7%) is localized on Pyrano[2,3-c]pyr-

–

azole (C1 N9) ring with small portions on the phenyl ring (27.9%) and

3.8874

3.4164

318.94

362.91

π-π

*

18.4% on the residual atoms. The LUMO, Ψ99, the electron density

H-6 → L (22%), H-6 → L + 3 (28%),

H-6 → L + 4 (35%), H-6 → L + 8

(19%)

n-

π

*

delocalized over the all atoms with percent (34.2%) on the phenyl ring,

–

31.5% on the Pyrano[2,3-c]pyrazole (C1 N9) and 26.4% on the resu-

–

dial atoms with small portion 7.9% on the thiophen ring (C17 C21).

4.4229

280.33

H-9 → L (10%), H-9 → L + 2 (11%),

H-9 → L + 4 (9%), H-8 → L + 1

(12%), H-8 → L (18%), H-8 → L + 3

(27%), H-8 → L + 4 (23%), H-8 → L

+ 5 (17%), H-8 → L + 7 (15%), H-7

→ L + 1 (13%)

π

-

π

*

In compound (10), the electron density of HOMO, Ψ104 is localized

mainly on the atoms of the Pyrano[2,3-c]pyrazole ring with percent

69.3%, 16.8% on the residual atoms with small portion 13.9% on the

–

carbon atoms of phenyl ring (C11 C16). The LUMO, Ψ105, the electron

density delocalized over all atoms, specially on the phenyl ring

4.3639

284.12

H-10 → L (8%), H-3 → L (13%), H-2

→ L (19%), H-2 → L + 1 (21%), H-1

→ L (19%), H-1 → L + 1 (25%), H →

L (20%), H → L + 1 (9%), H → L + 3

(10%)

π

*

–

(C11 C16) with 54.3% and Pyrano[2,3-c]pyrazole (C1 N9) with

35.9% with small portion 9.8% on the residual atoms. Also the HOMO,

Ψ134 of the compound (11), the electron density localized over all

atoms, the most percent (75.4%) is localized on the Pyrano[2,3-c]pyr-

4.1722

3.8073

297.17

325.46

H-14 → L (10%), H-9 → L (26%), H-6

→ L + 3 (15%), H-8 → L (18%), H-7

→ L (25%)

n-

π

*

–

azole (C1 N9) ring, with small portions on phenyl ring 23.4% and 1.2%

on the residual atoms. The LUMO, Ψ135, the electron density 100%

H-2 → L (19%), H-1 → L (25%), H →

L (38%)

π-π

*

–

localized mainly over all carbon atoms of phenyl ring (C11 C16). The

HOMO of the compound (12), Ψ138, the electron density localized

–

mainly over all atoms of Pyrano[2,3-c]pyrazole (C1 N9) group with

17

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Table 5

Table 5 (continued)

Computed excitation energies (eV), electronic transition conﬁgurations and

wave lengths (nm) of the obtained stable compounds; compounds (5–8) by using

B3LYP/Cep-31G for the, (f ≥ 0.001) f = oscillator strengths.

Compound

eV

nm

Major Contributions

Assignment

(12%), H-4 → L + 2 (11%), H-4

→ L + 4 (23%), H-4 → L + 9

(9%), H-3 → L + 4 (11%)

Compound

eV

nm

Major Contributions

Assignment

5

4.4509

278.56

H-8 → L(11%), H-8 → L + 4

(9%), H-8 → L + 5(19%), H-1 →

L + 1(13%), H-1 → L + 4(12%),

H → L(29%), H → L + 2(15%),

H → L + 4(10%), H → L + 5

(11%)

π

-

π

*

Table 6

Computed excitation energies (eV), electronic transition conﬁgurations and

wave lengths (nm) of the obtained stable compounds; compounds (9–12) by

using B3LYP/Cep-31G for the, (f ≥ 0.001) f = oscillator strengths.

4.3221

4.1895

286.54

295.87

H-8 → L (23%), H-8 → L + 1

(21%), H-8 → L + 2 (19%), H-8

→ L + 3 (11%), H-8 → L + 11

(9%), H-7 → L + 1(11%), H-7 →

L + 2(12%), H-7 → L + 3(14%),

H-7 → L + 11(8%)

Comp.

eV

nm

Major Contributions

Assignment

9

4.4217

280.40

H-4 → L + 4(16%), H-2 → L + 3

(12%), H-1 → L (9%), H-1 → L + 1

(12%), H-1 → L + 2(10%), H-1 → L

+ 3(13%), H → L(21%), H → L + 1

(12%), H → L + 2(23%)

π

-

π

*

H-11 → L (21%), H-11 → L + 4

(19%), H-11 → L + 5 (2%), H-11

→ L + 7(9%), H-10 → L(13%),

H-10 → L + 4(11%), H → L(7%)

H-10 → L + 5(18%)

4.3591

4.2331

284.43

292.88

H-7 → L (12%), H-5 → L + 1 (9%), H-

2 → L (11%), H-1 → L (22%), H-1 →

L + 1 (13%), H-1 → L + 2(8%), H-1

→ L + 5(9%), H → L (21%), H → L +

1 (7%), H → L + 2 (18%), H → L + 3

(9%)

π

-

π*

4.0152

4.3844

308.78

282.49

H-12 → L + 5 (11%), H-10 → L

+ 5 (9%), H-2 → L + 5 (13%), H

→ L (21%), H → L + 2(18%), H

→ L + 5 (28%)

n-

π

*

H-12 → L (17%), H-9 → L + 1 (14%),

H-8 → L (9%), H-8 → L + 1(27%), H-

8 → L + 2(12%), H-8 → L + 9(10%),

H-8 → L + 10(8%)

n-

π

*

6

7

H-10 → L (24%), H-10 → L + 3

(27%), H-10 → L + 4 (13%), H-

10 → L + 5 (12%), H-9 → L + 5

(11%)

n-

π

4.0949

6.1091

302.77

202.62

H-9 → L (18%), H-8 → L (29%), H-8

→ L + 1 (15%), H-8 → L + 2 (16%)

H-6 → L + 3 (12%), H-5 → L + 1

(11%), H-3 → L + 1 (13%), H-2 → L

(29%), H-2 → L + 5 (10%), H-1 → L

+ 1 (9%), H → L (11%), H → L + 2

(12%)

π

*

3.8476

3.6433

322.40

340.30

H-1 → L + 3 (19%), H → L

(21%), H → L + 1 (36%)

H-7 → L (13%), H-7 → L + 1

(29%), H-7 → L + 3 (18%), H-7

→ L + 5 (19%), H-7 → L + 6

(16%), H-7 → L + 8 (22%)

H-18 → L (9%), H-17 → L (11%),

H-16 → L (23%), H-16 → L + 1

(7%), H-16 → L + 3 (21%), H-16

→ L + 4 (12%), H-16 → L + 7

(14%), H-13 → L (12%), H-12 →

L (22%)

π

-

π

*

10

π

-

π*

π

6.061

204.57

n-

π

*

5.8779

5.8161

3.9899

4.4534

210.95

213.17

310.74

278.41

H-11 → L + 6 (13%), H-5 → L + 2

(11%), H-2 → L + 2 (9%), H → L

(29%), H → L + 1 (21%), H → L + 2

(9%)

π

-

π*

H-5 → L + 6 (12%), H-2 → L + 6

(11%), H-12 → L + 6 (13%), H-3 → L

+ 6 (12%), H → L + 6 (36%), H-18 →

L + 6 (11%)

n-

π

*

6.0333

4.8813

205.5

H-5 → L (39%), H-5 → L + 1

(24%), H-5 → L + 3 (19%)

H-3 → L (10%), H-2 → L (23%),

H-2 → L + 1 (11%), H → L

(31%), H → L + 1 (23%)

H-7 → L (11%), H-7 → L + 1

(13%), H-7 → L + 3 (12%), H-7

→ L + 4 (28%), H-7 → L + 7

(21%), H-7 → L + 10 (10%), H-7

→ L + 11 (12%), H-7 → L + 12

(13%)

π

-

π

*

254.00

π

H-7 → L (13%), H-7 → L + 1 (14%),

H-7 → L + 2 (28%), H-7 → L + 7

(16%), H-7 → L + 8 (12%), H-7 → L

+ 12 (10%)

π

*

4.7297

262.14

n-

π

*

11

H-20 → L + 5 (8%), H-15 → L + 5

(13%), H-18 → L (21%), H-18 → L +

1 (19%), H-18 → L + 3 (12%), H-18

→ L + 8 (9%), H-18 → L + 9 (12%),

H-4 → L + 3 (7%), H-1 → L (17%), H-

1 → L + 1 (13%), H-1 → L + 3 (10%),

H → L + 5 (8%)

π

-

π*

3.9084

3.1026

4.3276

317.22

399.61

286.5

H-14 → L (27%), H-14 → L + 1

(23%), H-14 → L + 3 (18%), H-

14 → L + 4 (12%), H-14 → L + 7

(10%)

n-

π

*

4.2222

3.9787

293.65

311.62

H-8 → L + 5 (19%), H-4 → L + 1

(14%), H-4 → L + 3 (13%), H-2 → L

(11%), H-2 → L + 1 (13%), H → L

(23%), H → L + 1 (21%)

π

-

π

*

H-11 → L (25%), H-11 → L + 1

(21%), H-11 → L + 3 (15%), H-

11 → L + 4 (11%), H-11 → L + 7

(13%)

n-

H-20 → L + 5 (11%), H-16 → L + 5

(13%), H-15 → L + 5 (12%), H-8 → L

(14%), H-4 → L + 5 (11%), H-2 → L

+ 5 (19%), H → L (17%)

π

8

H-12 → L + 8 (12%), H-3 → L

(10%), H-3 → L + 1 (29%), H-3

→ L + 2 (13%), H-2 → L + 1

(24%), H-1 → L (15%), H → L +

1 (13%)

π-π*

12

6.0443

5.6993

205.12

217.54

H-16 → L (12%), H-13 → L + 8

(10%), H-10 → L (29%), H → L

(13%), H → L + 7 (24%)

π

-

π

*

4.2169

294.04

H-8 → L (22%), H-8 → L + 1

(19%), H-8 → L + 2 (29%), H-8

→ L + 4 (12%), H-8 → L + 9

(10%), H-5 → L + 1 (13%), H-5

→ L (11%), H-5 → L + 1 (10%),

H-4 → L (9%)

n-

π

*

H-13 → L (16%), H-13 → L + 4

(18%), H-13 → L + 11 (19%), H-10

→ L + 4 (14%), H → L (17%), H → L

+ 7 (13%)

π

5.4015

229.54

H-13 → L (12%), H-10 → L (13%), H-

10 → L + 4 (17%), H-6 → L (22%), H-

2 → L (11%), H → L (37%)

π

-

π*

3.9634

3.5556

312.82

348.71

H → L (25%), H → L + 1 (23%),

H → L + 2 (38%)

π-π

*

H-8 → L + 4 (13%), H-8 → L + 9

(11%), H-5 → L + 2 (27%), H-5

→ L + 4 (10%), H-5 → L + 9

n-π*

18

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Table 7

Composition of the frontier molecular orbital for studied compounds (1–12) by using DFT/B3LYP/Cep-31G.

Comp. 1

Comp. 2

Comp. 3

Comp. 4

Comp. 5

Comp. 6

H%

L%

H%

L%

H%

L%

H%

L%

H%

L%

H%

L%

Pyrano[2,3-c]pyrazole

–

C1 N9

87.6

0.0

33.2

75.7

0.0

16.3

78.8

0.0

38.2

77.9

0.0

21.7

66.5

13.3

16.9

0.0

12.2

Thiophen ring

–

C17 C21

0.0

8.6

0.0

11.6

0.0

Phenyl ring

–

C11 C16

0.0

65.1

1.7

1.9

83.7

0.0

2.9

46.1

15.7

9.7

57.8

11.9

9.8

73.8

1.3

3.7

87.8

0.0

Residual atoms

12.4

22.4

18.3

12.4

23.7

79.4

Comp. 7

Comp. 8

Comp. 9

Comp. 10

Comp. 11

Comp. 12

H%

L%

H%

L%

H%

L%

H%

L%

H%

L%

H%

L%

Pyrano[2,3-c]pyrazole

–

C1 N9

69.8

0.0

13.8

0.0

78.5

0.0

11.7

0.0

53.7

0.0

31.5

7.9

69.3

0.0

35.9

0.0

75.4

0.0

79.3

0.0

83.4

0.0

Thiophen ring

–

C17 C21

Phenyl ring

–

C11 C16

22.9

7.3

0.0

14.7

6.8

88.3

0.0

27.9

18.4

34.2

26.4

13.9

16.8

54.3

9.8

23.4

1.2

100.0

0.0

20.7

0.0

2.9

Residual atoms

86.2

13.7

–

percent (79.3%), with 20.7% spreading over phenyl ring (C11 C16)

only. The LUMO, Ψ139, the electron density localized mainly over all

carbon atoms of Pyrano[2,3-c]pyrazole with 83.4% and 13.7% localized

on the residual atoms with small portion 2.9% on the phenyl ring

H-12 → L + 5 (11%), H-10 → L + 5 (9%), H-2 → L + 5 (13%), H → L

(21%), H → L + 2(18%), H → L + 5 (28%) and assigned to n-π*. Also, in

compound (2), 3-methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyr-

azolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5-amine, the ﬁrst excited state

–

(C11 C16).

assigned to an π → π* transition at 280.5 nm and 4.4201 eV, this tran-

sition represented by H-9 → L (11%), H-9 → L + 4 (12%), H-9 → L + 5

(9%), H-2 → L (17%), H → L (29%), H → L + 2 (14%), H → L + 4 (13%),

3.5. Excited state

H → L + 5 (14%). The second excited state is assigned to

π → π* tran-

sitions, represents a transitions H-10 → L + 2 (10%), H-7 → L (19%), H-

7 → L + 1 (27%), H-7 → L + 2 (11%), H-7 → L + 10 (9%), H-6 → L + 1

(11%), H-6 → L + 2 (16%) which observed around 287.85 nm and

The TD-DFT at the B3LYP level by using G03W program proved to

give accurate description of the UV–vis. spectra [53,54]. Time-

dependent density functional response theory (TD-DFT) has been

recently reformulated [55] to compute discrete transition energies and

oscillator strengths and has been applied to a number of different atoms

and molecule. Bauernschmitt and Ahlrichs [56] included hybrid func-

tionals proposed in the calculation of the excitation energies. These

hybrid methods typically constitute a considerable improvement over

conventional Hatree- Fock (HF) based methods. In this work, the opti-

mized geometry was calculated and was used in all subsequent calcu-

lations; the wave functions of SCF MOs were explicitly analyzed. The

calculated wave functions of the different MOs reﬂect and suggest the

fraction of the different fragments of the complex contributing to the

total wave functions of different states. The results indicate, that there is

an extent of electron delocalization in the different molecular orbitals.

4.3073 eV. The third excited state is assigned to

π → π* transition,

represents a transition appears at 298.4 nm and 4.1549 eV, H-10 → L

(7%), H-10 → L + 4 (10%), H-10 → L + 5 (8%), H-9 → L (12%), H-9 → L

+ 1 (11%), H-9 → L + 4 (6%), H-9 → L + 5 (7%), H-9 → L + 6 (11%), H-

8 → L + 4 (13%), H-8 → L + 5 (11%), H → L (24%), H → L + 4 (18%), H

→ L + 5 (14%). The fourth excited state at 310.41 nm and 3.9942 eV,

results as H-10 → L (6%), H-10 → L + 10 (8%), H-7 → L (11%), H-7 → L

+ 1 (9%), H-7 → L + 2 (10%), H-7 → L + 4 (6%), H-6 → L (13%), H-6 →

L + 1 (12%), H-6 → L + 4 (14%) and assigned to n-π*.

In compounds (3 and 4), there are ﬁve transitions can be observed as

given in Table 4. In compound (3), 3-methyl-1-phenyl-4-(thiophen-2-

yl)-4,6-dihydropyrazolo [4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one,

the ﬁrst excited state can be appeared at 280.01 nm and 4.4459 eV,

which results from H-9 → L (6%), H-9 → L + 1 (11%), H-9 → L + 3

(13%), H-9 → L + 4 (10%), H-9 → L + 5 (9%), H-9 → L + 6 (12%), H-8

→ L (11%), H-8 → L + 1 (23%), H-8 → L + 3 (21%), H-8 → L + 4 (21%),

The electronic transition could be described as a mixed n → π* and π

→ π* transitions. The energies of HOMO and LUMO states for the all

studied compounds are listed in Tables 4–6. The HOMO can perform as

an electron donor and the LUMO as the electron acceptor in reaction

proﬁle.

H-8 → L + 5 (9%), H-7 → L + 1 (11%), this assigned to π-π*. The second

excited state can be observed at 282.94 nm and 4.3821 eV, results as H-

10 → L (8%), H-3 → L (13%), H-2 → L (11%), H-2 → L + 1 (9%), H-1 → L

(25%), H-1 → L + 1 (21%), H-1 → L + 3 (18%), H → L (29%), H → L + 1

Table 4 indicates that there are four excited states are involved in

case of compounds (1 and 2). In case of compound (1), 6-amino-3-

methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]pyrazole-

5-carbonitrile, the ﬁrst exited state results from a combination eight

transitions, H-8 → L + 5(7%), H-1 → L(10%), H → L(13%), H-2 → L

(11%), H-1 → L + 3(16%), H → L + 1(24%), H → L + 3(13%), H-2 → L +

(18%), H → L + 3 (19%), this assigned to π-π*. The third excited state

results from H-12 → L (14%), H-9 → L (11%), H-9 → L + 3 (12%), H-8 →

L (6%), H-8 → L + 3 (29%), H-7 → L (19%), this assigned to n-π*

transition and can be observed at 291.1 nm. The fourth excited state can

be obtained at 318.94 nm and 3.8874 eV, this transition results from H-

2 → L (24%), H-1 → L (28%), H → L (34%). Finally, the ﬁfth transition

3(14%), this excited state assigned to

π-

π

* at 280.48 nm and 4.4206 eV.

The second excited state result from interaction between electronic

conﬁgurations, which represent

π → π* transition. This is transition re-

state observed at 362.91 nm and 3.4164 eV and assigned to n-π* tran-

sults from H-8 → L (11%), H-8 → L + 3 (9%), H-7 → L (12%), H-7 → L +

3 (8%), H-7 → L + 6 (10%), H-6 → L(13%), H-6 → L + 3(14%) and can

be observed around 293.05 nm and 4.2308 eV. The third excited state is

sition can be obtained from H-6 → L (22%), H-6 → L + 3 (28%), H-6 → L

+ 4 (35%), H-6 → L + 8 (19%). These values of electronic transitions

agree nicely with the experimental measurements. In compound (4), 7-

(chloromethyl)-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,6-dihydropyr-

azolo[4^′,3^′:5,6] pyrano[2,3-d]pyrimidin-5(1H)-one, the ﬁrst excited

state can be appeared at 280.33 nm and 4.4229 eV, which results from

assigned to

π → π* transition, represents a transition appears at 296.81

nm and 4.1772 eV, H-8 → L + 5 (12%), H-7 → L + 5 (8%), H-2 → L + 1

(11%),H-2 → L + 3(13%), H → L(24%), H → L + 1(23%), H → L + 5

(14%). The fourth excited state at 337.74 nm and 3.6710 eV, results as

19

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

Table 8

In vitro anti-inﬂammatory activity of the newly synthesized compounds compared to standard celecoxib and quercetin.

Groups

Cox-1 (µm IC₅₀

14.60 ± 0.00^f

)

Cox-2 (µm IC₅₀

0.04 ± 0.00^a

)

Selectivity index (COX-1/COX-2)

LOX (µm IC₅₀)

Celecoxib

365

———————————

3.35 ± 0.01^d

Quercetin

——————————

5.47 ± 0.12^a

——————————

0.25 ± 0.00^d

——————————

Compound 1

Compound 4

Compound 8

Compound 11

Compound 12

21.88

4.43 ± 0.15^f

10.67 ± 0.16^c

7.63 ± 0.06^b

0.06 ± 0.00^b

177.83

42.39

3.00 ± 0.06^c

0.18 ± 0.01^c

3.90 ± 0.10^e

14.23 ± 0.15 ^e

13.43 ± 0.15^d

0.04 ± 0.00^a

355.75

335.75

2.17 ± 0.12^a

0.04 ± 0.00^a

2.53 ± 0.06^b

H-9 → L (10%), H-9 → L + 2 (11%), H-9 → L + 4 (9%), H-8 → L + 1

(12%), H-8 → L (18%), H-8 → L + 3 (27%), H-8 → L + 4 (23%), H-8 → L

+ 5 (17%), H-8 → L + 7 (15%), H-7 → L + 1 (13%), this assigned to π-π*.

The second excited state can be observed at 284.12 nm and 4.3639 eV,

results as H-10 → L (8%), H-3 → L (13%), H-2 → L (19%), H-2 → L + 1

(21%), H-1 → L (19%), H-1 → L + 1 (25%), H → L (20%), H → L + 1

(9%), H → L + 3 (10%), this assigned to π-π*. The third excited state

results from H-14 → L (10%), H-9 → L (26%), H-6 → L + 3 (15%), H-8 →

L (18%), H-7 → L (25%), this assigned to n-π* transition and can be

observed at 297.17 nm. The fourth excited state can be obtained at

325.46 nm and 3.8073 eV, this transition results from H-2 → L (19%), H-

1 → L (25%), H → L (38%). The ﬁfth transition state observed at 362.9

Fig. 15. A statistical representation for the COX-1 and COX-2 enzymes inhib-

itory activity of newly synthesized compounds.

nm and 3.4165 eV and assigned to π-π*transition can be obtained from

H-6 → L (24%), H-6 → L + 3 (29%), H-6 → L + 4 (18%), H-6 → L + 6

(12%), H-6 → L + 9 (13%). These values of electronic transitions agree

nicely with the experimental data obtained from Uv–Vis measurements.

In Table 5, the number of excited states involved in compounds (5–8)

are given, in compound (5), 5-amino-3-methyl-1-phenyl-4-(thiophen-2-

yl)-1,4-dihydropyrazolo

there are four excited states, three of them are assigned to

and can be observed at 278.56, 286.54, 295.87 nm, respectively and one

[4^′,3^′:5,6]pyrano[2,3-d]pyrimidine-7-thiol,

π-π* transition

is assigned to n-π* transition, which can be observed at 308.78 nm. In

compound (6), Ethyl 5-amino-3-methyl-1-phenyl-4-(thiophen-2-yl)-4,7-

dihydro-1H-pyrrolo[3^′,2^′:5,6]pyrano[2,3-c]pyrazole-6-carboxylate,

there are three of excited states can be occurred, the ﬁrst one is assigned

to n-π* transition at 282.49 nm, while second and third assigned to π-π*

and can be observed at 322.40 nm and 340.30 nm. In case of compound

(7), 3-methyl-7-(4-nitrophenyl)-1-phenyl-4-(thiophen-2-yl)-4,6,7,8-tet-

rahydropyrazolo[4^′,3^′:5,6]pyrano[2,3-d]pyrimidin-5(1H)-one,

there

are six excited states can be observed, four of them are assigned to n-

π*

transition and can be observed at 204.57, 262.14, 317.22 and 399.61

nm, while there are two excited states are assigned to π-π* which can be

Fig. 16. A statistical representation for the LOX enzyme inhibitory activity of

observed at 205.5 and 254.00 nm. These values of electronic transitions

agree nicely with the experimental measurements. There are four

excited states can be obtained in case of compound (8), 5-amino-3-

methyl-1-phenyl-4-(thiophen-2-yl)-4,8-dihydropyrazolo[4^′,3^′:5,6]pyr-

newly synthesized compounds.

methyl)amino)-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrano[2,3-c]

pyrazole-5-carbonitrile, there are three electronic transition can be

occurred at 278.41, 293.65 and 311.62 nm. All of these transition are

ano[2,3-b]pyridin-7(1H)-one, two of them are assigned to

π

-

π

* transi-

tion, 286.5 and 312.82 nm and others assigned to n-

be observed at 294.04 and 348.71 nm.

π* transition and can

assigned to π-π* transitions, there is no any n-π* transition involved.

Also, the transitions of compound (12) 3-methyl-6-(((2S,3S,4S,5R,E)-

The electronic transition conﬁgurations and wave lengths for com-

pounds (9–12) are given in Table 6. For compound (9), 5-chloro-3-

methyl-1-phenyl-4-(thiophen-2-yl)-1,4-dihydropyrazolo[4^′,3^′:5,6]pyr-

ano[2,3-d]pyrimidine, there are four excited states, the ﬁrst and second

2,3,4,5,6-pentahydroxy hexylidene)amino)-1-phenyl-4-(thiophen-2-yl)-

1,4-dihydropyrano[2,3-c] pyrazole-5-carbonitrile, free from n-π* tran-

sitions. There are three excited states can be observed at 205.12, 217.54

and 229.54 nm, all of these transitions are assigned to π-π* transitions.

of them are assigned to

fourth are assigned to n-

observed at 280.40 and 284.43 nm, while the n-

π

-

π

* transition and the others of them, third and

* transition. the * transitions can be

* transitions can be

π

π-π

π

3.6. Pharmacology

observed at 292.88 and 302.77 nm. These values of electronic transi-

tions agree nicely with the experimental measurements. In compound

(10), 7-amino-3-methyl-5-oxo-1-phenyl-4-(thiophen-2-yl)-1,4,5,8-tet-

rahydropyrazolo[4^′,3^′:5,6]pyrano[2,3-b]pyridine-6-carbonitrile, there

are four excited states, two of them can be observed at 202.62 and

3.6.1. In vitro anti-inﬂammatory screening

Cyclooxygenases (COX) are responsible for the formation of prosta-

noids as thromboxane and prostaglandins. COX inhibitors can relieve

the symptoms of inﬂammation and pain [57]. All the newly synthesized

compounds inhibit both cyclooxygenase and lipoxygenase enzymes.

Compounds 1 and 8 inhibit Cox ꢀ 1 more than the standard celecoxib in

5.47 ± 0.12 and 7.63 ± 0.06 µm IC₅₀respectively, in comparison to

14.60 ± 0.00 of the standard celecoxib. Concerning Cox-2, Compounds

210.95 nm, these values assigned to

can be appeared at 213.17 and 310.74 nm, these transitions are assigned

to n- transitions. While, compound (11), 3-methyl-6-

((((2R,3S,4S,5R,6R)-2,3,4,5,6-pentahydroxytetrahydro-2H-pyran-2-yl)

π-π* transitions, while the others

π

*

20

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

damage. Results indicated that compounds 11 and 12 exhibited signif-

icant (p ≥ 0.05) in vitro total antioxidant activity as 44.93 ± 0.15 and

39.60 ± 0.10 U/ML, respectively higher than standard ascorbic acid

(29.40 ± 0.62). (Table 9) (Fig. 17).

Table 9

In vitro total antioxidant activity of the newly synthesized compounds.

Groups

Total antioxidant (IC₅₀U/ML)

Ascorbic acid

Compound 1

Compound 4

Compound 8

Compound 11

Compound 12

29.40 ± 0.62 ^d

22.26 ± 0.15 ^a

26.57 ± 0.15^c

24.27 ± 0.14^b

44.93 ± 0.15^f

39.60 ± 0.10 ^e

4. Conclusion

The authors herein endeavored to design an efﬁcient and environ-

mentally friendly protocol developed to synthesize 1,4-dihydropyrano

[2,3-c]pyrazole-5-carbonitrile (1) by the one-pot three-component

condensation reaction carried out by the reaction of 5-methyl-2-phenyl-

2,4-dihydro-3H-pyrazol-3-one, thiophene-2-carbaldehyde, and malo-

nonitrile. The start compound is used to obtain polycyclic heterocyclic

systems. In addition, The newly synthesized compounds

were found to be potent towards the antioxidant activity. Results

indicated that compounds 11 and 12 in vitro total antioxidant activity

were higher than those of standard ascorbic acid.

Declaration of Competing Interest

The authors declare that they have no known competing ﬁnancial

interests or personal relationships that could have appeared to inﬂuence

the work reported in this paper.

Acknowledgments

Fig. 17. A statistical representation for the antioxidant activity of the newly

The authors are very thankful to Taif University Researches Sup-

porting Project Number (TURSP-2020/91), Taif University, Taif, Saudi

Arabia.

prepared compound.

11 and 12 are more potent than other compounds in reducing their

activity. They also inhibit lipoxygenase enzyme to 2.17 ± 0.12 and 2.53

± 0.06 µm, respectively, in comparison to 3.35 ± 0.01 of the standard

quercetin. In conclusion, compounds 11 and 12 have more anti-

inﬂammatory activity than other compounds as their COX-1/COX-2

selectivity index are 335.75 and 355.75, respectively, compared to

21.88, 177.83, and 42.39 for compounds 1,4 and 8, respectively

(Table 8) (Figs. 15, 16).

References

[1] Y. Gu, Multicomponent reactions in unconventional solvents: state of the art, Green

Chem. 14 (2012) 2091–2128, https://doi.org/10.1039/C2GC35635J.

[2] E. Ruijter, R. Scheffelaar, R.V. Orru, Multicomponent reaction design in the quest

for molecular complexity and diversity, Angew. Chem. Int. Ed. 50 (2011)

6234–6246, https://doi.org/10.1002/anie.201006515.

[3] A. Shaabani, S.E. Hooshmand, Malononitrile dimer as a privileged reactant in

design and skeletal diverse synthesis of heterocyclic motifs, Mol. Diversity 22

(2018) 207–224, https://doi.org/10.1007/s11030-017-9807-y.

Different superscript letters in the same column are signiﬁcantly

different at p ≥ 0.05. Values are expressed as mean ± SD (n = 3).

The obtained results revealed that these compounds have a dual

mechanism of action as they inhibit both COX and 5- LOX to be novel

compounds to treat inﬂammation. They act by blocking both prosta-

glandins and leukotrienes formation. This dual mechanism of action

could be helpful for the management of both pain and inﬂammation

pathways. The sugar content of compounds 11 and 12 explained their

superior anti-inﬂammatory activity than other compounds. In this

concern, [58] reported that ibuprofen sugar derivatives showed better

anti-inﬂammatory activity and enhanced bioavailability. Other re-

searchers reported that newly synthesized pyranopyrazole compounds

exhibited anti-inﬂammatory activity and COX-1/2 inhibition [59] while

Kumar et al. [60] validated the use of pyranopyrazole compounds as

anti-inﬂammatory via docking studies. Also, the newly synthesized

compounds could be promising in the treatment of hepatocellular car-

cinoma as recent studies demonstrated that COX-2 inhibitors decrease

the immunosuppressive transforming growth factor-beta (TGFβ)

expression in hepatocytes and consequently inhibit epithelial-

mesenchymal transition (EMT) [61].

[4] P. Verma, S. Pal, S. Chauhan, A. Mishra, I. Sinha, S. Singh, V. Srivastava, Starch

functionalized magnetite nanoparticles: a green, biocatalyst for one-pot

multicomponent synthesis of imidazopyrimidine derivatives in aqueous medium

under ultrasound irradiation, J. Mol. Struct. 1203 (2020) 127410, https://doi.org/

10.1016/j.molstruc.2019.127410.

[5] N. Narayan, A. Meiyazhagan, R. Vajtai, Metal nanoparticles as green catalysts,

Materials 12 (2019) 3602, https://doi.org/10.3390/ma12213602.

[6] K. Eskandari, B. Karami, S. Khodabakhshi, ZnO nanoparticles–a recyclable catalyst

for the synthesis of bis (pyrazolyl) methanes, Chem. Heterocycl. Compd. 50 (2015)

1658–1664, https://doi.org/10.1007/s10593-015-1635-3.

[7] M. Bakherad, A. Keivanloo, M. Gholizadeh, R. Doosti, M. Javanmardi, Using

magnetized water as a solvent for a green, catalyst-free, and efﬁcient protocol for

the synthesis of pyrano [2, 3-c] pyrazoles and pyrano [4^′, 3^′: 5, 6] pyrazolo [2, 3-d]

pyrimidines, Res. Chem. Intermed. 43 (2017) 1013–1029, https://doi.org/

10.1007/s11164-016-2680-y.

[8] A. Mandour, E. El-Sawy, M. Ebaid, S. Hassan, Synthesis and potential biological

activity of some novel 3-[(N-substituted indol-3-yl) methyleneamino]-6-amino-4-

aryl-pyrano (2, 3-c) pyrazole-5-carbonitriles and 3, 6-diamino-4-(N-substituted

indol-3-yl) pyrano (2, 3-c) pyrazole-5-carbonitriles, Acta Pharmaceutica 62 (2012)

15–30, https://doi.org/10.2478/v10007-012-0007-0.

[9] N. Foloppe, L.M. Fisher, R. Howes, A. Potter, A.G. Robertson, A.E. Surgenor,

Identiﬁcation of chemically diverse Chk1 inhibitors by receptor-based virtual

screening, Bioorg. Med. Chem. 14 (2006) 4792–4802, https://doi.org/10.1016/j.

bmc.2006.03.021.

[10] N.J. Thumar, M.P. Patel, Synthesis and in vitro antimicrobial evaluation of 4H-

pyrazolopyran,-benzopyran and naphthopyran derivatives of 1H-pyrazole, Arkivoc

13 (2009) 363 –380 .

3.6.2. In vitro antioxidant activity screening

[11] F.M. Abdelrazek, P. Metz, N.H. Metwally, S.F. El-Mahrouky, Synthesis and

molluscicidal activity of new cinnoline and pyrano [2, 3-c] pyrazole derivatives,

Archiv der Pharmazie: Int. J. Pharmac. Med. Chem. 339 (2006) 456–460, https://

doi.org/10.1002/ardp.200600057.

Antioxidants are essential to relieve the oxidative stress, production

of reactive oxygen species and subsequently decrease several diseases’

pathogenesis. It also prevents necrosis and or apoptosis [62,63]. TAC is

an analyte frequently used to evaluate the antioxidant response against

the free radicals produced. Low total antioxidant capacity could be

indicative of oxidative stress or increased susceptibility to oxidative

[12] M.E. Zaki, H.A. Soliman, O.A. Hiekal, A.E. Rashad, Pyrazolopyranopyrimidines as a

class of anti-inﬂammatory agents, Zeitschrift für Naturforschung C 61 (2006) 1–5,

https://doi.org/10.1515/znc-2006-1-201.

[13] A. Tanitame, Y. Oyamada, K. Ofuji, M. Fujimoto, N. Iwai, Y. Hiyama, K. Suzuki,

H. Ito, H. Terauchi, M. Kawasaki, Synthesis and antibacterial activity of a novel

21

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

series of potent DNA gyrase inhibitors. Pyrazole derivatives, J. Med. Chem. 47

[34] M.M. Amer, M.A. Aziz, W.S. Shehab, M.H. Abdellattif, S.M. Mouneir, Recent

Advances in chemistry and pharmacological aspects of 2-pyridone scaffolds,

J. Saudi Chem. Soc. 25 (2021) 101259, https://doi.org/10.1016/j.

jscs.2021.101259.

(2004) 3693–3696, https://doi.org/10.1021/jm030394f.

[14] H. Mecadon, M.R. Rohman, I. Kharbangar, B.M. Laloo, I. Kharkongor,

M. Rajbangshi, B. Myrboh, L-Proline as an efﬁcicent catalyst for the multi-

component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2, 4-dihydropyrano [2, 3-c]

pyrazole-5-carbonitriles in water, Tetrahedron Lett. 52 (2011) 3228–3231, https://

doi.org/10.1016/j.tetlet.2011.04.048.

[35] W.H. El-Shwiniy, W.S. Shehab, W.A. Zordok, Spectral, thermal, DFT calculations,

anticancer and antimicrobial studies for bivalent manganese complexes of pyrano

[2, 3-d] pyrimidine derivatives, J. Mol. Struct. 1199 (2020) 126993, https://doi.

org/10.1016/j.molstruc.2019.126993.

[15] M. Hogale, B. Pawar, Synthesis and Biological Activity of 1-Aroyl-5-(p-sulfamoyl-

phenylazo)-3, 4-dimethylpyrano (2, 3-c) pyrazol-6 (1H)-ones, ChemInform 21

(1990) https://doi.org.10.1002/chin.199004162 .

[36] M.J. Frisch, Gaussian 98, Revision A. 9, 1998.

[37] W. Kohn, Density functional and density matrix method scaling linearly with the

number of atoms, Phys. Rev. Lett. 76 (1996) 3168, https://doi.org/10.1103/

PhysRevLett.76.3168.

[16] K. Saravana Mani, S.P. Rajendran, L-Proline catalyzed three component synthesis

of pyrano [2, 3-c] pyrazole-5-carbonitrile derivatives and in vitro antimalarial

evaluation, Synth. Commun. 47 (2017) 2036–2043, https://doi.org/10.1080/

00397911.2017.1362437.

[38] A.D. Becke, Density-functional exchange-energy approximation with correct

asymptotic behavior, Phys. Rev. A 38 (1988) 3098, https://doi.org/10.1103/

PhysRevA.38.3098.

[17] N.K. Bejjanki, A. Venkatesham, J. Madda, N. Kommu, S. Pombala, C.G. Kumar, K.

R. Prasad, J.B. Nanubolu, Synthesis of new chromeno-annulated cis-fused pyrano

[4, 3-c] isoxazole derivatives via intramolecular nitrone cycloaddition and their

cytotoxicity evaluation, Bioorg. Med. Chem. Lett. 23 (2013) 4061–4066, https://

doi.org/10.1039/C2MD20023F.

[39] C. Lee, W. Yang, R.G. Parr, Development of the Colle-Salvetti correlation-energy

formula into a functional of the electron density, Phys. Rev. B 37 (1988) 785,

https://doi.org/10.1103/PhysRevB.37.785.

[40] R.L. Flurry, Molecular orbital theories of bonding in organic molecules, 1968.

[41] R.H. Crabtree, Recent developments in the organometallic chemistry of N-

heterocyclic carbenes, Coord. Chem. Rev. 5 (2007) 595 .

[18] S.R. Mandha, S. Siliveri, M. Alla, V.R. Bommena, M.R. Bommineni,

S. Balasubramanian, Eco-friendly synthesis and biological evaluation of substituted

pyrano [2, 3-c] pyrazoles, Bioorg. Med. Chem. Lett. 22 (2012) 5272–5278, https://

doi.org/10.1016/j.bmcl.2012.06.055.

[42] S. Top, J. Tang, A. Vessieres, C. Carrez, C. Provot, G. Jaouen, Chem. Commun. (J.

Chem. Soc. Sect. D) (1996) 955 –956 .

[19] Z. Mahmoudi, M.A. Ghasemzadeh, H. Kabiri-Fard, Fabrication of UiO-66

nanocages conﬁned brønsted ionic liquids as an efﬁcient catalyst for the synthesis

of dihydropyrazolo [4^′, 3’: 5, 6] pyrano [2, 3-d] pyrimidines, J. Mol. Struct. 1194

(2019) 1–10, https://doi.org/10.1016/j.molstruc.2019.05.079.

[43] A. Siddekha, A. Nizam, M. Pasha, An efﬁcient and simple approach for the

synthesis of pyranopyrazoles using imidazole (catalytic) in aqueous medium, and

the vibrational spectroscopic studies on 6-amino-4-(4^′-methoxyphenyl)-5-cyano-3-

methyl-1-phenyl-1, 4-dihydropyrano [2, 3-c] pyrazole using density functional

theory, Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 81 (2011) 431–440,

https://doi.org/10.1016/j.saa.2011.06.033.

[20] X.-H. Yang, P.-H. Zhang, Z.-M. Wang, F. Jing, Y.-H. Zhou, L.-H. Hu, Synthesis and

bioactivity of lignin related high-added-value 2H, 4H-dihydro-pyrano [2, 3-c]

pyrazoles and 1H, 4H-dihydro-pyrano [2, 3-c] pyrazoles, Ind. Crops Prod. 52

(2014) 413–419, https://doi.org/10.1016/j.indcrop.2013.11.017.

˘

[44] R. Kurtaran, S. Odaba s ¸ıoglu, A. Azizoglu, H. Kara, O. Atakol, Experimental and

computational study on [2, 6-bis (3, 5-dimethyl-N-pyrazolyl) pyridine]-

(dithiocyanato) mercury (II), Polyhedron 26 (2007) 5069–5074, https://doi.org/

10.1016/j.poly.2007.07.021.

[21] H. Kashtoh, M.T. Muhammad, J.J. Khan, S. Rasheed, A. Khan, S. Perveen,

K. Javaid, K.M. Khan, M.I. Choudhary, Dihydropyrano [2, 3-c] pyrazole: novel in

ˇ

vitro inhibitors of yeast

α

-glucosidase, Bioorg. Chem. 65 (2016) 61–72, https://doi.

[45] I. Turel, L. Golic, P. Bukovec, M. Gubina, Antibacterial tests of bismuth (III)–

org/10.1016/j.bioorg.2016.01.008.

quinolone (ciproﬂoxacin, cf) compounds against Helicobacter pylori and some

other bacteria. Crystal structure of (cfH₂)₂[Bi₂Cl₁₀]⋅ 4H₂O, J. Inorg. Biochem. 71

(1998) 53–60, https://doi.org/10.1016/S0162-0134(98)10032-6.

[22] S.C. Kuo, L.J. Huang, H. Nakamura, Studies on heterocyclic compounds. 6.

Synthesis and analgesic and antiinﬂammatory activities of 3, 4-dimethylpyrano [2,

3-c] pyrazol-6-one derivatives, J. Med. Chem. 27 (1984) 539 –544, https://doi.

org.10.1021/jm00370a020 .

ˇ

´

ˇˇ´

´

[46] M. Becka, M. Vilkova, M. Soral, I. Potocnak, M. Breza, T. Beres, J. Imrich, Synthesis

and isomerization of acridine substituted 1, 3-thiazolidin-4-ones and 4-oxo-1, 3-

thiazolidin-5-ylidene acetates. An experimental and computational study, J. Mol.

Struct. 1154 (2018) 152–164, https://doi.org/10.1016/j.molstruc.2017.10.046.

[23] L. Rodinovskaya, A. Gromova, A. Shestopalov, V. Nesterov, Synthesis of 6-amino-4-

aryl-5-cyano-3-(3-cyanopyridin-2-ylthiomethyl)-2, 4-dihydropyrano [2, 3-c]

pyrazoles and their hydrogenated analogs. Molecular structure of 6-amino-5-

cyano-3-(3-cyano-4, 6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2, 4-

dihydropyrano [2, 3-c] pyrazole, Russian Chem. Bullet. 52 (2003) 2207 –2213,

https://doi.org.10.1023/B:RUCB.0000011880.05561.c1 .

´

[47] I. Turel, P. Bukovec, M. Quiros, Crystal structure of ciproﬂoxacin hexahydrate and

its characterization, Int. J. Pharm. 152 (1997) 59–65, https://doi.org/10.1016/

S0378-5173(97)04913-2.

˘

[48] E. Aktan, B. Babür, N. Seferoglu, B. Çatıkkas¸, F.B. Kaynak, Z. Seferoglu, Combined

spectroscopic, XRD crystal structure and DFT studies on 2-(ethylthio) pyrimidine-4,

6-diamine, J. Mol. Struct. 1145 (2017) 152–159, https://doi.org/10.1016/j.

molstruc.2017.05.058.

[24] X.-T. Li, A.-D. Zhao, L.-P. Mo, Z.-H. Zhang, Meglumine catalyzed expeditious four-

component domino protocol for synthesis of pyrazolopyranopyrimidines in

aqueous medium, RSC Adv. 4 (2014) 51580–51588, https://doi.org/10.1039/

C4RA08689A.

[49] J.G. Haasnoot, Mononuclear, oligonuclear and polynuclear metal coordination

compounds with 1, 2, 4-triazole derivatives as ligands, Coord. Chem. Rev. 200

(2000) 131–185, https://doi.org/10.1016/S0010-8545(00)00266-6.

[50] B.S. Holla, B.S. Rao, B. Sarojini, P. Akberali, One pot synthesis of

thiazolodihydropyrimidinones and evaluation of their anticancer activity, Eur. J.

Med. Chem. 39 (2004) 777–783, https://doi.org/10.1016/j.ejmech.2004.06.001.

[51] D. Seebach, Frontorbitale: Frontier Orbitals and Organic Chemical Reactions. Von

I. Fleming. John Wiley & Sons, London 1976. 1. Auﬂ., V, 249 S., geh. § 3, 95, Wiley

Online Library, 1977. https://doi.org/10.1002/nadc.19770250113.

[52] K. Krogmann, Die Kristallstruktur von K2 [Pd (C2O4) 2]⋅ 4 H2O, Zeitschrift für

anorganische und allgemeine Chemie 346 (1966) 188–202, https://doi.org/

10.1002/zaac.19663460311.

[25] B. Maleki, S.S. Ashraﬁ, Nano α-Al 2 O 3 supported ammonium dihydrogen

phosphate (NH_{4 H}2P_O4/A_l2_O3): preparation, characterization and its application as

a novel and heterogeneous catalyst for the one-pot synthesis of tetrahydrobenzo

[b] pyran and pyrano [2, 3-c] pyrazole derivatives, RSC Adv. 4 (2014)

42873–42891, https://doi.org/10.1039/C4RA07813F.

[26] C. Derabli, I. Boualia, A.B. Abdelwahab, R. Boulcina, C. Bensouici, G. Kirsch,

A. Debache, A cascade synthesis, in vitro cholinesterases inhibitory activity and

docking studies of novel Tacrine-pyranopyrazole derivatives, Bioorg. Med. Chem.

Lett. 28 (2018) 2481–2484, https://doi.org/10.1016/j.bmcl.2018.05.063.

´

[27] I. Gameiro, P. Michalska, G. Tenti, A. Cores, I. Buendia, A.I. Rojo, N.

´

D. Georgakopoulos, J.M. Hernandez-Guijo, M.T. Ramos, G. Wells, Discovery of the

´

ﬁrst dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for

Alzheimer’s disease, Sci. Rep. 7 (2017) 1–15, https://doi.org/10.1038/srep45701.

[28] M.R. Tipale, L.D. Khillare, A.R. Deshmukh, M.R. Bhosle, An efﬁcient four

component domino synthesis of pyrazolopyranopyrimidines using recyclable

choline chloride: urea deep eutectic solvent, J. Heterocycl. Chem. 55 (2018)

716–728, https://doi.org/10.1002/jhet.3095.

[53] I. Cioﬁni, P.P. Laine, F. Bedioui, C. Adamo, Photoinduced intramolecular electron

transfer in ruthenium and osmium polyads: Insights from theory, J. Am. Chem. Soc.

126 (2004) 10763–10777, https://doi.org/10.1021/ja0482278.

[54] I. Cioﬁni, C.A. Daul, C. Adamo, phototriggered linkage isomerization in

rutheniumꢀ dimethylsulfoxyde complexes: insights from theory, J. Phys. Chem. A

107 (2003) 11182–11190, https://doi.org/10.1021/jp0307607.

[29] L. Chen, H. Deng, H. Cui, J. Fang, Z. Zuo, J. Deng, Y. Li, X. Wang, L. Zhao,

Inﬂammatory responses and inﬂammation-associated diseases in organs,

Oncotarget 9 (2018) 7204, https://doi.org/10.18632/oncotarget.23208.

[30] W.S. Shehab, W.H. El-Shwiniy, Nanoparticles of manganese oxides as efﬁcient

catalyst for the synthesis of pyrano [2, 3-d] pyrimidine derivatives and their

complexes as potent protease inhibitors, J. Iran. Chem. Soc. 15 (2018) 431–443,

https://doi.org/10.1007/s13738-017-1244-4.

[55] M.E. Casida, Time-dependent density functional response theory for molecules,

Recent Advances In Density Functional Methods: (Part I), World Scientiﬁc, 1995,

pp. 155–192. https://doi.org/10.1142/9789812830586_0005.

[56] R. Bauernschmitt, R. Ahlrichs, Treatment of electronic excitations within the

adiabatic approximation of time dependent density functional theory, Chem. Phys.

Lett. 256 (1996) 454–464, https://doi.org/10.1016/0009-2614(96)00440-X.

[57] C. Litalien, P. Beaulieu, Molecular mechanisms of drug actions: From receptors to

effectors, Pediatric Critical Care, Elsevier (2011) 1553–1568, https://doi.org/

10.1016/B978-0-323-07307-3.10117-X.

[31] W.S. Shehab, G.T. El-Bassyouni, Synthesis and cyclization of β-keto-enol

derivatives tethered indole and pyrazole as potential antimicrobial and anticancer

activity, J. Iran. Chem. Soc. 15 (2018) 1639–1645, https://doi.org/10.1007/

s13738-018-1362-7.

[58] N. Song, Y. Li, X. Sun, F. Qu, Synthesis of (+/-) ibuprofen sugar derivatives, Yao

xue xue bao = Acta pharmaceutica Sinica 39 (2004) 105 –109 .

[32] M.H. AbdEl-Azim, M.A. Aziz, S.M. Mouneir, A.F. EL-Farargy, W.S. Shehab,

Ecofriendly synthesis of pyrano [2, 3-d] pyrimidine derivatives and related

heterocycles with anti-inﬂammatory activities, Archiv der Pharmazie 353 (2020)

2000084, https://doi.org.10.1002/ardp.202000084 .

[59] H.M. Faidallah, S.A. Rostom, Synthesis, anti-inﬂammatory activity, and COX-1/2

inhibition proﬁle of some novel non-acidic polysubstituted pyrazoles and pyrano

[2, 3-c] pyrazoles, Arch. Pharm. 350 (2017) 1700025, https://doi.org/10.1002/

ardp.201700025.

[33] W.S. Shehab, M.H. Abdellattif, S.M. Mouneir, Heterocyclization of polarized

system: synthesis, antioxidant and anti-inﬂammatory 4-(pyridin-3-yl)-6-(thiophen-

2-yl) pyrimidine-2-thiol derivatives, Chem. Cent. J. 12 (2018) 1–8, https://doi.

org/10.1186/s13065-018-0437-y.

[60] A. Kumar, P. Lohan, D.K. Aneja, G.K. Gupta, D. Kaushik, O. Prakash, Design,

synthesis, computational and biological evaluation of some new hydrazino

derivatives of DHA and pyranopyrazoles, Eur. J. Med. Chem. 50 (2012) 81–89,

https://doi.org/10.1016/j.ejmech.2012.01.042.

22

M.M.K. Amer et al.

Bioorganic Chemistry 114 (2021) 105136

[61] L.M. Zeldenryk, Occupational deprivation: a consequence of Australia’s policy of

assimilation, Aust. Occup. Ther. J. 53 (2006) 43–46, https://doi.org/10.1111/

j.1440-1746.2011.06980.x.

[62] Y. Gilgun-Sherki, Z. Rosenbaum, E. Melamed, D. Offen, Antioxidant therapy in

acute central nervous system injury: current state, Pharmacol. Rev. 54 (2002)

271–284, https://doi.org/10.1124/pr.54.2.271.

[63] P. Evans, Free radicals in brain metabolism and pathology, Br. Med. Bull. 49 (1993)

577–587, https://doi.org/10.1093/oxfordjournals.bmb.a072632.

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Synthesis, DFT calculation, pharmacological evaluation, and catalytic application in the synthesis of diverse pyrano[2,3-c]pyrazole derivatives

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