New pyrazolyl-dibenzo[b,e][1,4]diazepinones: room temperature one-pot synthesis and biological evaluation

Molecular Diversity

https://doi.org/10.1007/s11030-019-09958-z

ORIGINAL ARTICLE

New pyrazolyl‑dibenzo[b,e][1,4]diazepinones: room temperature

one‑pot synthesis and biological evaluation

Gaurangkumar C. Brahmbhatt¹· Tushar R. Sutariya¹· Hiralben D. Atara¹· Narsidas J. Parmar¹· Vivek K. Gupta²·

Irene Lagunes³· José M. Padrón³· Prashant R. Murumkar⁴· Mange Ram Yadav⁴

Received: 9 March 2019 / Accepted: 8 May 2019

Abstract

Several new (5-aryloxy-pyrazolyl)- and (5-aryl/olefn-sulfanyl-pyrazolyl)-dibenzo[b,e] [1,4] diazepinone scafolds have

been synthesized, by assembling 5-substituted 3-methyl-1-phenyl-pyrazole-4-carbaldehydes of varied nature with diferent

cyclic diketones and aromatic diamines successfully in the presence of indium chloride in acetonitrile, at room temperature.

Desired products are excellent in the purity and isolated without chromatography. All new structures are confrmed, on the

basis of single-crystal X-ray difraction data of representative 29e. Compounds reported in the present work revealed good

antioxidant, antimicrobial and antiproliferative activities with promising FRAP (ferric reducing antioxidant power), bacterial

resistance and human solid tumor cell growth inhibitory values, respectively. Compounds 25c and 29e, overall, registered

good to moderate activity against A549 (lung), HeLa (cervix), SW1573 (lung) T-47D (breast) and WiDr (colon) cell lines,

with GI₅₀values in the 2.6–5.1 μM and 1.8–7.5 μM ranges, respectively. Molecular docking was carried out to elucidate the

binding modes of the compounds (25c, 29e) to topoisomerase I and II.

Graphical abstract

Keywords MCR · Pyrazolyl-dibenzodiazepine · Antioxidant · Antiproliferative agents · Antibacterial activity ·

Antitubercular agents

Introduction

Electronic supplementary material The online version of this

article (https://doi.org/10.1007/s11030-019-09958-z) contains

Diazepine and pyrazole which represent seven- and fve-

supplementary material, which is available to authorized users.

membered nitrogen-containing rings, respectively, are the

structures of great importance, in the development of newer

Extended author information available on the last page of the article

Vol.:(0123456789)

1 3

Molecular Diversity

Fig. 1 Biologically signifcant diazepine molecular frameworks

molecular assemblies fnding a wide range of applications in

the diverse felds [1–9]. Diazepine heterocycles, for exam-

ple, deserve a great attention when biological applications of

the compounds are desired [1, 2]. Synthetic activity manipu-

lating diazepine nucleus had increased [10–16], particularly

after the protocol reporting synthesis o f diazepine scafold

appeared frst in early 1960s [17]. Diazepine heterocycles

and synthetic strategies aiming at class of these scafolds

hav e been often interesting topics of the research worldwide

[18–20]. Chlordiazepoxide and diazepam, which are well-

kno wn anxiolytics, belong to class of these heterocycles

[21]. Antipsycotics clozapine [22 , 23] and muscarinic recep-

tor M₁antagonist pirenzepines [24 ] are excellent diazepine

compounds. Apafant structure in th e same way are efective

inhibitors to platelet activation [25, 26].

diazepine [37, 38] and benzo-fused diazepine structures,

respectively. Bo th the skeletons are highly active and varied

in biological profles (Fig. 1 ). Diazepine he terocyclic skel-

etons occur in natural products, as well [39–41]. In view of

the importance of dibenzo[b,e][1,4]diazepine scafolds, it

is, therefore, worth constructing members of this family and

investigating their biological potentials, in the development

of new therapeutic agents.

Diazepine-fused carbocyclic or heterocyclic structures

with one of the diazepine nitrogens attached to alkyl or aryl

moiety represent potential therapeutic templates. Examples

include anticancer [42], antialzheimer [43] and psychoac-

tive drugs [44–48 ]. Diazepine core attachment to phenyl,

pyridine, thiophene and furan units has been also efective

to design new bioprofles, in dibenzo[b,e][1,4]diazepines

[49–54]. Previously, we reported quinolyl-dibenzo[b,e]

[1,4]diazepinones te thering quinoline unit to the diazepine

core [55, 56] (Fig. 1). In the present work, we envisaged

the pyraz ole with diazepine core and synthesized new pyra-

zolyl-dibenzo [b,e][1,4]diazepinones. Pyrazole derivatives

revealed a wide spectr um of activities such as analgesic and

anti-infammatory [57, 58], antiarrhythmic [59], antifungal

[60 ], analgesic [61–63 ], antipyretic [61–63 ], antinociceptive

[7 , 64], cytoto xic [65–67 ], anticancer [68], myelofbr osis

(ru xolitinib) [69–7 1 ] a nd antioxidant activities [72, 73].

On the other hand, diazepine is known for its antioxidant

and lipid peroxidation inhibitory profles, in vitro [74–77].

Pyrazole-appended benzodiazepines are therefore interesting

molecular templates anticipated to be having new biopro-

fles. All heterocycles are screened, in vitro, for their antimi-

crobial and antiproliferative activities, in combination with

the antioxidant potential determination.

1,4-Diazepine heterocycles repr esent an important class

of therapeutic profles showing a particular fusion of diaz-

epine unit with the heterocycle. Heterocycles of this class

are potential analgesic, antimalarial, antitr ypanosomal,

antileishmanial and antitumor agents [27–30]. Diazepine

amalgamating its pharmaceutical profles wit h that of other

heterocycles in the molecular templates thus remains to

be a most important target in the chemical synthesis [31].

Replacement of a skeleton or an element suitably by its

respective bioisosteric skeleton or element also worked pro-

ductive in many cases in the development of new bioactive

molecular assemblies. Dibenzo[b,e][1,4]diazepine deriva-

tives are known to show analg esic, hypnotic, anticonvul-

sant and sedative profles [28, 32, 33]. Now, dibenzo[b,e]

[1,4] diazepine with the benzene r eplaced b y its bioisos-

ter ic thiophene ring represents new molecular templates [32,

34–36]. Flumezapine and clozapine contain thiophene-fused

1 3

Molecular Diversity

3-methyl-1-phenyl-1H-pyrazole-5(4H)-one, according to

the method reported elsewhere [96] (Scheme 1). Alde-

hyde 1a gave 5-phenoxy-, 5-(p-Me/p-Cl) phenoxy- and

5-(phenyl/p-Cl-phenyl) sulfanyl-substituted-3-methyl-

1-phenyl-pyrazole-4-carbaldehydes 2a–e, with respective

phenols and thiophenols in dry DMF-K₂CO₃suspension,

stirred at 80 °C. 5-(Allyl/benzyl)sulfanyl-pyrazole-4-car-

baldehydes 2f–g, on the other hand, were obtained by

reacting aldehyde 1a with respective allyl/benzyl bro-

mide in a dry DMSO-Na₂S mixture at room temperature.

5-Substituted-pyrazole-4-carbaldehydes 2f–g are rarely

explored in the literature. Present work strategy [97] to

aford them in 20–30 min at room temperature is advanta-

geous over that reported by Gerrit L’abbe taking longer to

yield aldehyde [98].

Results and discussion

Chemistry

Multicomponent reactions (MCRs) play a key role in the

synthesis of diverse and complex scafolds, especially

those which contain nitrogen heterocycles. Achieved in

the past decade by MCRs are heterocycles bearing pyrrole

[78], enantioenriched piperidine [79] and dihydropyridine

with high optical purity, as centr al cores. Oxonium [80]

and azomethine ylides [81] proved to be precursors to

diverse range of indole-based heterocycles [82 ]. MCRs

incorporated isatin-derived azomethine ylide [81, 83] and

methylene indole into enantioselective spiro-heter ocycles,

too. MCRs promise not only excellent enantioselectivity,

but also atom economy, bond-forming efciency and com-

plexity besides diversity-oriented synthesis [84]. Moreo-

ver, it accomplishes present-day requirements of new

synthesis say experimental simplicity, favorable economic

factors and low environment impact.

A mixture containing pyrazole-carbaldehydes 2a, ben-

zene-1,2-diamine 3 and cyclohexanedione 5, leading to form

MCR product 7a, was used as a model reaction to optimize

the reaction conditions. Results are summarized in Table 1.

Catalyst- and solvent-free 110 °C heating method (entry 1)

yielded 65% of the desired product after 3.5 h. HCl (30%,

20 µL) (entry 2), glacial HOAC (20 µL) (entry 3) and InCl₃

(25 mol%) (entry 4) were then used as catalysts. HOAC-cat-

alyzed solvent-free heating among them yielded a maximum

80% of the product in 3.5 h (entry 3). Undesired impurities

formed at higher temperature made the workup laborious

and lengthy. The solvent-free protocol we used taking quino-

line-carbaldehyde therefore couldn’t accommodate pyrazole-

carbaldehyde [55]. So we examined refuxing ethanol (entry

5), refuxing water (entry 6) and refuxing acetonitrile (entry

7), below solvent-free heating temperature of 110 °C, with a

view to avoid formation of impurities. It led to 60% yields of

the products in acetonitrile, in 3 h (entry 7), relatively better

than traces which were formed in both ethanol and water.

Next, we tried HCl, glacial HOAC and InCl₃as catalysts

in respective refuxing solvents (entries 8–14). While 79%

of product was formed in HCl or InCl₃, traces of the prod-

uct were formed in glacial HOAC in 4.5 h (entries 8–14).

Here, the decomposed impurities associated with the prod-

uct were almost negligible. Next, room temperature reaction

was examined in the presence of InCl₃in diferent solvents

(entries 15–17). It gave impurity-free 92% of desired product

in acetonitrile, which is the highest among that obtained

in other solvents. Aprotic nature of acetonitrile might have

favored this reaction, as it gave poor results in protic ethanol

and water. Isolation of products required triturating tech-

niques when protic solvents were used. Table 2 summarizes

the synthesis of other products by the optimal reaction con-

dition, along with their physical constants.

Seven-membered ring synthesis employed a com-

bination of four-atom diene, generated in situ or used

directly, with two-atom dienophile or dipolarophile [83,

85]. Reactions of allylic or heteroatom-substituted allylic

and nitrogen-stabilized oxyallyl cations as dipolarophiles

[86] and vinyl-azeridine [87, 88] as diene yielded aze-

pine or oxazepine heterocycle s with excellent purity. On

the other hand, enaminones, derived from diamines and

diketones, in the reaction with aldehydes formed seven-

membered ring, diazepine unit, in the presence of acid

catalysis [89]. Access to dibenzo[b,e][1,4]diazepine

scafolds, particularly, can be well demonstrated by the

multicomponent domino reaction which assembles an

aldehyde substrate with enaminone of the diketone with

benzene-1,2-diamine. Aldehydes such as benzaldehyde,

pyridine-2/3/4-carbaldehydes, thiophene-2-carbaldehyde

and furan-2-carbaldehyde have been employed success-

fully in the reaction to achieve aryl/heteroaryl-tethered

diazepine-fused heterocycles. McGowan and his co-

workers synthesized class of these scafolds in two steps,

in acetic acid in refuxing ethanol [90]. Orlov and others

developed MCR strategy via Michael adduct formation

[91]. Greener and eco-friendly aspects of the MCR among

them, however, remained advantageous [92–94]. Recently,

BINOL-derived chiral phosphoric acid-cat alyzed MCRs

provided enantioselective synthesis o f several bioactive

dibenzo[1,4]diazepine heterocycles [95]. Development of

newer bioprofles and search for efciency of the reaction

therefore become prime intentions of the research activi-

ties in the chemical and newer drug synthesis.

Various three-component combinations taking the ben-

zene-1,2-diamine 3/4 and 1,3-cyclohexanedione 5/6 with

pyrazol-carbaldehydes 2a–g were employed to achieve

the one-pot synthesis of pyrazolyl-dibenzo[b,e][1,4]

5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbalde-

hyde 1a was prepared by Vilsmeier–Haack reaction of

1 3

Molecular Diversity

Scheme 1 Synthesis of 5-chloro/(phenoxy/(p-Me/p-Cl)phenoxy/

(phenyl/p-Cl-phenyl) sulfanyl-3-methyl-1-phenyl-1H-pyrazole-4-car-

baldehydes 2a–e, and 5-(allyl/benzyl)sulfanyl-3-methyl-1-phenyl-

1H-pyrazol-4-carbaldehydes 2f–g. Reagents and conditions: (i) dry

DMF, K₂CO₃, 80 °C, 2.0–2.5 h, (ii) dry DMSO, Na₂S, 30–40 min, rt

diazepinones 7a–34 g, following optimized method at room

temperature (Scheme 2).

appeared singlet separately; one peak for methyl protons

at 0.77–1.08 δ ppm and second for other methyl pro-

tons at 0.918–1.09 δ ppm. Carbonyl carbon attached to

skeleton C-8 carbon appeared at 194.07–194.74 δ ppm

New pyrazole-carbaldehydes, 2f and 2g, and MCR

products 7a–34g have been characterized by elemental,

1

mass spectrometry, IR, H NMR and ¹³C NMR (APT)

in 8a, 10b, 12c, 14d, 16e, 18f and 20 g. The CH-11 H

1

spectral data. A H NMR singlet pyrazol–CHO proton

NMR doublet proton appeared in the 5.60–7.37 δ ppm

range (J = 4.8–5.6 Hz) and ¹³C NMR APT peak in the

44.26–50.88 δ ppm range. NH-10 proton showed dou-

blet in the 5.11–5.90 δ ppm range (J = 4.8–5.6 Hz). NH-5

proton is singlet in the δ 8.67–9.35 ppm range. Charac-

teristic IR ν C–H and ν N–H vibrations are observed in

the 2995–3065 cm⁻¹and 3224–3454 cm⁻¹ranges attrib-

utable to methine and secondary amine groups, respec-

tively. Characteristic carbonyl C=O band is observed in

appeared at 9.626–9.986 δ ppm, while ¹³C APT –CHO

carbon appeared at 185.74–186.22 δ ppm. The absence

of the pyrazol –CHO proton in MCR products con-

firmed diazepine ring formation. Benzo[b,e][1,4]diaz-

epin-1-one skeleton C-1 (of CO), C-2 and C-4 carbons

appeared in 192.20–193.02 δ ppm, 21.81–51.32 δ ppm

and 28.80–44.96 δ ppm ranges, respectively. Protons

of each one of two C–3 carbon-attached methyl groups

1 3

Molecular Diversity

Table 1 Optimization of the reaction conditions^astudying the synthesis of compound 7a

Entry

Solvent

Catalyst

Temperature (°C)

Time^b(h)

Yield^c(%)

1.

2.

3.

4.

5.

6.

7.

8.

–

110 °C

Refux

rt

3.5–4.0

3.5

3.0

2.5

2.0

3.0

3.5

4.0

3.0

4.0–4.5

3.0

2.5

6.0

65%

50%

80%

50%

Trace

60%

30%

75%

20%

40%

55%

10%

79%

20%

Trace

92%

–

30% HCl (20 μL)

Acetic acid(40 μL)

InCl₃(25 mol %)

–

Ethanol

Water

Acetonitrile

Ethanol

Water

Acetonitrile

Ethanol

Water

Acetonitrile

–

30% HCl (20 μL)

Acetic acid(40 μL)

InCl₃(25 mol %)

30% HCl (20 μL)

Acetic acid(40 μL)

InCl₃(25 mol %)

Acetic acid(40 μL)

InCl₃(25 mol %)

9.

10.

11.

12.

13.

14.

15.

16.

17.

rt

Texts for optimized conditions are in bold fonts

^aReaction conditions: Equimolar (0.1 mmol) aldehyde 2a; 1, 2-diamine 3; 1, 3-diketone 5; diferent catalysts, diferent solvents (15 mL)

^bDetermined by TLC, ^cyields of isolated products

the 1724–1880 cm⁻¹range. Acyclic ethereal C–O bond

Biological evaluation and structure–activity

vibrations are observed in the 1258–1327 cm⁻¹range.

relationship analysis

Single-crystal X-ray diffraction data of representative

29e (Fig. 2) were used to confirm all new proposed struc-

tures. ORTEP view of 29e agrees with structures pro-

posed in Scheme 2. The compound has monoclinic crystal

system and space group P 21/c, with the unit cell param-

eters: a = 16.5898 (11), b = 10.7522(5), c = 16.516(12)

A^o, and number of molecules per unit cell Z equal to 4.

The geometry of the molecule w as calculated using the

WinGX [99], PARSTV [100] and PLATON [101] soft-

ware. Cryst al and experimental data of compound are

shown in Table 3.

Structure–activity relationship study from antimicrobial,

antitubercular and antioxidant (FRAP value) activities

Table 4 displays MIC (minimum inhibitory concentration)

values of heterocycles against three Gram-positive and three

Gram-negative bacterial strains as well as two fungal species,

in µg/mL, along with their M. Tuberculosis H37RV growth

inhibition values, in % GI. MIC of at least one control drug

was considered r e f erence for evaluating the potency of the

compound [102, 103]. Compounds 25c, 26c and 30e bearing

1 3

Molecular Diversity

Table 2 Synthesis of various

dibenzo[b,e][1,4]diazepinone

scafolds and their physical

constants

Entry

R

H

Time (h) Yield^a% M.P. °C^bEntry

R

H

Time (h) Yield^a% M.P. °C^b

7a

8a

9b

5.5

87

76

67

78

79

86

87

74

87

73

86

64

69

210–212 21a

228–230 22a

200–202 23b

224–226 24b

224–226 25c

222–224 26c

224–226 27d

214–216 28d

220–222 29e

218–220 30e

208–210 31f

196–198 32f

214–216 33 g

184–186 34 g

5.7

79

69

77

72

87

75

89

86

79

68

58

76

70

72

214–216

222–224

198–200

284–286

176–178

186–188

206–208

224–226

226–228

248–250

192–194

148-150

216-218

156-158

–COPh 5.7

5.6

–COPh 5.8

5.6

–COPh 6.0

5.5

–COPh 6.0

5.2

–COPh 5.5

5.9

–COPh 6.0

5.7

–COPh 5.9

–COPh 5.6

5.4

–COPh 5.3

5.6

–COPh 6.0

5.7

–COPh 5.2

5.5

–COPh 5.9

2.0

–COPh 2.2

1.9

–COPh 2.0

H

10b

11c

12c

13d

14d

15e

16e

17f

18f

19 g

20 g

H

^aIsolated yield

^bUncorrected

chlorophenyl-tethered pyrazolyl moiety are excellent to mod-

erate in the inhibitory power against all six bacterial species.

Compound 25c revealed ampicillin-comparable S. pneumo-

niae, C. tetani, S. typhi and V. cholerae bacterial inhibitions.

The B. subtilis bacterial resistivity of this compound, however,

resembles that of norfoxacin control drug. Compounds 26c

and 30e resemble both chloramphenicol and ciprofoxacin

control drugs in S. pneumoniae bacteria inhibition. Compound

26c additionally revealed C. tetani, B. subtilis, S. typhi as well

as E. coli and V. cholerae bacterial inhibitory powers, compa-

rable to that of chloramphenicol or norfoxacin or ampicillin.

Compound 29e, active against all three Gram-positive bacte-

ria, and compound 30e, active against two Gram-negative S.

typhi and E. coli bacteria, showed ampicillin-comparable MIC

values. Compound 30e in addition showed chloramphenicol-

comparable B. subtilis and V. cholerae bacterial resistance

powers as well as ciprofoxacin-comparable C. Tetani bacte-

rial resistance power. The compound resembles both of these

control drugs in the S. Pneumoniae bacterial inhibition. Other

compounds in general showed ampicillin-comparable bacte-

rial resistivity. While compounds 9b, 11c, 13a, 19g, 20g, 21a,

27d, 31f, 32f and 33 g are resistive against C. tetani bacteria,

compound 7a against B. subtilis bacteria. Compounds 8a, 12c,

17f are active against S. pneumoniae and C. Tetani bacteria.

C. Tetani bacterial resistance of 12c, however, was more than

that of ampicillin. Similarly, compound 24b, among 13c, 29c

and 24b which are active against all three Gram-positive bac-

teria, has C. Tetani bacterial resistance even more than that of

ampicillin. Compound 24b additionally showed V. cholerae

and E. coli bacterial resistance powers. S. pneumoniae and C.

tetani bacterial resistance powers of compound 22a resem-

ble that of both chloramphenicol and ciprofoxacin drugs.

Finally, compounds 18f and 23b showed ampicillin- and

chloramphenicol-comparable S. typhi resistance powers,

respectively.

All compounds are very poor in their resistance against

A. fumigates. Resistance in many cases against C. albicans

fungi is, however, not disappointing (Table 4). For example,

MIC values of candidates 9b, 11c, 12c, 27d and 29c are

relatively better against C. albicans, than that of reference

griseofulvin drug. Compounds 10b, 15e, 16e, 18f, 22e, 23b,

24b, 25c, 26c, 28d, 33g, on the other hand, have griseofulvin

equivalent resistivity against this fungal species.

Antitubercular activity study

Lowenstein–Jensen (L–J) MIC method was used to deter-

mine M. tuberculosis H37Rv growth inhibitory values of

compounds, to know their antitubercular potential [104].

The % GI values are given in Table 4. Notable M. tuber-

culosis H37Rv growth inhibitory candidates include 11c,

12c, 29e and 30e, which showed % GI values in the 85–96%

range. The % GI values of compounds 8a, 15e, 16e, 19g

and 25c, on the other hand, fall in the 75–80% range, which

make them moderate antitubercular agents.

Antioxidant activity study

Ferric reducing antioxidant power (FRAP) values were

determined using Benzie and Strain’s modifed FRAP

method [105]. Results are summarized in Table 4. Aryl-

(oxy/thio)-pyrazole moiety containing 8a, 9b, 13d, 25c

and 29e as well as alkyl-sulfanyl-tethered pyrazole bearing

17f and 20g heterocycles registered FRAP values in the

392–468 (mm/100 g) range, indicating that they are good

in resistance toward reduction of ferric tripyridyl triazine

1 3

Molecular Diversity

Scheme 2 Synthesis of 11-(5-(aryl/alkyl/alkenyl)oxy/(aryl/alkyl/alk-

enyl)sulfanyl-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2,3,4,5,10,11-hex-

ahydro-1H-dibenzo[b,e][1,4]diazepin -1-ones, and their 8-benzoyl

and 3,3-dimethyl-substituted products 7a–34g. Reaction condition:

acetonitrile, InCl₃(25 mol %), room temperature, 6 h

(Fe(III)-TPTZ) complex into a blue color ferrous tripyridyl

triazine (Fe(II)-TPTZ) complex, determined spectrophoto-

metrically at 593 nm at low pH.

displays GI₅₀(growth inhibition) values of compounds,

along with that of clinically used anticancer drugs, against

six diferent human solid tumor cell lines. Compounds 25c

and 29e have excellent antiproliferative potentials against

all tumor cell lines, on line with that of at least one of the

control drugs. With 4.2 μM GI₅₀value against lung A549

cell line, compound 25c registered antiproliferative potential

even better than that of clinically used cisplatin drug. The

The in vitro antiproliferative activity

Sulforhodamine B (SRB) assay was used to de ter mine anti-

proliferative potential of compounds [106, 107]. Table 5

1 3

Molecular Diversity

Fig. 2 The ORTEP view of the

molecule of 29e with displace-

ment ellipsoids drawn at 40%

Ph

N

l

C

S

N

H

N

O

N

H

Table 3 Crystal and

experimental data of compound

29e

CCDC No

1560011

Crystal description

Crystal size

Empirical formula

Formula weight

White block

0.3×0.2×0.2 mm

C₃₁H₂₉Cl₁N₄O₁S₁

541.09

Radiation, wavelength

Unit cell dimensions

Crystal system

Mo Kα, 0.71073 Å

a=16.8598(11), b=10.7522(5), c=16.5166(12) Å, β=110.713(8)^°

monoclinic

P 21/c

Space group

Unit cell volume

No. of molecules per unit cell, Z

Temperature

Absorption coefcient

F (000)

2800.6(3)

4

293(2) K

0.242 mm⁻¹

1136

Scan mode

ω scan

3.52<θ<26.00

h=−20–15, k=−13–13, l=−20–20

12435/5491

3122

0.0265

θ range for entire data collection

Range of indices

Refections collected/unique

Refections observed (I>2 σ (I))

Rint

Rsigma

Structure determination

Refnement

0.0562

Direct methods

Full-matrix least-squares on F²

No. of parameters refned

Final R

276

0.0462

0.0865

w_R(F²)

Weight

Goodness-of-ft

Final residual electron density

Measurement

Software for structure solution:

Software for refnement:

Software for molecular plotting:

1/[σ²(Fo²)+(0.0452 P)²+ 0.4709P], where P=[Fo²+2Fc²]/3

1.010

−0.435<Δρ<0.460 eÅ⁻³

X’calibur system, Oxford difraction make,UK

SHELXS97 (Sheldrick, 2008)

SHELXL97 (Sheldrick, 2008)

ORTEP-3 (Farrugia, 1997) PLATON

Software for geometrical calculation PLATON (Spek, 2009) PARST (Nardelli, 1995)

1 3

Molecular Diversity

Table 4 The In vitro antimicrobial, antitubercular and antioxidant (FRAP values) activities of diazepine heterocycles 7a–34g

Code no.

Antimicrobial activity (MIC, µgmL⁻¹

)

Anti-TB^a

FRAP

(%) inhibi- Value^b

tion (%)

Gram-positive bacteria

Gram-negative bacteria

Fungi

A.F.

S.P.

C.T.

B.S.

S.T.

V.C.

E.C.

C.A.

MTCC

227

MTCC

1936

MTCC

449

MTCC

441

MTCC

98

MTCC

3906

MTCC 443 MTCC

3008

7a

8a

9b

250

100

250

200

250

125

200

250

125

200

125

250

200

500

200

62.5

200

125

62.5

200

125

62.5

250

200

250

0.5

500

250

125

200

250

200

250

200

125

200

125

200

62.5

250

200

125

250

200

250

500

5

250

500

250

500

250

200

500

250

200

125

100

500

250

62.5

500

1

500

250

500

200

250

500

250

500

250

100

200

250

200

250

50

200

125

62.5

250

200

125

250

500

5

500

250

500

250

500

250

500

250

500

250

100

125

100

250

200

250

50

500

250

200

500

250

500

250

200

500

250

200

125

200

62.5

200

100

500

250

500

250

>500

500

250

–

1000

250

500

250

1000

500

1000

500

–

67

77

6

283.78

420.67

459.84

249.24

377.34

303.29

443.97

363.86

285.47

299.44

448.89

294.58

272.10

392.70

295.31

302.24

333.44

288.08

435

180.34

325.23

290.50

468.04

215.94

257.56

365.90

464.58

346.67

10b

11c

12c

13d

14d

15e

16e

17f

18f

19 g

20 g

21a

22a

23b

24b

25c

26c

27d

28d

29e

30e

31f

32f

33 g

34 g

A

72

86

85

58

68

78

75

64

36

75

68

40

55

51

65

79

62

30

22

90

88

35

67

25

57

–

250

500

>500

500

–

500

250

–

500

–

1000

500

250

500

250

1000

500

1000

250

200

250

500

5

–

0.05

B

100

250

50

100

50

–

250

100

50

25

10

–

C

50

D

50

25

E

10

100

–

10

F

–

99

G

100

500

H

I

MIC value comparable to that of control drug is in bold and FRAP values more than 400 are in bold fonts

S.P. Streptococcus pneumoniae, C.T. Clostridium tetani, B.S. Bacillus subtilis, S.T. Salmonella typhi, V.C. Vibrio cholerae, E.C. Escherichia coli,

A.F. Aspergillus fumigatus, C.A. Candida albicans

[A]: gentamycin, [B]: ampicillin, [C]: chloramphenicol, [D]: ciprofoxacin, [E]: norfoxacin, [F]: isoniazide, [G]: nystatin, [H]: griseofulvin, [I]:

ascorbic acid

^aConcentration of compounds used against M. tuberculosis H37Rv bacteria=250 μg/mL, standard antimicrobials used: isoniazide (0.2 μg/mL)

^bConcentration of compounds=200 μg/mL and reference: ascorbic acid (A.A.)=176 μg/mL, ^bA.A. mm/100 gm sample

1 3

Molecular Diversity

Table 5 The in vitro

Entry

Cell line (origin)^a

antiproliferative activity of

diazepine heterocycles 8a–34g

against six diferent human solid

tumor cell lines, in GI₅₀value

A549

(lung)

HBL-100

HeLa

SW1573

(lung)

T– 47D

(breast)

WiDr

(breast)

(cervix)

(colon)

8a

9b

5.0 ( 1.2)

31( 4.7)

5.6( 1.7)

27( 2.2)

6.4( 1.8)

22 ( 9.1)

14 ( 0.7)

35 ( 7.8)

27 ( 1.1)

6.7 ( 3.2)

25( 3.7)

3.9 ( 0.2)

21 ( 2.2)

38 ( 6.8)

4.2 ( 0.5)

2.9 ( 0.5)

15 ( 2.1)

6.4 ( 1.2)

4.9 ( 0.2)

1.5 ( 0.3)

–

14 ( 0.5)

39 ( 6.9)

96

25 ( 5.8)

-nd

12 ( 4.2)

22 ( 4.1)

15 ( 4.2)

16 ( 1.8)

7.7 ( 1.8)

-nd

10 ( 2.1)

38 ( 3.4)

37 ( 17)

13 ( 2.9)

19 ( 1.1)

9.0 ( 2.4)

16 ( 2.3)

-nd

14 ( 2.2)

42 ( 7.4)

41 ( 0.7)

26 ( 6.2)

-nd

64 ( 14)

-nd

41 ( 3.8)

-nd

34 ( 11)

50 ( 5.6)

-nd-nd

27 ( 5.4)

-nd-nd

90

48 ( 3.8)

-nd

35 ( 4.4)

-nd

36 ( 17)

85 ( 21)

-nd

28 ( 8.0)

90

10b

11c

12c

14d

15e

17f

19 g

20 g

21a

22a

23b

24b

25c

29e

31f

33 g

[A]

[B]

[C]

-nd

25 ( 5.4)

57 ( 11)

44 ( 2.9)

92

25 ( 2.1)

-nd

21 ( 0.5)

-nd

4.9 ( 0.2)

6.3 ( 1.7)

-nd

26 ( 8.5)

67 ( 0.071)

70 ( 40)

9.5 ( 0.1)

27 ( 2.9)

21 ( 9.8)

24 ( 3.7)

-nd

34 ( 7.2)

-nd

42 ( 6.3)

-nd

2.6 ( 0.3)

3.3 ( 0.3)

40 ( 2.1)

44 ( 2.2)

2.0 ( 0.3)

3.3 ( 1.6)

0.6 ( 0.4)

5.1 ( 0.6)

1.8 ( 0.3)

-nd

40 ( 1.4)

3.0 ( 0.4)

14 ( 1.5)

0.26 ( 0.12)

3.5 ( 1.3)

7.0 ( 0.5)

-nd

3.5 ( 0.8)

7.5 ( 2.6)

-nd

1.9 ( 0.2)

1.4 ( 0.1)

0.23 ( 0.05)

15 ( 2.3)

22 ( 5.5)

2.0 ( 0.5)

26 ( 5.3)

23 ( 3.1)

1.8 ( 0.7)

[A]: cisplatin, [B]: etoposide, [C]: camptothecin

^aValues are given in µM and are means of two to four experiments; standard deviation is given in parenthe-

ses. -nd=not displayed (>100 µM)

breast HBL-100, cervix HeLa and lung SW1573 cell line

inhibitory potentials of this compound are almost near to

that of control cisplatin drug. The compound is etoposide

equivalent in the inhibition of breast T-47D and colon WiDr

cell lines. Compound 29e showed similar activity against

same cell lines. In addition, etoposide-comparable resistiv-

ity of 29e was found against breast A549 and cervix HeLa

cell lines, with GI₅₀values 2.9 and 3.3 μM, respectively.

The breast HBL-100 and lung SW1573 cell line inhibitory

powers of the compound on the other hand are comparable

to that of cisplatin reference drug. Other compounds which

are notable in the breast A549 cell line inhibitory powers

include 8a, 10b, 12c, 17f, 20g, 22a and 33g, registering GI₅₀

values in the 3.9–10 μM range. While compound 8a addi-

tionally showed lung SW1573 cell line inhibition, both 12c

and 22a showed cervix HeLa cell line inhibition, comparable

to that of clinically used etoposide drug. Additional resistiv-

ity of compound 20g was found, near to that of etoposide

against cervix HeLa with 13 μM GI₅₀values and more than

etoposide against lung SW1573 cell lines, with 9.5 μM GI₅₀

values. Finally, compound 21a revealed activity against

T-47D cell line superior to that of cisplatin and etoposide

and against WiDr cell line very close to cisplatin and supe-

rior to etoposide control drug.

Figure 3 shows the structure activity relationship studies

of the compounds. Nature of moiety attached to C-3, C-8

and C-11 carbons of the dibenzo[b,e][1,4] diazepin-1-one

framework found efective to tune the bioactivity of this

skeleton. In general, dimethyl groups at C-3 carbon enhance

the antiproliferative activity. Benzoyl moiety at C-8 carbon

has little efect, in combination with p-Cl-phenoxy at C-11

carbon. With simple phenoxy at C-11 carbon and benzoyl at

C-8 carbon, it displayed good resistivity against lung A549,

breast HBL-100, cervix HeLa and lung SW1573 cell lines.

The C-11-tethered p-Cl-phenylsulfanyl skeleton, however,

displayed good bioactivity irrespective of the presence of

C-8 benzoyl or C-3 methyl moieties. Benzylsulfanyl at C-11

carbon confers the skeleton with the similar trend of enhanc-

ing bioactivity, in combination with either C-3 methyl or

C-8 benzoyl groups. Methyl at C-3 and benzoyl at C-8 in

heterocycles have profound efect on pharmaceutical prop-

erties. Phenoxy, p-Cl-phenoxy and (p-Cl-phenyl/benzyl)

sulfanyl at C-11 carbon conferred the heterocycles with an

excellent activity, even on line with that of clinically used

1 3

Molecular Diversity

Fig. 3 Structure–activity relationship studies of pyrazolyl-dibenzo[b,e][1,4] diazepinone scafolds

drugs. Similar conclusion can be made from the antimicro-

bial activity profles of compounds 25c, 26c, 29e and 30e.

the compounds were found to sit comfortably in the active

sites just like etoposide, but when the docking pose of the

etoposide and these two compounds were studied relative

to the DNA, then it could be observed that the hydrogen

bond distances between the DNA and the test compounds

were found to be more in comparison to the hydrogen bond

distance between the etoposide and the DNA. The cutof

value for the hydrogen bonding was kept at 5 Å. As shown in

Fig. 4A, DNA (DT9) is making a hydrogen bond with etopo-

side with a distance of 3.739 Å. Here, oxygen of carbonyl

group of thymine, part of DNA (DT9), is making hydrogen

bond with the hydroxyl group present on pyranose ring of

the etoposide. As shown in Fig. 4B, compound 25c is mak-

ing a hydrogen bond with DNA (DG10) with a distance of

4.515Å. Oxygen of carbonyl group of guanine, a part of

DNA, is making a hydrogen bond with –NH group present in

the central diazepine ring of compound 25c. As for as com-

pound 29e is concerned, it does not form any hydrogen bond

with the DNA (Fig. 4c); however, it did show hydrogen bond

with DNA (DG14) when the cutof value was relaxed to 8.5

Å. A higher activity of compound 25c over compound 29e is

also refected through their docking scores (Table 6). Com-

pound 25c showed a docking score (−1.37) which is better

than the docking score (−0.95) of compound 29e. Etoposide

showed a docking score of −3.59 which is far better than

the docking scores of both of these compounds. Binding

energy was also recorded for these compounds, and it was

observed that etoposide showed much less binding energy

(− 70.81 kcal/mole) as compared to both the compounds

25c and 29e, i.e., −31.78 kcal/mole and − 25.97 kcal/mole,

respectively.

Molecular modeling

The outcome of the antiproliferative screening test for the

test compounds indicated that compounds 25c and 29e

showed activity close to that of etoposide, a known topoi-

somerase II inhibitor. The activity was found to be even bet-

ter than etoposide in HeLa, SW1573, T-47D and WiDr cell

lines. Structurally similar type of compounds has already

been reported to sho w topoisomerase I inhibitory activity

in the literature [108–113]. In comparison to camptothecin

a known topoisomer ase I inhibitor, these two compounds

showed signifcantly good activity but lesser than that of

camptothecin. Considering their noticeable activity in cell

line assay in comparison to the known topoisomerase I and

II inhibitors and the literature reports of topoisomerase I

inhibitory activity of structurally similar compounds, we

were curious to know about the possible binding of these

compounds in the active sites of topoisomerase I as well

as II.

Docking studies were performed for compounds 25c and

29e along with etoposide in the active site of human topoi-

somerase II alpha as per previously reported protocol [112,

113]. The crystal structure having PDB ID: 5GWK (human

topoisomerase II alpha complexed with DNA and etoposide)

was downloaded from rcsb.org. It was aimed to study the

binding interactions of compounds 25c and 29e with the

enzyme in comparison to the standard drug etoposide. Some

interesting points were observed in this docking study. Both

1 3

Molecular Diversity

Compounds 25c and 29e and camptothecin were also

docked in the active site of topoisomerase I (having PDB

ID: 1T8I) resulting into docking scores of − 6.26, − 6.06

and − 9.27, respectively. Interestingly docking scores for

these compounds for topoisomerase I are better than those of

topoisomerase II. Experimental cell line inhibition of these

compounds was also found to be better than etoposide but

lesser than that of camptothecin. From these results, it could

be concluded that these compounds could be acting as mix-

type of inhibitors leading to inhibition of both the enzymes.

However, before reaching to any conclusion, enzyme bind-

ing studies (with topoisomerase I and II) would be necessary

to confrm this observation.

Conclusions

In conclusion, a library of several new antiproliferative

molecular templates, all of which contain central diazepine

core unit which is tethered to diferent pyrazol motifs, have

been synthesized by MCR protocol which is promoted by

indium chloride in acetonitrile at room temperature. The

method is highly efcient and required no chromatography

to isolate desired products. Heterocycles 25c, 26c, 29e and

30e among all new pyrazolyl-dibenzo[b,e] [1,4]diazepinone

scafolds revealed promising multibacterial resistance pow-

ers. Compounds 25c and 29e additionally showed good to

moderate cervix HeLa, lung SW1573, breast T-47D and

colon WiDr human tumor cell line inhibitory efects. Pyra-

zolyl-dibenzo[b,e][1,4] diazepinones which bear benzoyl at

C-8 or (aryl-ether)/(benzylsulfanyl) at C-11 represent other

signifcant scafolds.

Experimental

Chemistry

Materials and methods

All the solvents and reagents were used as received from the

commercial sources. Melting points of the compounds were

taken on μThermocal₁₀and are uncorrected. IR spectra were

recorded on a Shimadzu FT-IR 8401 spectrometer using KBr

Fig. 4 Docking poses of a etoposide; b compound 25c and c com-

pound 29e relative to DNA in the active site of human topoisomerase

II alpha

disks, expressed in wave numbers (cm⁻¹). ¹H NMR and ¹³

C

Table 6 Details of the docking

Compounds

Glide score

Binding energy (kcal/ No. of H bonds with Distance of H

score, binding energy and

hydrogen bonding

mole)

DNA

bonds (Å)

Etoposide

25c

29e

−3.59

−1.37

−0.95

−70.81

−31.78

−25.97

1

0

3.739

4.515

–

1 3

Molecular Diversity

NMR spectra were recorded on a Bruker Avance 400 spec-

trometer operating at 400 MHz for ¹H NMR and 100 MHz

for ¹³C NMR as solutions in DMSO-d₆, unless and otherwise

indicated. Chemical shifts are expressed in parts per million

(ppm, d) and referenced to the residual protic solvent. Cou-

pling constants are expressed in Hertz (Hz). Symbol letters

used for showing splitting pattern of the ¹H NMR peak are

s; for singlet, d; for doublet, t; for triplet, q; for quartet; and

m; for multiplet. The degree of substitution (C, CH, CH₂

and CH₃) was determined by the APT method. ESI mass

spectra were measured on a Shimadzu LCMS-2010 spec-

trometer. TLC was performed on Merck 60 F₂₅₄pre-coated

silica plates, and spots were detected either by means of UV

(254 nm, 366 nm) light exposure or permanganate solution

[KMnO₄(3 g), K₂CO₃(20 g), NaOH (5 mL, 5% in H₂O),

H₂O (300 mL)] or 2,4-dinitrophenylhydrazine solution [2,4-

DNP (12 g), conc. H₂SO₄(6 mL) and water (8 mL), EtOH

(20 mL)] interactions.

(25 mL), with 10–15 min. Additional stirring at room tem-

perature resulted in sodium salt of aldehyde. Some 13 mmol

of respective alkyl(1.55 mL of benzyl bromide, or 1.12 mL

of allyl bromide) was added with the stirring 15–20 min

extra and baseline spot for sodium salt of aldehyde in TLC

was monitored, using a 2.0:8.0 EtOAc: n-Hexane mixture

as mobile phase. Baseline spot of sodium salt of aldehyde

disappeared when desired product was formed. The reaction

mass was poured into ice-cooled water, and solid product

formed was simply fltered and washed with water. Finally,

product was received in highly pure form without further

purifcation (85–95% yield).

5‑(Allyl sulfanyl)‑3‑methyl‑1‑phenyl‑1H‑pyrazole‑4‑car‑

baldehyde, 2f White Solid; yield 2.36 g, 91%; m.p.

58–60 °C; R_f[30% EtOAc/n-Hexane] 0.45; IR (KBr) ν_max

/

cm⁻¹= 3050(Ar–CH), 1686(−C=O), 1587(C=N), 1545

1

(Ar–C =C), 1286(Ar–CH₃), 812(C–H) cm⁻¹; H NMR

(400 MHz; DMSO-d₆) δ 2.44 (s, 3H, 3–CH₃), 3.34 (d,

J = 7.6 Hz, 1H, 3′–CH), 4.80 (d, J= 1.2 Hz, 1H, 1′–CH),

4.84 (d, J = 1.2 Hz, 1H, 1′–CH), 4.92 (t, J = 8.8 Hz, 1H,

3′–CH), 5.59 (m, 1H, 2′–CH), 7.55 (m, 5H, Ar–H), 9.98

(s, 1H,–CHO); ¹³C NMR (100 MHz; DMSO-d₆) δ 13.1,

38.5, 118.7, 123.0, 126.1, 128.9, 129.0, 132.8, 138.0, 140.0,

150.2, 186.2; Anal. Calcd for C₁₄H₁₄N₂OS: C, 65.09; H,

5.46; N, 10.84; Found: C, 65.15; H, 5.59; N, 11.02; m/z

(ESI) 259 [M+H]⁺.

Experimental procedure

Synthesis of 5‑chloro‑3‑methyl‑1‑phenyl‑1H‑pyrazole‑4‑car‑

baldehydes, 1a The title compound was prepared by

Vilsmeier–Haack reaction, which is reported elsewhere

[81]. Stirring 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one

(0.058 mol, 10.0 g) with Vilsmeier–Haack reagent, i.e., a

yellow chloroiminium salt, derived from DMF (0.174 mol,

13.3 mL) and POCl₃(0.287 mol, 25.86 mL), was observed

initially at 0 °C and then refuxed at 85 °C, to complete its

conversion into 5-chloro-3-methyl-1-phenyl-1H-pyrazol-

4-carbaldehyde 1a was monitored by the TLC. Cream white

solid product precipitated out after the reaction mass was

added to ice-cooled water and received through ordinary

fltration method (Yields 80–85%, m.p. 146‒148 °C).

3‑Methyl‑1‑phenyl‑5‑(benzylsulfanyl)‑1H‑pyrazole‑4‑car‑

baldehyde, 2 g White Solid; yield 3.22 g, 95%; m.p.

52–54 °C; R_f[30% EtOAc/n-Hexane] 0.52; IR (KBr) ν_max

/

cm⁻¹=3065(Ar–CH), 1687(C=O), 1590(C=N), 1535(−

C=O), 1301(Ar–CH₃), 852(C–H) cm⁻¹; ¹H NMR (400 MHz;

DMSO-d₆) δ 2.38 (s, 3H, 3–CH₃), 3.91 (s, 2H, S–CH₂–Ph),

6.96–7.52 (m, 10H, Ar–H), 9.62 (s, 1H, –CHO); ¹³C NMR

(100 MHz; DMSO-d₆) δ 13.1, 123.2, 126.0, 127.4, 128.3,

128.7, 128.8, 128.9, 136.4, 137.9, 139.8, 150.1, 185.7; Anal

Calcd for C₁₇H₁₄N₂OS: C, 69.36; H, 4.79; N, 9.52; Found:

C, 69.54; H, 4.88; N, 9.40; m/z (ESI) 295 [M+H]⁺.

Synthesis of 5‑(aryloxy/sulfanyl)‑3‑methyl‑1‑phe‑

nyl‑1H‑pyrazole‑4‑carbaldehydes, 2a–e A respective phe-

nol/thiophenol (10.0 mmol) derivative was added portion-

wise to a stirred suspension of K₂CO₃(2.07 g, 1.5 mmol) in

dry DMF (25 mL), followed by addition of 5-chloro-3-me-

thyl-1-phenyl-1H-pyrazole-4-carbaldehyde 1a (2.205 g,

10.0 mmol) in small portions and refux (80 °C). The pro-

gress of the reaction was monitored by TLC using a 2.0:8.0

EtOAc: n-Hexane mixture as mobile phase. After comple-

tion, the reaction mass was poured into ice-cooled water

and the solid product formed after few minutes which can

be isolated by ordinary fltration method (Yields 85–95%).

Synthesis of 11‑(5‑(aryl/alkyl‑oxy/sulfanyl)‑3‑me‑

thyl‑1‑phenyl‑1H‑pyrazol‑4‑yl)‑2,3,4,5,10,11‑hexahy‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑ones and their 8‑ben‑

zoyl and/or 3, 3‑dimethyl‑derivatives, 7a–34 g A mixture

containing 1.0 mmol of benzene-1,2-diamine 3 (0.108 g of

3 or 0.212 g of 4) and 1.0 mmol of 1,3-cyclohexandione 5

(0.112 g of 5 or 0.140 g of 6) was stirred for a few minutes

in dry acetonitrile containing InCl₃catalyst in 25 mmol %

load. Then equimolar amount of pyrazole-4-carbaldehyde 2a

(0.22 g, 1 mmol) was added, and its consumption against 3

and 5 into desired products 7a was monitored by TLC using

an 8.0:2.0 EtOAc: n-hexane mixture as mobile phase. It took

5.5–6.0 h to complete the reaction. The solid product thus

Synthesis of 5‑(alkyl‑sulfanyl)‑3‑methyl‑1‑phenyl‑1H‑pyra‑

zole‑4‑carbaldehydes, 2f‑g Some fnely crushed 30 mmol

of sodium sulfde (2.34 g) was added portion-wise to a

stirred suspension of 5-chloro-3-methyl-1-phenyl-1H-pyra-

zole-4-carbaldehyde 1a (2.205 g, 10 mmol) in dry DMSO

1 3

Molecular Diversity

appeared in the reaction mass was fltered and washed thrice

by three 5 mL portions of acetonitrile. All desired products

7a–34g were received quantitatively (60–90%) in pure form

and required no further purifcation.

2.04 (d, J=6.0 Hz, 1H, 3–CH₂), 2.39 (s, 3H, Pyrazol–CH₃),

5.52 (d, J = 5.2 Hz, 1H, 10–NH), 5.69 (d, J= 5.2 Hz, 1H,

11–CH), 6.41–7.26 (m, 13H, Ar–H), 8.79 (s, 1H, 5–NH);

¹³C NMR (100 MHz; DMSO-d₆) δ 13.5, 21.0, 31.0, 36.1,

48.5,110.3, 112.3, 116.2, 117.4, 120.7, 120.9, 121.5, 121.6,

122.9, 126.7, 126.7, 129.5, 133.4, 138.0, 139.0, 143.7,

148.6, 155.2, 156.4, 192.5; Anal Calcd for C₂₉H₂₅ClN₄O₂:

C, 70.08; H, 5.07; N, 11.27; Found: C, 70.22; H, 5.19; N,

11.39; m/z (ESI) 497.0 [M+H]⁺.

1 1 ‑ ( 3 ‑ M e t h y l ‑ 5 ‑ p h e n o x y ‑ 1 ‑ p h e n y l ‑ 1 H‑ p y r a ‑

zole‑4‑yl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 7a White Solid; yield 403 mg, 87%; m.p.

210–212 °C; R_f[80% EtOAc/n-Hexane] 0.55; IR (KBr)

ν_max/cm⁻¹=3354 & 3248 (Ar–NH), 3045(Ar–CH), 2947(–

CH₂–), 1821(C=O), 1666 (C=N), 1581 (Ar–C=C), 1327

(C–O–C), 840 (Ar–CH) cm⁻¹; ¹H NMR (400 MHz; DMSO–

d₆) δ 1.09 (d, J = 5.6, 1H, 3–CH₂), 1.43 (dd, J = 4.8 Hz,

1H, 4–CH₂), 1.55 (dd, J = 4.8 Hz, 1H, 4–CH₂), 1.71 (dd,

J=5.2 Hz, 1H, 3–CH₂), 1.95 (dd, J=5.2 Hz, 1H, 2–CH₂),

2.32 (t, J=8.6 Hz, 1H, 2–CH₂), 2.38 (s, 3H, Pyrazol–CH₃),

5.51 (d, J = 5.6 Hz, 1H, 10–NH), 5.62 (d, J= 5.2 Hz, 1H,

11–CH), 6.41–7.29 (m, 13H, Ar–H), 8.76 (s, 1H, 5–NH);

¹³C NMR (100 MHz; DMSO– d₆) δ 13.5, 20.9, 31.0, 36.0,

48.5, 110.3, 112.4, 114.4, 120.7, 120.9, 121.3, 121.6, 122.8,

122.9, 126.4, 129.4, 129.8, 133.6, 138.2, 139.1, 144.0 148.5,

156.4, 156.4, 192.5; Anal Calcd for C₂₉H₂₆N₄O₂: C, 75.30;

H, 5.67; N, 12.11; O, 6.92 Found: C, 75.47; H, 5.89; N,

12.36; O, 7.25; m/z (ESI) 463.4 [M+H]⁺.

11‑(3‑Methyl‑1‑phenyl‑5‑(phenylsulfanyl)‑1H‑pyra‑

zol‑4‑yl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 13d White Solid; yield 417 mg, 87%; m.p.

224–226 °C; R_f[80% EtOAc/n–Hexane] 0.62; IR (KBr) ν_max

/

cm⁻¹=3410 (Ar–NH), 3040 (Ar–CH), 2964 (–CH₂–), 1708

(−C=O), 1659 (C=N), 1512 (Ar–C=C), 1298 (C–O–C), 840

(Ar–CH) cm⁻¹; ¹H NMR (400 MHz; DMSO-d₆) δ 1.53 (d,

J=8 Hz, 1H, 4–CH₃), 1.77 (d, J=8 Hz, 2H, 3–CH₂), 2.07

(q, J=8 Hz, 1H, 4–CH₂), 2.20 (s, 3H, Pyrazol–CH₃), 2.37

(d, J = 8 Hz, 1H, 2–CH₂), 2.58 (s, 1H, 2–CH₂), 5.30 (d,

J=5.2 Hz, 1H, 10–NH), 5.76 (d, J=5.2 Hz, 1H, 11–CH),

6.47–7.28 (m, 14H, Ar–H), 8.95 (s, 1H, 5–NH); ¹³C NMR

(100 MHz; DMSO-d₆) δ 13.1, 21.4, 31.4, 36.4, 50.8, 109.7,

120.8, 121.3, 121.8, 123.1, 125.4, 126.1, 126.3, 127.9, 128.9,

129.4, 129.9, 133.6, 136.2, 138.7, 139.4, 148.3, 157.1, 192.9;

Anal Calcd for C₂₉H₂₆N₄OS: C, 72.78; H, 5.48; N, 11.71;

Found: C, 72.92 H, 5.53; N, 11.83; m/z (ESI) 479.9 [M+H]⁺.

1 1 ‑ ( 3 ‑ M e t hy l ‑ 1 ‑ p h e ny l ‑ 5 ‑ ( p‑ to l y l ox y ) ‑ 1 H‑ py ra ‑

zole‑4‑yl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 9b White Solid; yield 319 mg, 67%; m.p.

200–202 °C; R_f[80% EtOAc/n-Hexane] 0.54; IR (KBr) ν_max

/

11‑[3‑Methyl‑1‑phenyl‑5‑(phenylsulfanyl)‑1H‑pyrazol‑4‑yl]‑

8‑Benzoyl‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 14d Yellow Solid; yield 431 mg, 74%;

m.p = 214–216 °C; R_f[80% EtOAc/n-Hexane] 0.66; IR

(KBr) ν_max/cm⁻¹= 3410 (Ar–NH), 3047 (Ar–CH), 2928

(–CH₂–), 1708 (–C=O), 1680 (–C=O) 1602 (C=N), 1481

cm⁻¹=3450 (Ar–NH), 3020 (Ar–CH), 2957(−CH₂−), 2780

(O–CH₃), 1811 (C=O), 1609 (C=N), 1593 (Ar–C=C), 1250

(C–O–C), 848 (Ar–CH) cm⁻¹; ¹H NMR (400 MHz; DMSO-

d₆) δ 1.18 (t, J=0.0 Hz, 1H, 4–CH₂), 1.54 (d, J=15.6 Hz,

2H, 2–CH₂), 1.79 (s, 1H, 4–CH₂), 1.98 (d, J = 12.4 Hz,

2H, 3–CH₂), 2.15 (s, 3H, Pyrazol–CH₃), 2.25 (s, 3H, Ph–

CH₃), 5.52 (d, J = 5.2 Hz, 1H, 10–NH), 5.59 (s, 1H, 11–

1

(Ar–C=C), 1293 (C–O–C), 850 (Ar–CH) cm–¹; H NMR

(400 MHz; DMSO-d₆) δ 1.48 (s, 1H, 4–CH₂), 1.77 (d,

J=11.6 Hz, 2H, 2–CH₂) 2.10 (d, J=6.4 Hz, 1H, 4–CH₂),

2.29 (s, 1H, 3–CH₂), 2.35 (s, 3H, Pyrazol–CH₃), 2.52 (d,

J = 12 Hz, 1H, 3–CH₂), 5.83 (d, J= 4.8 Hz, 1H, 10–NH),

6.31 (d, J=5.2 Hz, 1H, 11–CH), 6.59–7.64 (m, 18H, Ar–H),

9.17 (s, 1H, 5–NH); Anal Calcd for C₃₆H₃₀N₄O₂S: C, 74.73;

H, 5.61; N, 9.17; O, 5.24; S, 5.25; Found: C, 74.95; H, 5.86;

N, 9.39; O, 5.49; S, 5.52; m/z (ESI) 583.24 [M+H]⁺.

CH), 6.32–7.23 (m, 13H, Ar–H), 8.75 (s, 1H, 5–NH); ¹³

C

NMR (100 MHz; DMSO-d₆) δ 13.5, 20.4, 20.9, 31.1, 36.0,

48.5, 110.3, 112.3, 114.2, 120.7, 120.9, 121.3, 121.5, 122.8,

126.4, 129.4, 130.1, 131.7, 133.5, 138.3, 139.1, 144.3,

148.4, 154.4, 156.5, 192.5; Anal Calcd for C₃₀H₂₈N₄O₂:

C, 75.61; H, 5.92; N, 11.76; Found: C, 75.50; H, 5.62; N,

11.96; m/z (ESI) 477.2 [M+H]⁺.

11‑[5‑(4‑Chlorophenoxy)‑3‑methyl‑1‑phenyl‑1H‑pyra‑

zol‑4‑yl]‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 11c Creamy White Solid; yield 392 mg,

79%; m.p. 204–206 °C; R_f[80% EtOAc/n-Hexane] 0.42;

IR (KBr) ν_max/cm⁻¹=3420 (Ar–NH), 2989 (–CH₂–), 1824

(C=O), 1624 (C=N), 1587 (Ar–C=C), 1267 (C–O–C), 877

11‑(5‑((4‑Chlorophenyl) sulfanyl)‑3‑methyl‑1‑phenyl‑1H‑pyra‑

zol‑4‑yl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 15e White Solid; yield 447 mg, 87%; m.p.

220–222 °C; R_f[80% EtOAc/n-Hexane] 0.76; IR (KBr) ν_max

/

cm⁻¹=3302 (Ar–NH), 3070 (Ar–CH), 2954 (–CH₂–), 1874

(–C=O), 1735 (C=N), 1581 (Ar–C=C), 1280 (C–O–C), 833

(Ar–CH) cm⁻¹; ¹H NMR (400 MHz; DMSO-d₆) δ 1.59 (s,

1H, 4–CH₂), 1.80 (s, 2H, 3–CH₂) 2.12 (d, J=13.2 Hz, 1H,

4–CH₂), 2.42 (s, 3H, Pyrazol–CH₃), 2.61 (s, 1H, 2–CH₂), 2.64

1

(Ar–CH) cm⁻¹; H NMR (400 MHz; DMSO-d₆) δ 1.18

(s, 1H, 3–CH₂), 1.53 (d, J = 2.4 Hz, 2H, 2–CH₂), 1.61 (d,

J = 3.2 Hz, 1H, 4–CH₂), 1.82 (t, J = 0.8 Hz, 1H, 4–CH₂),

1 3

Molecular Diversity

(s, 1H, 2–CH₂), 5.42 (s, 1H, 10–NH), 5.76 (s, 1H, 11–CH),

6.54–7.48 (m, 13H, Ar–H), 8.96 (s, 1H, 5–NH); ¹³C NMR

(100 MHz; DMSO– d₆) δ 13.1, 21.5, 31.5, 36.4, 50.4, 109.7,

120.8, 121.3, 121.9, 123.2, 125.5, 127.0, 128.0, 128.0, 128.9,

129.2, 130.0, 130.6, 133.6, 135.2 138.8, 139.3, 148.4, 157.2,

192.9; Anal Calcd for C₂₉H₂₅ClN₄OS: C, 67.89; H, 4.91; Cl,

6.91; N, 10.92; O, 3.12; S, 6.25 Found: C, 67.95; H, 5.15; Cl,

6.75; N, 11.25; O, 3.32; S, 6.53; m/z (ESI) 514.2 [M+H]⁺.

(400 MHz; DMSO-d₆) δ 0.77(s, 3H, 3–CH₃), 0.91(s, 3H,

3–CH₃), 1.08 (s, 3H, Pyrazol–CH₃), 1.33 (d, J = 16 Hz,

1H, 4–CH₂), 1.46 (d, J = 16.4 Hz, 1H, 4–CH₂), 1.79 (d,

J=16 Hz, 1H, 2–CH₂), 2.02 (d, J=16 Hz, 1H, 2–CH₂), 5.59

(d, J=5.6 Hz, 1H, 10–NH), 6.49 (d, J=6.0 Hz, 1H, 11–CH),

6.37–7.69 (m, 18H, Ar–H), 8.91 (s, 1H, 5–NH); ¹³C NMR

(100 MHz; DMSO-d₆) δ 13.4, 26.1, 30.3, 31.4, 44.0, 47.9,

49.4, 108.8, 112.4, 114.3, 120.7, 121.4, 122.8, 122.9, 125.3,

126.7, 128.8, 129.1, 129.4, 129.6, 129.9, 132.2, 132.5, 138.1,

138.7, 143.6, 143.9, 148.7, 154.1, 156.3, 192.4, 194.7; Anal

Calcd for C₃₈H₃₄N₄O₃: C, 76.75; H, 5.76; N, 9.42; Found: C,

76.96; H, 5.85; N, 9.60; m/z (ESI) 595 [M+H]⁺.

11‑(5‑(Benzylsulfanyl)‑3‑methyl‑1–phenyl‑1H‑pyra‑

zol‑4‑yl)‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 19 g Yellow Solid; yield 316 mg, 64%;

m.p. 214–216 °C; R_f[80% EtOAc/n-Hexane] 0.57; IR (KBr)

νmax/cm–¹=3300 (Ar–NH), 3065 (Ar–CH), 2870 (–CH₂–),

1730 (–C=O), 1689 (C=N), 1571 (Ar–C=C), 1288 (C–O–

C), 846 (Ar–CH) cm⁻¹; ¹H NMR (400 MHz; DMSO-d₆) δ

1.85 (s, 3H, Pyrazol–CH₃), 1.96 (sq, 2H, 3–CH₂), 2.27 (q,

J=6 Hz, 2H, 4–CH₂), 2.73 (q, 2H, J=6 Hz, 2–CH₂), 3.87

(q, 2H, J = 4 Hz, –CH₂–Ph), 5.17 (d, J = 5.6 Hz, 1H, 10–

NH), 5.94 (d, J=4.8 Hz, 1H, 11–CH), 6.53–7.39 (m, 14H,

Ar–H), 9.07 (s, 1H, 5–NH); ¹³C NMR (100 MHz; DMSO–

d₆) δ 12.7, 21.4, 31.1, 36.3, 50.9, 109.5, 120.1, 120.7, 121.5,

122.7, 125.1, 127.1, 127.1, 128.3, 128.4, 128.5, 128.7,

131.1, 132.7, 136.7, 138.5, 139.2, 146.3, 156.5, 192.7; Anal

Calcd for C₃₀H₂₈N₄OS C, 73.14; H, 5.73; N, 11.37; Found:

C, 73.38; H, 5.96; N, 11.55; m/z (ESI) 493.8 [M+H]⁺.

11‑[3‑Methyl‑5‑(4‑methylphenoxy)‑ 1‑phenyl‑1H‑pyra‑

zol‑4‑yl]‑ 3, 3‑Dimethyl‑2,3,4,5,10,11‑hexahy‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one, 23b White Solid;

yield 389 mg, 77%; m.p. 198–200 °C; R_f[80% EtOAc/n-

Hexane] 0.50; IR (KBr) ν_max/cm⁻¹=3340 (Ar–NH), 3165

(Ar–CH), 2962 (–CH₂–), 1732 (–C=O), 1585 (C=N),

1

1571 (Ar–C=C), 1280 (C–O–C), 849 (Ar–CH) cm⁻¹; H

NMR (400 MHz; DMSO-d₆) δ 0.77 (s, 3H, 3–CH₃), 0.92

(s, 3H, 3–CH₃), 1.29 (d, J=16.0 Hz, 1H, 2–CH₂), 1.48 (d,

J=16.0 Hz, 1H, 2–CH₂), 1.74 (d, J=15.6 Hz, 1H, 4–CH₂),

2.03 (d, J = 16.0 Hz, 1H, 4–CH₂), 2.17 (s, 3H, Pyrazol–

CH₃), 2.38 (s, 3H, Ph–CH₃), 5.50 (d, J = 5.2 Hz, 1H, 10–

NH), 5.56 (s, 1H, 11–CH), 6.29–7.23 (m, 13H, Ar–H), 8.66

(s, 1H, 5–NH); ¹³C NMR (100 MHz; DMSO-d₆) δ 13.5,

20.3, 26.0, 30.7, 31.2, 44.2, 48.4, 49.4, 109.1, 112.4, 114.2,

120.7, 120.9 120.2, 121.6, 122.8, 126.4, 129.4, 130.2, 131.6,

133.7, 138.3, 139.0, 144.2, 148.5, 154.1, 154.4, 192.2; Anal

Calcd for C₃₂H₃₂N₄O₂: C, 76.16; H, 6.39; N, 11.10; Found:

C, 76.35; H, 6.52; N, 10.98; m/z (ESI) 505.4 [M+H]⁺.

11‑(5‑(Benzylsulfanyl)‑3‑methyl‑1‑phenyl‑1H‑pyrazol‑4‑yl)‑

8‑Benzoyl‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]

diazepin‑1‑one, 20 g Yellow Solid; yield 411 mg, 69%; m.p.

184–186 °C, R_f[80% EtOAc/n–Hexane] 0.57; IR (KBr) ν_max

/

cm⁻¹=3410 (Ar–NH), 3040 (Ar–CH), 2964 (–CH₂–), 1708

(–C=O), 1659 (–C=N), 1460 (Ar–C=C), 1258 (−C–O–C−),

850 (Ar–CH) cm⁻¹; ¹H NMR (400 MHz; DMSO-d₆) δ 2.01

(s, 2H, 4–CH₂), 2.26 (s, 3H, pyrazol–CH₃), 2.71 (s, 2H, 2–

CH₂), 3.15 (m, 2H, 3–CH₂), 4.82 (t, 2H, J=1.2 Hz, –CH₂–

Ph), 5.89 (d, J=4.8 Hz, 1H, 10–NH), 6.19 (d, J=4.8 Hz,

1H, 11–CH), 6.78–7.65 (m, 14H, Ar–H), 9.23 (s, 1H, 5–

NH); ¹³C NMR (100 MHz; DMSO-d₆) δ 13.14, 21.59, 31.54,

36.50, 50.50, 50.89, 108.67, 120.48, 120.84, 121.30, 123.38,

123.46, 126.26, 126.34, 126.71, 127.51, 127.65, 127.85,

128.37, 128.78, 130.16, 132.11, 133.20, 138.97, 141.63,

142.12, 147.28, 155.78, 156.05, 192.36, 194.24; Anal Calcd

for C₃₇H₃₂N₄O₂S C, 74.47; H, 5.41; N, 9.39; Found: C,

74.50; H, 5.49; N, 9.51; m/z (ESI) 596.74 [M+H] ⁺.

8 ‑ B e n z o y l ‑ 3 , 3 ‑ d i m e t h y l ‑ 1 1 ‑ ( 3 ‑ m e t h y l ‑ 1 ‑ p h e ‑

nyl‑5‑(p‑tolyloxy)‑1H‑pyrazol‑4‑yl)‑2,3,4,5,10,11‑hexahy‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one, 24b White Solid;

yield 438 mg, 72%; m.p. 284–286 °C; R_f[80% EtOAc/n-

Hexane] 0.46, IR (KBr) ν_max/cm⁻¹=3325 & 3294 (Ar–NH),

2995 (Ar–CH), 2954 (–CH₂–), 1722 (–C=O), 1589 (C=N),

1

1567 (Ar–C=C), 1287 (C–O–C), 846 (Ar–CH) cm⁻¹; H

NMR (400 MHz; DMSO-d₆) δ 0.79 (s, 3H, 3–CH₃), 0.92

(s, 3H, 3–CH₃), 1.42 (m, J=17.2 Hz, 2H, 4–CH₂), 1.82 (d,

J=14.8 Hz, 1H, 2–CH₂), 2.03 (d, J=16.4 Hz, 1H, 2–CH₂),

2.12 (s, 3H, Pyrazol–CH₃), 2.43 (s, 3H, Ph–CH₃), 5.58 (d,

J=4.8 Hz, 1H, 10–NH), 6.47 (d, J=5.2 Hz, 1H, 11–CH),

6.16–7.68 (m, 17H, Ar–H), 8.88 (s, 1H, 5–NH); ¹³C NMR

(100 MHz; DMSO-d₆) δ 13.5, 20.3, 26.2, 30.3, 31.4, 44.0,

47.9, 49.4, 108.8, 11.5, 112.3, 114.1, 114.9, 120.7, 121.4,

122.9, 123.6, 125.3, 126.6, 128.9, 129.5, 130.2, 131.7,

132.3, 138.2, 138.8, 139.6, 143.8, 148.7, 154.2, 156.4,

192.4, 194.6; Anal Calcd for C₃₉H₃₆N₄O₃: C, 76.95; H, 5.96;

N, 9.20;; Found: C, 76.89; H, 6.12; N, 9.28; m/z (ESI) 609.5

[M+H]⁺.

11‑(3‑Methyl‑5‑phenoxy‑1‑phenyl‑1H‑pyrazol‑4‑yl)‑ 8‑Ben‑

zoyl‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e]

[1,4]diazepin‑1‑one, 22b Yellow Solid; yield 410 mg, 69%;

m.p. 222–224 °C; R_f[80% EtOAc/n-Hexane] 0.57; IR (KBr)

ν_max/cm⁻¹= 3300 & 3224 (Ar–NH), 3010 (Ar–CH), 2960

(–CH₂–), 1820 (–C=O), 1780 (C=0), 1648 (C=N), 1540

1

(Ar–C=C), 1320 (C–O–C), 822 (Ar–CH) cm⁻¹; H NMR

1 3

Molecular Diversity

11‑(5‑(4‑Chlorophenoxy)‑3‑methyl‑1‑phenyl‑1H‑pyra‑

zo l ‑ 4 ‑ y l ) ‑ 3 , 3 ‑ d i m e t hy l ‑ 2 , 3 , 4 , 5 , 1 0 , 1 1 ‑ h ex a hy‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one, 25c White Solid;

yield 457 mg, 87%; m.p. 176–178 °C; R_f[80% EtOAc/n-

Hexane] 0.47; IR (KBr) ν_max/cm⁻¹=3327 & 3290 (Ar–NH),

3002 (Ar–CH), 2987 (–CH₂–), 1724 (–C=O), 1590 (C=N),

1H, 10–NH), 6.29 (d, J = 5.2 Hz, 1H, 11–CH), 6.59–7.64

(m, 18H, Ar–H), 9.12 (s, 1H, 5–NH); ¹³C NMR (100 MHz;

DMSO– d₆) δ 13.0, 26.6, 30.0, 31.7, 44.5, 49.7, 49.9, 108.5,

120.9, 123.1, 125.4, 125.5, 125.9, 126.8, 128.0, 128.7,

128.9, 129.1, 129.3, 129.5, 130.1. 132.1, 132.5, 136.3,

138.6, 139.4, 143.4, 148.7, 154.6, 192.8, 194.5; Anal Calcd

for C₃₈H₃₄N₄O₂S: C, 74.73; H, 5.61; N, 9.17; O, 5.24; S,

5.25; Found: C, 74.95; H, 5.86; N, 9.39; O, 5.49; S, 5.52;

m/z (ESI) 611.8 [M+H]⁺.

1

1569 (Ar–C=C), 1284 (C–O–C), 845 (Ar–CH) cm⁻¹; H

NMR (400 MHz; DMSO-d₆) δ 0.83 (s, 3H, 3–CH₃), 0.94

(s, 3H, 3–CH₃), 1.38 (s, 1H, 2–CH₂), 1.54 (s, 1H, 2–CH₂),

1.81 (s, 1H, 4–CH₂), 2.09 (s, 1H, 4– CH₂), 2.39 (s, 3H,

Pyrazol–CH₃), 5.51 (s, 1H, 10–NH), 5.64 (s, 1H, 11–CH),

6.39–7.12 (m, 13–H, Ar–H), 8.68 (s, 1H, 5–NH); ¹³C NMR

(100 MHz; DMSO– d₆) δ 13.4, 26.1, 30.5, 31.3, 44.3, 48.5,

49.5, 109.1, 112.4, 116.2, 120.7, 120.9, 121.5, 121.6, 122.9,

126.6, 126.7, 129.5, 129.7, 133.5, 138.0, 139.0, 143.6,

148.7, 154.0, 154.2, 192.2; Anal Calcd for C₃₁H₂₉ClN₄O₂:

C, 70.91; H, 5.57; N, 10.67; Found: C, 70.91; H, 5.57; N,

10.67; m/z (ESI) 526 [M+H]⁺.

11‑(5‑((4‑Chlorophenyl)sulfanyl)‑3‑methyl‑1‑phe‑

nyl‑1H‑pyrazol‑4‑yl)‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one, 29e White Solid;

yield 427 mg, 79%; m.p. 226–228 °C; R_f[80% EtOAc/n–

Hexane] 0.72; IR (KBr) ν_max/cm⁻¹=3319 & 3257 (Ar–NH),

3012 (Ar–CH), 2986 (–CH₂–), 1832 (–C=O), 1790 (C=O),

1580 (C=N), 1579 (Ar–C=C), 1270 (C–O–C), 855 (Ar–CH)

1

cm⁻¹; H NMR (400 MHz; DMSO– d₆) δ 0.93 (s, 3H, 3–

CH₃), 1.02 (s, 3H, 3–CH₃) 1.61 (d, J=14.8 Hz, 1H, 4–CH₂),

1.93 (d, J=15.6 Hz, 1H, 4–CH₂), 2.28 (s, 1H, 2–CH₂), 2.39

(d, J = 15.2 Hz, 1H, 2–CH₂), 2.21 (s, 3H, Pyrazol–CH₃),

5.38 (s, 1H, 10–NH), 5.75 (s, 1H, 11–CH), 6.55–7.48 (m,

13H, Ar–H), 8.91 (s, 1H, 5–NH); ¹³C NMR (100 MHz;

DMSO– d₆) δ13.0, 26.7, 30.0, 31.7, 44.8, 49.8, 50.6, 108.6,

120.8, 121.3, 121.9, 123.2, 125.4, 127.8, 128.0, 129.0,

129.2, 130.1, 130.6, 133.7, 135.3, 138.7, 139.5, 148.5,

154.9, 192.6; Anal Calcd for C₃₁H₂₉ClN₄OS: C, 68.81; H,

5.40; Cl, 6.55; N, 10.35; O, 2.96; S, 5.93; Found: C, 68.99;

H, 5.55; Cl, 6.69; N, 10.40; O, 2.85; S, 6.10; m/z (ESI) 541.1

[M+H]⁺.

11‑(5‑(4‑Chlorophenoxy)‑3‑methyl‑1‑phenyl‑1H‑pyra‑

zol‑4‑yl)‑8‑Benzoyl‑3,3‑dimethyl‑2,3,4,5,10,11‑hexahy‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one, 26c Yellow Solid;

yield 472 mg, 75%; m.p. 186–188 °C; R_f[80% EtOAc/n-

Hexane] 0.39; IR (KBr) ν_max/cm⁻¹= 3322 & 3298 (Ar–

NH), 3015 (Ar–CH), 2979 (–CH₂–), 1824 (–C=O), 1787

(C=O), 1587 (C=N), 1572 (Ar–C=C), 1264 (C–O–C), 849

1

(Ar–CH) cm⁻¹; H NMR (400 MHz; DMSO– d₆) δ 0.84

(s, 3H, 3–CH₃), 0.94 (s, 3H, 3–CH₃), 1.48 (d, J=16.4 Hz,

1H, 4–CH₂), 1.55 (d, J = 16.0 Hz, 1H, 4–CH₂), 1.88 (d,

J=6.0 Hz, 1H, 2–CH₂), 2.11 (d, J=16.0 Hz, 1H, 2–CH₂),

2.39 (s, 3H, Pyrazol–CH₃), 5.59 (d, J = 5.2 Hz, 1H, 10–

NH), 6.54 (d, J=5.6 Hz, 1H, 11–CH), 6.35–7.68 (m, 17H,

Ar–H), 8.91 (s, 1H, 5–NH); ¹³C NMR (100 MHz; DMSO–

d₆) δ 13.4, 26.5, 30.1, 31.5, 44.1, 47.9, 49.5, 109.0, 112.4,

116.1, 120.7, 121.6, 122.8, 125.4, 126.8, 126.9, 128.7,

129.0, 129.5, 129.6, 129.7, 132.2, 132.2, 137.9, 138.7,

143.2, 143.7, 148.8, 154.0, 155.1, 192.4, 194.6; Anal Calcd

for C₃₈H₃₃ClN₄O₃: C, 72.54; H, 5.29; Cl, 5.64; N, 8.91;

Found: C, 72.34; H, 5.45; Cl, 5.86; N, 8.71; m/z (ESI) 630.1

[M+H]⁺.

11‑(5‑((4‑Chlorophenyl)sulfanyl)‑3‑methyl‑1‑phe‑

n y l ‑ 1 H ‑ p y r a z o l ‑ 4 ‑ y l ) ‑ 8 ‑ B e n z o y l ‑ 3 , 3 ‑ d i m e ‑

thyl‑2,3,4,5,10,11‑hexahydro‑1H‑dibenzo[b,e][1,4]diaz‑

epin‑1‑one, 30e Yellow Solid; yield 439 mg, 68%; m.p.

248–250 °C; R_f[80% EtOAc/n–Hexane] 0.64; IR (KBr)

ν_max/cm⁻¹= 3315 & 3258 (Ar–NH), 3015 (Ar–CH), 2988

(–CH₂–), 1834 (–C=O), 1797 (C=O), 1584 (C=N), 1581

1

(Ar–C=C), 1272 (C–O–C), 854 (Ar–CH) cm⁻¹; H NMR

(400 MHz; DMSO– d₆) δ 0.92 (s, 3H, 3–CH₃), 1.01 (s, 3H,

3–CH₃) 1.66 (d, J=15.6 Hz, 1H, 4–CH₂), 1.97 (d, J=16 Hz,

1H, 4–CH₂), 2.18 (d, J=16 Hz, 1H, 2–CH₂), 2.33 (s, 4H,

2–CH₂& Pyrazol–CH₃), 5.79 (d, J = 4 Hz, 1H, 10–NH),

6.39 (d, J=4.4 Hz, 1H, 11–CH), 6.53–7.64 (m, 17H, Ar–H),

9.13 (s, 1H, 5–NH); ¹³C NMR (100 MHz; DMSO– d₆) δ

12.9, 26.9, 29.8, 31.7, 44.5, 49.8, 49.8, 108.6, 120.9, 123.1,

125.5, 125.5, 126.2, 127.5, 128.1, 128.7, 128.9, 129.0,

129.0, 129.5, 130.3, 130.5, 132.1, 132.4, 135.2, 138.6,

139.2, 143.4, 148.8, 154.6, 192.8, 194.4; Anal Calcd for

C₃₈H₃₃ClN₄O₂S: C, 70.74; H, 5.16; Cl, 5.49; N, 8.68; O,

4.96; S, 4.97; Found: C, 70.96; H, 5.39; Cl, 5.75; N, 8.92;

O, 4.78; S, 5.20; m/z (ESI) 646.2 [M+H]⁺.

8 ‑ B e n zoy l ‑ 3 , 3 ‑ d i m e t hy l ‑ 1 1 ‑ ( 3 ‑ m e t hy l ‑ 1 ‑ p h e ‑

nyl‑5‑(phenylsulfanyl)‑1H‑pyrazol‑4‑yl)‑2,3,4,5,10,11‑hex‑

ahydro‑1H‑dibenzo[b,e][1,4]diazepin–1‑one, 28d Yel-

low Solid; yield 526 mg, 86%; m.p. 224–226 °C; R_f[80%

EtOAc/n–Hexane] 0.62; IR (KBr) ν_max/cm⁻¹=3315 & 3250

(Ar–NH), 3014 (Ar–CH), 2982 (–CH₂–), 1830(–C=O),

1788 (C=O), 1579 (C=N), 1577 (Ar–C=C), 1268 (C–O–

1

C), 852 (Ar–CH) cm⁻¹; H NMR (400 MHz; DMSO–

d₆) δ 0.88 (s, 3H, 3–CH₃), 0.99 (s, 3H, 3–CH₃), 1.55 (d,

J = 16 Hz, 1H, 4–CH₂), 1.90 (d, J = 16 Hz, 1H, 4–CH₂),

2.14 (d, J=16.4 Hz, 1H, 2–CH₂), 2.31 (d, J=16.4 Hz, 1H,

2–CH₂), 2.36 (s, 3H, Pyrazol–CH₃), 5.81 (d, J = 5.2 Hz,

1 3

Molecular Diversity

11‑(5‑(Allylsulfanyl)‑3‑methyl‑1‑phenyl‑1H‑pyra‑

z o l ‑ 4 ‑ y l ) ‑ 3 , 3 ‑ d i m e t h y l ‑ 2 , 3 , 4 , 5 , 1 0 , 1 1 ‑ h e x a h y ‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one, 31f White Solid;

Yield 357 mg, 76%; m.p. 148–150 °C; R_f[80% EtOAc/n–

Hexane] 0.57; IR (KBr) ν_max/cm⁻¹= 3209, 3090, 2969,

2889, 1959, 1889, 1740, 1590, 1486, 1388, 296, 1187,

Vibrio cholerae (MTCC 3906) and Escherichia coli

(MTCC 443), and two fungal species: Aspergillus fumig-

atus (MTCC 3008) and Candida albicans (MTCC 227),

following NCCLS-recommended broth microdilution

MIC (minimum inhibitory concentration) method [102,

103]. Required microbial strains used in the study were

received from (MTCC) Institute of Microbial Technol-

ogy, Chandigarh, India. Mueller–Hinton broth was used

as a medium of nutrient to grow microbial species and to

dilute the suspension of the compound. Broth contain-

ing Sabouraud dextrose was used as nutrition for fun-

gal strains. Ampicillin, chloramphenicol, ciprofloxacin

and norfloxacin were the reference drugs used to com-

pare results of test compounds. Griseofulvin and nystatin

were reference drugs to evaluate antifungal potential of

the compound. Bacterial strains were allowed to inoculate

into mueller–hinton agar, overnight. It led to the suspen-

sion of a number of colonies, directly in saline solution,

and finally to the turbidity of the McFarland standard,

i.e., 108 CFU (colony-forming unit) per milliliter well

inoculum size for test strain. In the same way, Sabouraud

dextrose broth was treated in case of fungus species, fol-

lowing the procedures of the standardization inoculums

described above. Dilution and dissolution of test com-

pound were made in DMSO to prepare culture medium.

A solution which is 2000 µg/mL in the compound or

standard drug concentration was used as a stock solution.

Dilution of the stock solution was made further to obtain

concentration, required for the primary and secondary

screenings. Three different concatenations: 1000 µg/mL,

500 µg/mL and 250 µg/mL, of the compound were run

in the primary screening. Further dilutions were made

to obtain 200 µgm/mL, 100µg/mL and 62.5 µg/mL con-

centrations of the compound, after finding the primary

screening indicative of the active compound, for second-

ary screening, The central tube, free from antibiotics, was

subcultured by applying a loopful evenly over a quarter

of plate of medium which was used for growth of test

organism. The tubes were then incubated at 37 °C for

24 h in case of bacteria and 48 h in case of fungi. The

growth in the tube containing antimicrobial agent was

then compound with control growth and measured in the

magnitude of the turbidity.

1

1099, 850, 758, 746 cm⁻¹; H NMR (400 MHz; DMSO–

d₆) δ 1.08 (s, 6H, 3–CH₃), 1.84 (s, 3H, Pyrazol–CH₃) 2.12

(s, 2H, 4–CH₂), 3.13 (s, 2H, 2–CH₂), 4.85 (d, J=12 Hz, 2H,

–S–CH₂), 5.17 (s, 1H, CH), 5.51 (s, 1H, CH), 5.82 (s, 1H,

CH), 7.26 (s, 1H, 11–CH), 6.56–7.38 (m, 9H, Ar–H), 8.60

(s, 1H, 10–NH), 8.96 (s, 1H, 5–NH); ¹³C NMR (100 MHz;

DMSO– d₆) δ 13.1, 27.4, 29.5, 32.0, 38.8, 44.9, 50.2, 51.2,

109.0, 116.1, 118.5, 120.6, 121.2, 121.9, 123.2, 125.7,

127.8, 129.0, 129.4, 133.3, 133.9, 139.0, 140.0, 146.8,

154.9, 192.8; Anal Calcd for C₂₈H₃₀N₄OS: C, 71.46; H,

6.43; N, 11.90; Found: C, 71.55; H, 6.63; N, 11.84;; m/z

(ESI) 471 [M+H]⁺.

11‑(5‑(Benzylsulfanyl)‑3‑methyl‑1‑phenyl‑1H‑pyra‑

z o l ‑ 4 ‑ y l ) ‑ 3 , 3 ‑ d i m e t h y l ‑ 2 , 3 , 4 , 5 , 1 0 , 1 1 ‑ h e x a h y ‑

dro‑1H‑dibenzo[b,e][1,4]diazepin‑1‑one, 33 g Yellow

Solid; yield 375 mg, 72%; m.p. 156–158 °C; R_f[80%

EtOAc/n–Hexane] 0.57; IR (KBr) ν_max/cm⁻¹= 3205,

3070, 2988, 1680, 1689, 1490, 1460, 1368, 1299, 1289,

1247, 1197, 1160, 1125, 1040, 1058, 994, 901, 850, 758,

688 cm⁻¹; ¹H NMR (400 MHz; DMSO– d₆) δ 1.08 (s, 3H,

3–CH₃), 1.10 (s, 3H, 3–CH₃), 1.83 (s, 3H, Pyrazole–CH₃),

2.15 (d, J = 6 Hz, 2H, 4–CH₂), 2.11 (t, 2H, J = 4.8 Hz, 2–

CH₂), 3.83 (s, 2H, –CH₂–Ph), 5.10 (d, J = 4.4 Hz, 1H, 10–

NH), 5.93 (d, J=5.6 Hz, 1H, 11–CH), 6.52–7.41 (m, 14H,

Ar–H), 9.01 (s, 1H, 5–NH); ¹³C NMR (100 MHz; DMSO–

d₆) δ 13.1, 27.5, 29.4, 32.1, 44.9, 50.2, 51.3, 108.9, 120.6,

121.2, 122.0, 123.2, 125.6, 127.6, 127.7, 128.8, 128.9,

129.2, 129.3, 131.6, 133.3, 137.3, 139.0, 139.7, 146.8,

154.8, 193.0; Anal Calcd for C₃₂H₃₂N₄OS: C, 73.81; H,

6.19; N, 10.76; Found: C, 73.96; H, 6.42; N, 10.93; m/z

(ESI) 521.8 [M + H]⁺.

Biological activity studies

Methodology for in vitro antimicrobial screening

or minimum inhibitory concentration (MIC)

measurement

The minimum concentration of the compound which

can inhibit the growth of the microorganism completely

was considered and recorded as minimum inhibitory con-

centration (MIC, µg/mL). Both the tube containing only

seeded broth and the tube containing solvent control were

maintained under identical condition, to make sure that the

solvent has no infuence on growth of strain. All bio-assays

were repeated at least three times, and the deviation of the

observed value remained 2 µg/mL.

In vitro antimicrobial activity screening tests

of the heterocycles

Evaluation of antimicrobial potential screened all new

compounds against three Gram-negative bacteria: Strep-

tococcus pneumoniae (MTCC 1936), Clostridium tetani

(MTCC 449) and Bacillus subtilis (MTCC 441), three

Gram-positive bacteria: Salmonella typhi (MTCC 98),

1 3

Molecular Diversity

In vitro antitubercular activity screening of the compounds

was recorded at 593 nm and used in the calculation with

that of respective blank solutions. The antioxidant activ-

ity is expressed as ascorbic acid equivalent (mM/100 g of

dried compound).

In vitro antitubercular activity measurement of the test

compound employed Lowenstein–Jensen (L–J) MIC

medium method, in which M. tuberculosis H37Rv was

used specific bacterial strain. The % inhibition of M.

tuberculosis H37Rv bacterial strain caused by the com-

pound was determined and is displayed in Table 4. For

principal screening, 6.25 mg/ml concentration of the test

compound was used. Test compound solution was added

to the liquid L–J medium, and the content thus received

was sterilized by inspissations method [104]. The bacterial

culture grown on L–J medium was then collected in bijou

bottles containing 0.85% saline. DMSO was employed in

the preparation of the desired concentration. Incubation

of tubes at 37 °C for 24 h was followed by streaking of

M. tuberculosis H37Rv bacteria (5 × 104 bacilli per tube).

These tubes were subjected to incubation at 37 °C. Incu-

bation was allowed for 12, 22 and 28 days for the bacilli

to grow. Control tubes in which the medium alone was

incubated with M. tuberculosis H37Rv bacteria and tubes

which contained test component both were compared in

terms of inhibitory efect. The M. tuberculosis H37Rv

bacterial strain was tested against a known control drug

namely isoniazide. Only the compound which registered

M. tuberculosis H37Rv bacterial inhibition above or at

least 90%, in the primary screening, was considered for

retesting at lower concentration, in the L–J medium.

Calculation: FRAP value can be calculated by following

equation:

Ascorbic acid concentration (mM/100 g of sample)

ΔA_593nmof test sample

ΔA_593nmof test standard

Standard (mM)

Standard (mg)

=

×

× 10⁵

Antiproliferative activity study

Antiproliferative activity of the compounds was deter-

mined following National Cancer Institute (NCI) protocol

[89] according to which the experiment was performed

using 96-well plates. Here, every compound was screened

against a panel of six representative human tumor cell

lines: A549 (lung), HBL–100 (breast), HeLa (cervix),

SW1573 (lung), T–47D (breast) and WiDr (colon), to

determine its GI₅₀value, following sulforhodamine B

(SRB) assay [106, 107].

Molecular modeling studies

Molecular modeling studies were performed using Maestro

9.0 (Maestro 9.0 version, Schrodinger, LLC, New York, NY,

USA). All the structures of the synthesized compounds were

drawn and cleaned using standard option ‘building tools’

in Maestro 9.0 software. All the obtained structures were

further minimized using OPLS 2005 force feld in stand-

ard option “Ligprep 2.3”. Etoposide was added in the data-

base as reference compounds which were also minimized

as per the same protocol. The lowest energy conformers so

obtained were further used for performing molecular dock-

ing studies using “Glide 5.5”. The three-dimensional crystal

structures of human topoisomerase II alpha in complex with

DNA and etoposide (PDB ID: 5GWK) were downloaded

from RCSB (www.rcsb.org). Standard option Receptor Grid

Generation in Maestro 9.0 used for receptor was used for

gird generation The van der Waals radii of the ligands were

scaled to 3.0 with partial charge cutof 0.25. All the obtained

lowest energy conformers were docked as per the previously

reported protocol [108].

In vitro antioxidant activity study

The FRAP assay [105] was employed to reveal the anti-

oxidant activity of compounds. In other words, capacity

of the compound resists reduction of ferric tripyridyl tria-

zine (Fe(III)-TPTZ) complex into a blue-colored ferrous

tripyridyl triazine (Fe(II)-TPTZ) complex, spectrophoto-

metrically at 593 nm at low pH. The reagents used in the

study include 300 mmol/liter acetate bufer solution, of

pH 3.6 (3.1 g of CH₃CO₂Na·3H₂O and 16 mL of glacial

CH₃COOH were dissolved in distilled water to make liter

of bufer solution). 10 mmol of TPTZ (2,4,6-tripyridyl-s-

triazine) in 40 mmol/L HCl and 20 mmol/liter FeCl₃solu-

tion were dissolved in distilled water. The working FRAP

solution was prepared by mixing 25 mL of above acetate

bufer solution, 2.5 mL of TPTZ solution and 2.5 mL of

FeCl₃solution, always fresh. Sample solution was pre-

pared by dissolving the compound in the 5–10 mg range

in 25 mL DMF. Standard solution was prepared after dis-

solving 1.0 mmol of ascorbic acid (MW 176.13 g/mol)

in 100 ml of distilled water. An aliquot 400µL of sample

or 200µL of standard was mixed with 3.0 mL of FRAP

working solution and incubated the resulting mixture at

37 °C for 10 min. Absorbance of the incubated mixture

Acknowledgements All authors sincerely express thanks to the Head,

Department of Chemistry of Sardar Patel University, for providing

necessary research facilities. Particularly, authors GCB and TRS are

grateful to the UGC, New Delhi, for research fellowships under the

UGC scheme of BSR and RFSMS. IL thanks CONACYT (Mexico)

for a postdoctoral grant. IL and JMP thank the Spanish Government

for fnancial support through project PGC2018-094503-B-C22 (MCIU/

AEI/FEDER, UE). The authors also acknowledge fnancial support

(Project No. 699 EMEQ-404/2014, dated March 11, 2016) of the

1 3

Molecular Diversity

Tetrahedron Lett 5:6178–6180. https://doi.org/10.1016/j.tetle

t.2013.08.092

SERB, DST, New Delhi, India. M.R.Y. is thankful to UGC, New Delhi,

for awarding UGC-BSR Faculty Fellowship [No. F.18-1/2011(BSR)].

Thanks are also due to DST, New Delhi, in general, and PURSE central

facility (vide sanction letter DO. no. SR/59/Z–23/2010/43 dated March

16, 2011) for mass analysis, in particular, as well as UGC-CPEPA,

Phase II for the assistance in general and for NMR facility, in particular,

sponsored under award letter no.F.No.1-14/2002-2016(NS/PE) dated

April 28, 2016.

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amidation of aryl iodides and amino acid amides to synthe-

size C

₃-(Z)-1H-benzo[e][1,4]diazepin-2(3H)-ones. Mol Divers

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Molecular Diversity

Afliations

Gaurangkumar C. Brahmbhatt¹· Tushar R. Sutariya¹· Hiralben D. Atara¹· Narsidas J. Parmar¹· Vivek K. Gupta²·

Irene Lagunes³· José M. Padrón³· Prashant R. Murumkar⁴· Mange Ram Yadav⁴

3

* Narsidas J. Parmar

BioLab, Instituto Universitario de Bio-Orgánica ‘‘Antonio

González’’ (IUBO–AG), Centro de Investigaciones

Biomédicas de Canarias (CIBICAN), Universidad

de La Laguna, C/Astrofísico Francisco Sánchez 2,

38206 La Laguna, Spain

njpchemdeptspu@yahoo.co.in

1

Department of Chemistry, Sardar Patel University, Dist.

Anand, Vallabh Vidyanagar, Gujarat 388120, India

2

4

Post–Graduate Department of Physics, University of Jammu,

Faculty of Pharmacy, The Maharaja Sayajirao University

of Baroda, Vadodara 390 001, India

Jammu, Tawi 180006, India

1 3

Article Doi

New pyrazolyl-dibenzo[b,e][1,4]diazepinones: room temperature one-pot synthesis and biological evaluation

DOI: 10.1007/s11030-019-09958-z

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Article abstract of DOI:10.1007/s11030-019-09958-z

Full text of DOI:10.1007/s11030-019-09958-z

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