An efficient approach for the synthesis and antimicrobial evaluation of some new benzocoumarins and related compounds

Article abstract of DOI:10.1080/00397911.2021.1925917

A convenient synthetic approach for pharmaceutically important benzocoumarin-based heterocyclic compounds has been studied. β-enaminonitrile has been used for the synthesis of a broad diversity of new benzocoumarins and related compounds over different reaction steps. Various synthetic approaches were used in this research for synthesis of heterocyclic systems such as acid-catalyzed hydrolysis, decarboxylation, deamination, ring opening and ring closure. The molecular structures of the newly synthesized derivatives were established by elemental analyses and spectral data (IR, ¹H-NMR, and ¹³C-NMR). Some of the newly synthesized compounds were explored for their antimicrobial activities.

Full text of DOI:10.1080/00397911.2021.1925917

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
An efficient approach for the synthesis
and antimicrobial evaluation of some new
benzocoumarins and related compounds
Mohamed H. Hekal, Fatma S. M. Abu El-Azm & Sandy S. Samir
To cite this article: Mohamed H. Hekal, Fatma S. M. Abu El-Azm & Sandy S. Samir
(2021) An efficient approach for the synthesis and antimicrobial evaluation of some new
benzocoumarins and related compounds, Synthetic Communications, 51:14, 2175-2186, DOI:
10.1080/00397911.2021.1925917
To link to this article: https://doi.org/10.1080/00397911.2021.1925917
View supplementary material
Published online: 12 May 2021.
Submit your article to this journal
Article views: 60
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 14, 2175–2186
https://doi.org/10.1080/00397911.2021.1925917
An efficient approach for the synthesis and antimicrobial
evaluation of some new benzocoumarins and
related compounds
Mohamed H. Hekal , Fatma S. M. Abu El-Azm, and Sandy S. Samir
Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 2 January 2021
A convenient synthetic approach for pharmaceutically important
benzocoumarin-based heterocyclic compounds has been studied.
b-enaminonitrile has been used for the synthesis of a broad diversity
of new benzocoumarins and related compounds over different reac-
tion steps. Various synthetic approaches were used in this research
for synthesis of heterocyclic systems such as acid-catalyzed hydroly-
sis, decarboxylation, deamination, ring opening and ring closure. The
molecular structures of the newly synthesized derivatives were estab-
KEYWORDS
Benzo[f]coumarin;
b-enaminonitrile; deaminati-
on; keto-enol tautomerism;
nitrogen nucleophiles;
ring opening of
1
lished by elemental analyses and spectral data (IR, H-NMR, and 13C-
benzo[f]coumarin
NMR). Some of the newly synthesized compounds were explored for
their antimicrobial activities.
GRAPHICAL ABSTRACT
Introduction
On account of the rise in the number of immune-compromised hosts, further cases of
microbial infections have been announced significantly. Many of the microorganisms
acquire resistance through a period of time against available medications. Subsequently,
there is an imperative necessity to develop alternate antimicrobial agents. Coumarin
compounds are considered as a remarkable category in the field of organic synthesis
and natural products. So, researchers are interested from many years to examine the
CONTACT Mohamed H. Hekal
mohahekal2007@yahoo.com
Chemistry Department, Faculty of Science, Ain Shams
University, Cairo, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

2176
M. H. HEKAL ET AL.
Figure 1. Several drugs and agrochemicals bearing coumarin as a core moiety.
important biological properties of these natural coumarins or to prepare their analogs
for curative purposes.[1] Coumarin skeleton was used as an intermediate for the synthe-
sis of bioactive heterocyclic compounds which exhibit several pharmacological effects
including anti-inflammatory,[2,3] antimicrobial,[4] anti-cancer,[3,5] antifungal,[6] anti-
[7–9]
[11]
coagulant
antioxidant,[10] and anti-tubercular
properties. Coumarins exist
greatly in drugs, agrochemicals and natural products (Figure 1). The natural Osthole is
O-methylated coumarin present in Cnidium MONNIERI, a classic Chinese herbal drug
that has been applied as a fungicidein China for a long time, and displays antifungal
activity against Rhizoctonia solani and a broad series of other phytopathogenic
fungi;[12–14] Acenocoumarol and Warfarin are anticoagulants work as the vitamin K
antagonists and usually used in the prevention of thrombosis and thromboembol-
ism;[15–17] and Coumoxystrobin (SYP-3375) is a strobilurin fungicide that displays a
wide spectrum of antifungal activity.[18–20]
Results and discussion
As a part of our interest in the synthesis of a broad scope of heterocyclic systems with
biological evaluations[21–29] and in continuation of our investigation on the reactivity of
3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles (1),[30–34] we are interested in our
running study on the utility of 3-amino-1-(p-tolyl)-1H-benzo[f]chromene-2-carbonitrile
1[30] in the synthesis of new benzo[f]coumarins and related compounds. Thus, in this
research, the behavior of b-enaminonitrile 1 toward different organic and inorganic
acids has been examined. Subsequently, stirring the b-enaminonitrile 1 with concen-
trated H2SO4 at room temperature yielded benzo[f]coumarin-2-carboxamide derivative
2 in which the cyano group in the b-enaminonitrile 1 undergoes partial hydrolysis to
the carboxamide group alongside the deamination of the amino group (Scheme 1). The
supportive evidence for structure 2 derived from the IR spectrum which displayed
absorption bands at 3311, 3230, 1758 and 1686 cmꢀ1 corresponding to (NH2), (C¼O of
lactone) and (C¼O of amide group), respectively with the absence of absorption band
1
for CꢁN group. Also, the H-NMR (DMSO-d6) spectrum exhibited the following sig-
nals at d (ppm): 2.21 (s, 3H, CH3), 4.04 (d, 1H, J ¼ 1.5 Hz), 5.37 (d, 1H, J ¼ 1.5 Hz),
6.99–8.00 (m, 12H, Ar-H þ NH2).
On the other hand, heating the b-enaminonitrile 1 with glacial acetic acid in presence
of fused sodium acetate produced 1-(p-tolyl)-1,2-dihydro-3H-benzo[f]coumarin (3)
(Scheme 1). In this reaction, full hydrolysis followed by decarboxylation of the cyano
group occurred with the deamination. However, compound 3 was previously synthe-
sized by different methodology through one-pot condensation of Meldrum’s acid with

R
SYNTHETIC COMMUNICATIONSV
2177
Scheme 1. Behavior of b-enaminonitrile 1 toward different organic and inorganic acids.
b-naphthol and 4-methylbenzaldehyde.[35] The structure of benzo[f]coumarin derivative
1
3 was characterized by IR, H-NMR, 13C-NMR and microanalysis.
Likewise, refluxing b-enaminonitrile 1 with formic acid involved only the deamin-
ation of the amino group to give the unexpected product 1-(p-tolyl)-2,3-dihydro-1H-
benzo[f]coumarin-2-carbonitrile (4) rather than the corresponding fused pyrimidinone
derivative 5[36,37] or our recently obtained novel chromeno[2,3-b]azet-9-one derivative 6
(Scheme 1).[32]
Inspection of the present literature, revealed that the 2-cyano-benzo[f]coumarin
derivative 4 has been formerly prepared under similar reaction conditions,[38] displaying
1
in the H-NMR spectrum d values [4.39 (d, 1H, J ¼ 6.1 Hz), 5.14 (d, 1H, J ¼ 6.1 Hz)] dif-
ferent to ours [5.58 (s, 2H, Ha and Hb (exchangeable with D2O))]. This is owing to in
the solution compound 4 exists in the enol tautomer [B] as a result of keto-enol tauto-
1
merism (cf. Figure 2). So we conclude that the H-NMR spectrum of benzo[f]coumarin
derivative 2 showed the predominance of the tautomeric form [B] in solution.
Surprisingly, the 2-cyano-benzo[f]coumarin derivative 4 was also obtained from
endeavor to chloroacetylate the b-enaminonitrile 1 with chloroacetyl chloride in glacial
acetic acid rather than the corresponding chloroacetamido derivative 8 (Scheme 2).
9-(Chloromethyl)-12-(p-tolyl)-10,12-dihydro-11H-benzo[5,
6]chromeno[2,3-d]pyrimi-
din-11-one (7) was likewise formed from another attempt to chloroacetylate the
b-enaminonitrile 1 with chloroacetyl chloride in dioxane containing a catalytic amount

2178
M. H. HEKAL ET AL.
Figure 2. The predominance of the tautomeric form [B] in solution of compound 4.
Scheme 2. Reaction of b-enaminonitrile 1 with chloroacetyl chloride.
of triethylamine (0.2 mL) (Scheme 2). Compound 7 was previously synthesized via
Radziszewski’s reaction of the chloroacetamido derivative 8 using urea hydrogen perox-
ide (UHP).[39] The demise of ꢀCꢁN in the IR spectrum of compound 7 and the exist-
ence of ꢀNH at 3166 cmꢀ1 and ꢀC¼O at 1654 cmꢀ1 corroborative the suggested
structure. The 1H-NMR and 13C-NMR spectra were completely in accord with the
assigned structure 7. (c.f. Experimental section)
Moreover, the chemical behavior of 2-cyano-benzo[f]coumarin 4 toward selected
nitrogen nucleophiles was also studied. Thus, when compound 4 was subjected to react
with ammonium acetate in an oil bath gave unexpected product that was identified as
the benzo[f]coumarin derivative 3 instead of the benzo[f]quinolin-3(2H)-one derivative
9 (Scheme 3). Chemical evidence for benzo[f]coumarin derivative 3 was gained from its
reaction with hydrazine hydrate in boiling ethanol which yielded the hydrazide deriva-
tive 10 as a sole product in fairly good yield (Scheme 3). The appearance of ꢀOH at
3313 cmꢀ1, ꢀNH2 at 3268, 3217 cmꢀ1 alongside ꢀC¼O at 1650 cmꢀ1 in the IR spectrum
1
of compound 10 as well as the appearance of acidic protons in the H-NMR spectrum
at 4.12 (br.s, 2H, NH2, exchangeable by D2O), 9.05 (br.s, 1H, NH, exchangeable by
D2O) and 9.60 (br.s, 1H, OH, exchangeable by D2O) was in favor with the designated

R
SYNTHETIC COMMUNICATIONSV
2179
Scheme 3. Reaction of compound 4 with some nitrogen nucleophiles.
structure. Compound 10 was supposed to be formed via nucleophilic attack of hydra-
zine hydrate to carbonyl group of benzo[f]coumarin 3 followed by ring opening.
It is noteworthy that hydrazinolysis of 2-cyano-benzo[f]coumarin 4 using excess
hydrazine hydrate in refluxing dioxane undergoes degradation process in which 5-iminopyr-
azolidin-3-one (11) was deposited on hot in addition to b-naphthol which was obtained
after acidification of the mother liquor (Scheme 3). The structures of b-naphthol and
5-iminopyrazolidin-3-one (11) were confirmed by IR, 1H-NMR and 13C-NMR (c.f.
Experimental section).
In like manner, 2-cyano-benzo[f]coumarin 4 was subjected to degradation when
treated with semicarbazide hydrochloride in presence of fused sodium acetate under
reflux to furnish the unexpected product that was identified as 5-amino-4-(4-methylben-
zylidene)-2,4-dihydro-3H-pyrazol-3-one (12) (Scheme 3). Structure 12 was fully sup-
ported by spectral data beside the elemental analyses. IR spectrum of compound 12
lacked the absorption band of cyano group and showed presence of absorption band at
3279, 3192 cmꢀ1 corresponding to NH2 group in addition to absorption band at
1
1712 cmꢀ1 for CO group. Whereas, its H-NMR spectrum displayed a singlet signal at d
2.29 ppm attributed to methyl group beside two singlet signals at d 6.46 and 10.20 ppm
assigned acidic protons of NH2 and NH groups, respectively. Also, aromatic protons
appeared at d 7.16–7.60 ppm and the olefinic proton at d 7.81 ppm which completely
agree with the proposed structure 12.
A conceivable mechanism for the formation of compounds (11) and (12) from 2-cyano-
benzo[f]coumarin 4 is outlined in Scheme 4.

2180
M. H. HEKAL ET AL.
Scheme 4. Degradation of 2-cyano-benzo[f]coumarin 4.
Moreover, our current study was prolonged to explore the chemical behavior of 2-
cyano-benzo[f]coumarin 4 toward some bidentate nucleophiles. Therefore, refluxing of
compound 4 with 1,2-diamino ethane in dioxane afforded benzo[f]imidazo[1,2-a]quin-
oline 13 which deposited on hot as a white crystalline solid in a good yield (Scheme 5).
IR spectrum of compound 13 showed two broad bands at 3353, 3247 cmꢀ1 corresponds
to 2NH groups and absence of the absorption bands of both carbonyl and cyano func-
1
tional groups. In addition, H-NMR and 13C-NMR spectra of compound 13 strongly
confirmed the assigned structure (c.f. Experimental section).
On the other hand, ring opening of 2-cyano-benzo[f]coumarin 4 was achieved via its
reaction with o-aminothiophenol in refluxing dioxane in presence of few drops of gla-
cial acetic acid to yield benzo[d]thiazole derivative 14 as a sole product (Scheme 5).
Whereas, Refluxing of compound 4 with o-aminophenol in presence of a catalytic

R
SYNTHETIC COMMUNICATIONSV
2181
Scheme 5. Reaction of 2-cyano-benzo[f]coumarin 4 toward some bidentate nucleophiles.
amount of triethylamine gave 2-(benzo[d]oxazol-2(3H)-ylidene)-1-(p-tolyl)-1,2-dihydro-
3H-benzo[f]chromen-3-one (15) (Scheme 5). Structures of compounds 14 and 15 were
well supported by elemental analyses as well as spectral data. IR spectrum of compound
15 devoid the absorption band of nitrile group and showed presence of a broad absorp-
tion band at 3232 cmꢀ1 related to NH group alongside with a,b-unsaturated carbonyl
1
group at 1682 cmꢀ1. While, its H-NMR spectrum revealed that in solution, compound
15 presents in two forms [C] and [D] (cf. Figure 3) in ratio 56.7:43.3 due to 1,3-proton
shift. Thus, the 1H-NMR spectrum of 15 displayed two singlet signals at d 2.12,
2.24 ppm attributed to protons of methyl group in the two forms [C] and [D], two sing-
let signals at d 5.16, 12.23 ppm for NHb & NHd, respectively which were exchangeable
by D2O, and two singlet signals at d 5.74, 5.79 ppm assigned to Ha & Hc, respectively in
addition to a multiplet signal in the region of d 6.99–7.92 ppm attributed to 14 aro-
matic protons.
Antimicrobial evaluation
The antimicrobial activity of some of the newly synthesized compounds (2–4, 7, 10,
12–15) was determined using agar well diffusion method. These compounds were tested

2182
M. H. HEKAL ET AL.
Figure 3. 1,3-proton shift of compound 15.
Table 1. Antimicrobial screening results of the tested compounds.
Compd. no.
E. coli
K. pneumonia
S. aureus
C. albicans
2
3
NA
NA
NA
NA
16.3 0.5
NA
NA
NA
4
7
10
12
13
14
NA
NA
NA
NA
NA
NA
NA
NA
14.6 0.5
NA
17.3 0.5
20.3 0.6
NA
11.6 0.5
10.6 0.5
NA
NA
NA
NA
NA
NA
NA
NA
NA
15
NA
27 0.5
NA
NA
NA
25 0.5
NA
NA
12.3 0.5
NA
22 0.1
NA
NA
NA
NA
21 0.5
Gentamicin
Ampicillin
Nystatin
00, no activity (inhibition zone < 7 mm); weak activity (7–10 mm); moderate activity (11–15 mm); strong activity
(>15 mm). Solvent: DMSO.
in vitro for their antibacterial activity against two Gram negative bacteria, namely,
Escherichia coli (ATCC:10536) and Klebsiella pneumonia (ATCC:10031), one Gram posi-
tive bacteria, namely, Staphylococcus aureus (ATCC:13565) in addition to the pathogenic
fungi Candida albicans (ATCC:10231) using nutrient agar medium. A strong activity
was observed with compounds 2, 4, and 7 against Staphylococcus aureus while moderate
activity was observed with compounds 12, 13, and 15 against Staphylococcus aureus.
The inhibitory concentration was determined for each of the active compounds along
with Gentamicin, Ampicillin and Nystatin as positive controlled. Only compound 10
exhibit moderate activity against Klebsiella pneumonia while other compounds have no
activity against Klebsiella pneumonia. No activity was detected for all the synthesized
compounds toward Escherichia coli and Candida albicans. Results are shown in Table 1.
The presence of amino and carbonyl groups in ampicillin help this antibiotic to pass
through the pores of the outer membrane of Gram-positive bacteria, such as
Staphylococcus aureus and thus inhibits the third and final stage of bacterial cell wall
synthesis in binary fission, which ultimately leads to cell lysis. Likewise, compounds 2,
4, and 7 exhibited strong activity; this is may be due to the presence of NH2, NH and
CO groups (cf. Figure 4).
Experimental
All melting points were measured on a Griffin and George melting-point apparatus
(Griffin & Georgy Ltd., Wembley, Middlesex, UK) and are uncorrected. IR spectra were

R
SYNTHETIC COMMUNICATIONSV
2183
Figure 4. Structure of ampicillin and some of the designed target compounds.
recorded on Pye Unicam SP1200 spectrophotometer (Pye Unicam Ltd., Cambridge,
1
UK) by using the KBr wafer technique. H-NMR spectra were determined on a Varian
Gemini 300 MHz on Bruker Avance III using tetramethylsilane as an internal standard
(chemical shifts in d scale), while 13C NMR spectra were run at 75 MHz. Elemental
analyses were carried out at the Microanalytical Unit, Faculty of Science, Ain Shams
University, using a Perkin-Elmer 2400 CHN elemental analyzer (Waltham, MA), and
satisfactory analytical data ( 0.4) were obtained for all compounds. The homogeneity of
the synthesized compounds was controlled by thin layer chromatography (TLC), using
aluminum sheet silica gel F254 (Merck). Antimicrobial activity was carried out at bio-
chemistry central lab, Faculty of Science, Cairo University.
3-Oxo-1-(p-tolyl)-2,3-dihydro-1H-benzo[f]chromene-2-carboxamide (2)
A mixture of enaminonitrile 1 (1.56 g, 5 mmol) and concentrated sulfuric acid
(10 mL) was stirred at room temperature for 30 min, then poured on cold water
(50 mL). The precipitated solid was filtered off, dried and recrystallized from benzene
(15 mL) to give compound 2 as beige crystals, mp 266–268 ꢂC, and yield: 56%. IR
(KBr, ꢀ, cmꢀ1): 3311, 3230 (NH2), 3030 (CH aromatic), 1758 (C¼Olactone), 1686
(C¼Oamide). 1H-NMR (300 MHz, DMSO-d6) d (ppm): 2.21 (s, 3H, CH3), 4.04 (d,
1H, J ¼ 1.5 Hz), 5.37 (d, 1H, J ¼ 1.5 Hz), 6.99–8.00 (m, 10H, Ar-H), 7.28 (br s, 2H,
NH2, exchangeable with D2O). 13C-NMR (75 MHz, DMSO-d6) d (ppm): 20.52, 55.31,
116.14, 117.15, 120.32, 120.33, 122.85, 125.21, 126.68, 126.88, 127.50, 128.32, 128.69,
129.58, 129.81, 130.26, 130.71, 136.74, 136.98, 149.25, 164.76, 168.06, and 178.92. MS
m/z (%): 331 (Mþ, 16.2), 318 (70.4), 237 (51.8), 185 (48.6), 125 (100), 87 (57.5).
Anal. Calcd. for C21H17NO3 (331.37): C, 76.12; H, 5.17; N, 4.23. Found: C, 76.33; H,
5.25; N, 4.09.
Antimicrobial assay
The sterilized media was poured onto the sterilized Petri dishes (20–25 mL, each petri
dish) and allowed to solidify at room temperature. Microbial suspension was prepared

2184
M. H. HEKAL ET AL.
in sterilized saline equivalent to McFarland 0.5 standard solution (1.5 ꢃ 105 CFU mLꢀ1
)
and its turbidity was adjusted to OD ¼ 0.13 using spectrophotometer at 625 nm.
Optimally, within 15 min after adjusting the turbidity of the inoculum suspension, a
sterile cotton swab was dipped into the adjusted suspension and was flooded on the
dried agar surface then allowed to dry for 15 min with lid in place. Wells of 6 mm
diameter was made in the solidified media with the help of sterile borer. 100 lL of the
solution of the tested compound was added to each well with the help of micropipette.
The plates were incubated at 37 ꢂC for 24 h in case of antibacterial activity. This experi-
ment was carried out in triplicate and zones of inhibition were measured in mm. scale.
1
Full experimental details and spectroscopic data (IR, H-NMR and 13C-NMR spectra)
for compounds 3, 4, 7, 10–15 can be found via the Supplementary Content section of
this article’s Web page.
ORCID
Mohamed H. Hekal
http://orcid.org/0000-0001-6059-9666
References
[1] Musa, M. A.; Cooperwood, J. S.; Omar, M.; Khan, F. A Review of Coumarin Derivatives
in Pharmacotherapy of Breast Cancer. Curr. Med. Chem. 2008, 15, 2664–2679. DOI: 10.
2174/092986708786242877.
[2] Arora, R. K.; Kaur, N.; Bansal, Y.; Bansal, G. Novel Coumarin-Benzimidazole Derivatives
as Antioxidants and Safer Anti-inflammatory Agents. Acta Pharm. Sin. B. 2014, 4,
368–375. DOI: 10.1016/j.apsb.2014.07.001.
[3] Bansal, Y.; Sethi, P.; Bansal, G. Coumarin: A Potential Nucleus for anti-Inflammatory
Molecules. Med. Chem. Res. 2013, 22, 3049–3060. DOI: 10.1007/s00044-012-0321-6.
[4] Nagamallu, R.; Kariyappa, A. K. Synthesis and Biological Evaluation of Novel
Formylpyrazoles Bearing Coumarin Moiety as Potent Antimicrobial and Antioxidant
Agents. Bioorg. Med. Chem. Lett. 2013, 23, 6406–6409.
[5] Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. Montmorillonite KSF as an Inorganic,
Waterstable, and Reusable Catalyst for Knoevenagel Synthesis of Coumarin-3-Carboxylic
Acids. J. Org. Chem. 1999, 64, 1033–1035. DOI: 10.1021/jo981794r.
[6] Al-Amiery, A. A.; Kadhum, A. A. H.; Mohamad, A. B. Antifungal Activities of New
Coumarins. Molecules 2012, 17, 5713–5723. DOI: 10.3390/molecules17055713.
[7] Weigt, S.; Huebler, N.; Strecker, R.; Braunbeck, T.; Broschard, T. H. Developmental
Effects of Coumarin and the Anticoagulant Coumarin Derivative Warfarin on Zebrafish
(Danio rerio) Embryos. Reprod. Toxicol. 2012, 33, 133–141. DOI: 10.1016/j.reprotox.2011.
07.001.
[8] Dey, S.; Lo, H. J.; Wong, C. H. An Efficient Modular One-Pot Synthesis of Heparin-Based
Anticoagulant Idraparinux. J. Am. Chem. Soc. 2019, 141, 10309–10314. DOI: 10.1021/jacs.
9b03266.
[9] Dey, S.; Lo, H. J.; Wong, C. H. Programmable One-Pot Synthesis of Heparin
Pentasaccharide Fondaparinux. Org. Lett. 2020, 22, 4638–4642. DOI: 10.1021/acs.orglett.
0c01386.
[10] Gacche, R. N.; Jadhav, S. G. Antioxidant Activities and Cytotoxicity of Selected Coumarin
Derivatives: Preliminary Results of Astructure-Activity Relationship Study Using
Computational Tools. J. Exp. Clin. Med. 2012, 4, 165–169. DOI: 10.1016/j.jecm.2012.04.
007.

R
SYNTHETIC COMMUNICATIONSV
2185
[11] Kawate, T.; Iwase, N.; Shimizu, M.; Stanley, S. A.; Wellington, S.; Kazyanskaya, E.; Hung,
D. T. Synthesis and Structure-Activity Relationships of Phenyl-substituted Coumarins with
Anti-tubercular Activity that Target FadD32. Bioorg. Med. Chem. Lett. 2013, 23,
6052–6059. DOI: 10.1016/j.bmcl.2013.09.035.
[12] Vogl, S.; Zehl, M.; Picker, P.; Urban, E.; Wawrosch, C.; Reznicek, G.; Saukel, J.; Kopp, B.
Identification and Quantification of Coumarins in Peucedanum ostruthium (L.) Koch by
HPLC-DAD and HPLC-DAD-MS. J. Agric. Food Chem. 2011, 59, 4371–4377. DOI: 10.
1021/jf104772x.
[13] Wei, Y.; Zhang, T.; Ito, Y. Preparative Isolation of Osthol and Xanthotoxol from
Common Cnidium Fruit (Chinese Traditional Herb) Using Stepwise Elution by High-
Speed Counter-Current Chromatography. J. Chromatogr. A. 2004, 1033, 373–377. DOI:
10.1016/j.chroma.2004.01.058.
[14] Shi, Z.; Wang, F.; Zhou, W.; Zhang, P.; Fan, Y. J. Application of Osthol Induces a
Resistance Response against Powdery Mildew in Pumpkin Leaves. IJMS. 2007, 8,
1001–1012. DOI: 10.3390/i8091001.
[15] Holbrook, A. M.; Pereira, J. A.; Labiris, R.; McDonald, H.; Douketis, J. D.; Crowther, M.;
Wells, P. S. Systematic Overview of Warfarin and Its Drug and Food Interactions. Arch.
Intern. Med. 2005, 165, 1095–1106. DOI: 10.1001/archinte.165.10.1095.
[16] Cesar, J. M.; Avello, A. G.; Navarro, J. L.; Herraez, M. V. Aging and Oral Anticoagulant
Therapy Using Acenocoumarol. Blood Coagul. Fibrinolysis. 2004, 15, 673–676. DOI: 10.
1097/00001721-200412000-00007.
[17] Ufer, M. Comparative Pharmacokinetics of Vitamin
K
Antagonists: Warfarin,
Phenprocoumon and Acenocoumarol. Clin. Pharmacokinet. 2005, 44, 1227–1246. DOI: 10.
2165/00003088-200544120-00003.
[18] Guan, A. Y.; Liu, C. L.; Li, M.; Zhang, H.; Li, Z. N.; Li, Z. M. Design, Synthesis and
Structure-Activity Relationship of Novel Coumarin Derivatives. Pest Manag. Sci. 2011, 67,
647–655. DOI: 10.1002/ps.2103.
[19] Liu, C.; Guan, A.; Yang, J.; Chai, B.; Li, M.; Li, H.; Yang, J.; Xie, Y. Efficient Approach to
Discover Novel Agrochemical Candidates: Intermediate Derivatization Method. J. Agric.
Food Chem. 2016, 64, 45–51. DOI: 10.1021/jf5054707.
[20] Guan, A.; Liu, C.; Yang, X.; Dekeyser, M. Application of the Intermediate Derivatization
Approach in Agrochemical Discovery. Chem. Rev. 2014, 114, 7079–7107. DOI: 10.1021/
cr4005605.
[21] Hekal, M. H.; Abu El-Azm, F. S. M. New Potential Antitumor Quinazolinones Derived
from Dynamic 2-Undecyl Benzoxazinone: Synthesis and Cytotoxic Evaluation. Synth.
Commun. 2018, 48, 2391–2402. DOI: 10.1080/00397911.2018.1490433.
[22] Hekal, M. H.; Abu El-Azm, F. S. M. Efficient MW-Assisted Synthesis of Some New
Isoquinolinone Derivatives with In Vitro Antitumor Activity. J. Het. Chem. 2017, 54,
3056–3064. DOI: 10.1002/jhet.2916.
[23] Mahmoud, M. R.; Abou-Elmagd, W. S. I.; Derbala, H. A.; Hekal, M. H. Synthesis and
Spectral Characterisation of Some Phthalazinone Derivatives. J. Chem. Res. (S) 2012, 36,
75–82. DOI: 10.3184/174751912X13274297624330.
[24] Mahmoud, M. R.; Abu El-Azm, F. S. M.; Ismail, M. F.; Hekal, M. H.; Ali, Y. M. Synthesis
and Antitumor Evaluation of Novel Tetrahydrobenzo[40,50]Thieno[30,20:5,6]Pyrimido[1,2-
b]Isoquinoline Derivatives. Synth. Commun. 2018, 48, 428–438. DOI: 10.1080/00397911.
2017.1406520.
[25] Mahmoud, M. R.; El-Shahawi, M. M.; Abou-Elmagd, W. S. I.; Hekal, M. H. Novel
Synthesis of Isoquinoline Derivatives Derived from (Z)-4-(1,3-Diphenylpyrazol-4-
yl)Isochromene-1,3-Dione. Synth. Commun. 2015, 45, 1632–1641. DOI: 10.1080/00397911.
2015.1030760.
[26] Hekal, M. H.; El-Naggar, A. M.; Abu El-Azm, F. S. M.; El-Sayed, W. M. Synthesis of New
Oxadiazol-Phthalazinone Derivatives with anti-Proliferative Activity; Molecular Docking,
Pro-Apoptotic, and Enzyme Inhibition Profile. RSC Adv. 2020, 10, 3675–3688. DOI: 10.
1039/C9RA09016A.

2186
M. H. HEKAL ET AL.
[27] Hekal, M. H.; Abu El-Azm, F. S. M.; Atta-Allah, S. R. Ecofriendly and Highly Efficient
Microwave-Induced Synthesis of Novel Quinazolinone-Undecyl Hybrids with In Vitro
Antitumor Activity. Synth. Commun. 2019, 49, 2630–2641. DOI: 10.1080/00397911.2019.
1637001.
[28] Mahmoud, M. R.; Abou-Elmagd, W. S. I.; Derbala, H. A.; Hekal, M. H. Novel Synthesis of
Some Phthalazinone Derivatives. Chin. J. Chem. 2011, 29, 1446–1450. DOI: 10.1002/cjoc.
201180264.
[29] Abdelgawad, N.; Ismail, M. F.; Hekal, M. H.; Marzouk, M. I. Design, Synthesis, and
Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer
Agents. J. Heterocyclic Chem. 2019, 56, 1771–1779. DOI: 10.1002/jhet.3544.
[30] Ali, A. M.; Hekal, M. H. Convenient Synthesis and anti-Proliferative Activity of Some
Benzochromenes and Chromenotriazolopyrimidines under Classical Methods and Phase
Transfer Catalysis. Synth. Commun. 2019, 49, 3498–3509. DOI: 10.1080/00397911.2019.
1675173.
[31] Abu El-Azm, F. S. M.; El-Shahawi, M. M.; Elgubbi, A. S.; Madkour, H. M. F. Design,
Synthesis, anti-Proliferative Activity, and Molecular Docking Studies of Novel
Benzo[f]Chromene,
Chromeno
[2,3-d]Pyrimidines
and
Chromenotriazolo[1,5-
c]Pyrimidines. Synth. Commun. 2020, 50, 669–683. DOI: 10.1080/00397911.2019.1710850.
[32] Abu El-Azm, F. S. M.; El-Shahawi, M. M.; Elgubbi, A. S.; Madkour, H. M. F. Synthesis of
New Benzo[f]Chromene-Based Heterocycles Targeting anti-Proliferative Activity. J. Iran.
Chem. Soc. 2021, 18, 1081–1092. DOI: 10.1007/s13738-020-02092-w.
[33] Dey, S.; Wong, C.-H. Programmable One-Pot Synthesis of Heparin Pentasaccharides
Enabling Access to Regiodefined Sulfate Derivatives. Chem. Sci. 2018, 9, 6685–6691. DOI:
10.1039/C8SC01743C.
[34] Cheng, C. W.; Zhou, Y.; Pan, W. H.; Dey, S.; Wu, C. Y.; Hsu, W. L.; Wong, C. H.
Hierarchical and Programmable One-Pot Synthesis of Oligosaccharides. Nat. Commun.
2018, 9, 5202–5210. DOI: 10.1038/s41467-018-07618-8.
[35] Mehrabi, H.; Ashraf, F. N.; Karimi, R. R. One-Pot Three-Component Condensation of
b-Naphthol with Arylaldehydes and Meldrum’s Acid: Synthesis of 1-Aryl-1,2-Dihydro-
Benzo[f]Chromen-3-Ones. J. Chem. Res. 2017, 41, 250–252. DOI: 10.3184/
174751917X14902201357374.
[36] Okasha, R.; Alblewi, F.; Afifi, T.; Naqvi, A.; Fouda, A.; Al-Dies, A.-A.; El-Agrody, A.
Design of New Benzo[h]Chromene Derivatives: Antitumor Activities and Structure-
Activity Relationships of the 2,3-Positions and Fused Rings at the 2,3-Positions. Molecules
2017, 22, 479–496. DOI: 10.3390/molecules22030479.
[37] Salem, M. S.; Farhat, M.; Errayes, A. O.; Madkour, H. M. F. Antioxidant Activity of Novel
Fused Heterocyclic Compounds Derived from Tetrahydropyrimidine Derivative. Chem.
Pharm. Bull. 2015, 63, 866–872. DOI: 10.1248/cpb.c15-00452.
[38] Mkaouar, K.; Iriepa, I.; Iriepa, D. D.; Contelles, J. M.; Ismaili, L.; Chabchoub, F. Synthesis
of ( )-Cis-1-Aryl-3-Oxo-2,3-Dihydro-1H-Benzo[f]Chromene-2-Carbonitriles and ( )-Tra
ns-4-Aryl-2-Oxo-3,4-Dihydro-2H-Benzo[h]Chromene-3-Carbonitriles. Chem. Select 2019,
4, 12902–12905.
[39] Chaker, A.; Zribi, F.; Nepveu, F.; Chabchoub, F. Microwave Irradiation: Novel and Facile
Methods for the Synthesis of New Pyrimidinones. Chin. Chem. Lett. 2014, 25, 1207–1210.
DOI: 10.1016/j.cclet.2014.03.048.