Anti-convulsant potential of quinazolinones

Article abstract of DOI:10.1039/c6ra01284a

A series of novel quinazoline derivatives were synthesized, virtually screened through different filters and evaluated for their anticonvulsant activity against electrically and chemically induced seizures, compared with that of the standard drugs methaqualone and sodium valproate. Compound 48, 3-(2-aminophenyl)-7-chloro-2-phenylquinazolin-4(3H)-one, was found to be the most potent compound of the series accompanied by relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that compounds 12, 48, 49 and 50 could be useful templates for future design, optimization, and investigation to construct more active analogs.

Full text of DOI:10.1039/c6ra01284a

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Anti-convulsant Potential of Quinazolinones
Harun M. Patel †, Malleshappa Noolvi §*, Atul Shirkhedkar †, Abhijeet Kulkarni †,
Received 00th January 20xx,
Accepted 00th January 20xx
Chandrakantsing V. Pardeshi†, Sanjay Surana †
DOI: 10.1039/x0xx00000x
Abstract
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Series of novel quinazoline derivatives were synthesized, virtually screened through different filters and
evaluated for the anticonvulsant activity against electrically and chemically induced seizures and compared
with the standard drugs methaqualone and sodium valproate. Compound 48, 3-(2-aminophenyl)-7-chloro-2-
phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series accompanied with
relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference
drugs. The obtained results showed that compounds 12, 48, 49 and 50 could be useful as a template for future
design, optimization, and investigation to construct more active analogs.
Keywords: Quinazoline; Anticonvulsant, MES, PTZ, Neurotoxicity
† Department of Pharmaceutical Chemistry, R.C. Patel College of
Pharmacy, Shirpur, Dhule 425405, Maharashtra, India
§ Department of Pharmaceutical Chemistry, Shree Dhanvantary
Pharmacy College, Kim (Surat)-3941110, Gujrat, India
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1. Introduction
Epilepsy is one of the most common neurological disorders, affecting about 1% of the world’s population.1 Being one of the
world’s oldest recognized disorders; it is surrounded by fear, discrimination, social and frightening manifestations.2 A global
campaign against epilepsy conducted by World Health Organization (WHO) in partnership with International Bureau for Epilepsy
(IBE) and International League Against Epilepsy (ILAE) suggests that around 1% of world population at any time (about 50
million people worldwide) is afflicted with this neurological disorder.3-6
Methaqualone (quinazoline analog) is an important landmark in the field of synthetic anticonvulsants; its chloro analog
(mecloqualone) found to possess marked anticonvulsant potency, which is 1.5 times more potent than phenytoin sodium, against
electroshock-induced convulsions and 10 times more active than troxidone against pentylene tetrazol (PTZ)-induced seizures.7-12
A
persistent problem with these compounds arises from the fact that, nearly every derivative exhibited neurotoxicity values (TD50’s)
that are less than or only slightly higher than the effective doses (ED50’s); consequently, the protective index (PI) corresponding to
TD50/ED50 is too low. 13,14
In view of the previous rationale and in continuation of an ongoing program aiming at finding new structure leads with potential
anticonvulsant activities 15, a new series of 4(3H)-quinazoline pharmacophore was designed with substituted moieties, possessing
different electronic environment in hope of developing potent and safe new effective compounds.
2. Rationale
Various reported facts were analyzed before the chemical synthesis of our target compounds. First fact was: modifications at
second and third positions of methaqualone have led to the generation of many CNS active agents such as afloqualone, etaqualone,
mebroqualone and mecloqualone (Fig. 1). Second fact was: presence of the phenyl group at second position of quinazolin-4(3H)-
one was more significant than methyl and yielded more potent CNS active agents. 16, 17 Third fact explained that: substitution of the
quinazolinone ring with halogens or an electron rich group at sixth, seventh or eighth positions greatly enhanced the anticonvulsant
18,19
activity and reported to possess better activity, longer duration and lower toxicity than phenytoin.
Fig. 1 represents the
structural similarities and pharmacophoric features of some reported anticonvulsants quinazolinones and our designed compounds.
Fig. 1 shows that structure of the title final compounds fulfilled all the pharmacophoric structural requirements. These
requirements includes: quinazolin-4(3H)-one moiety as hydrophobic portion, N of quinazoline ring as electron donor system, the
carbonyl group as hydrogen bonding site and the phenyl ring at 2-position as hydrophobic domain responsible for controlling the
pharmacokinetic properties of the antiepileptic activity. Based on the previously mentioned facts, 16-18 current study was carried out
in hope of developing potent, safe, new and effective anticonvulsant agents with the low dose related toxicity and without
idiosyncratic side effects.
3. Chemistry
Anthranilic acid 1 and 4-chloro 2-amino benzoic acid 39, reaction with benzoyl chloride 2 yielded 2-phenyl-4H-3,1-benzoxazin-4
20
one 3 and 7-chloro 2-phenyl-4H-3,1-benzoxazin-4 one 40 by N-acylation via dehydrative cyclization mechanism. The reaction
of different primary amines containing anilines, sulphonamides, thiadiazoles and hydrazides with 2-phenyl-4H-3,1-benzoxazin-4
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one 3 and 7-chloro 2-phenyl-4H-3,1-benzoxazin-4 one 40 respectively in dry pyridine yielded the corresponding quinazoline-V4ie-woAnreticle Online
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derivatives as shown in Scheme 1-2. Further reaction of 40 with hydrazine hydrate afforded the compound 107 and 108, which on
further condensation with appropriate aromatic aldehydes in glacial acetic acid afforded the arylidene derivatives 109-129
(Scheme 3).
4. Computational Study
The current in silico study was carried out by PASS version (version 9.1, http://www.ibmc.msk.ru/PASS). This software estimates
the predicted activity and toxicity spectrum of a compound as probable activity (Pa) and probable inactivity (Pi). Prediction of this
spectrum by PASS is based on SAR analysis of the training set containing more than 205,000 compounds exhibiting more than
3750 kinds of biological activities. 21, 22
5. Methodology for drug likeness and in silico ADME study
Pharmacokinetic property optimization is a rather complex undertaking that is likely to require changes in those molecular
determinants that are responsible for binding affinity and specificity like hydrogen bonds. It is well known that numerous drug
candidates have failed during clinical tests because of problems related to ADME (absorption, distribution, metabolism and
excretion) properties. We analyzed Lipinski’s rule of five to evaluate drug likeness, or determine if a chemical compound with a
24
certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans.23,
However, it is important to note that there are many violations of this rule among existing drugs and vice versa, and therefore,
qualifying the “rule of five” does not guarantee that a molecule is “drug-like”.23 Topological polar surface area (TPSA) is now
being recognized as a good indicator of drug absorbance in the intestines and blood-brain barrier crossing. 25 The percentage of
absorption (% ABS) was calculated using TPSA. Caco-2 cells are a model for the gut-blood barrier. Caco-2 permeability is good
indicators of drug absorbance in the intestine. MDCK cells and logBB are good markers to determine blood-brain barrier crossing
ability of compounds. PlogKhsa shows the prediction of binding to human serum albumin. Similarly studied number of violations
of Jorgensen’s rule of three. The three rules are: QPlogS > -5.7, QPCaco > 22 nm/s, Primary Metabolites < 7. Compounds with
fewer (and preferably no) violations of these rules are more likely to be orally available.
6. Results and Discussion
The virtual screening protocol used in this study is based on the application of sequential filters in order to select a restricted
number of compounds to be submitted for biological evaluation. The workflow of the virtual screening campaign is outlined in
Fig. 2. Very first, in silico prediction of the anti-convulsant activity have been done and the molecules, which were showing more
than 50% anti-convulsant activity has been considered for the next filter of Lipinski’s rule of five and ADME prediction, which
becomes an essential tool to facilitate drug discovery. As a part of our study, the compliance of compounds to Lipinski’s rule of
five was evaluated. As discussed by Lipinski, molecular properties are closely related to the oral bioavailability of a drug. The
QikProp 3.2 was used to analyze drug likeness (Lipinski’s Rule of Five) and in silico ADME evaluation; the results are given in
Table 1S (supplementary) and it was found that all the synthesized compounds comply with these rules with few exceptions. In
addition, it is well known that numerous drug candidates have failed during clinical tests because of problems related to ADME
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(absorption, distribution, metabolism and excretion) properties. The result for ADME prediction is shown in Table 1S. We
similarly studied number of violations of Jorgensen’s rule of three. The three rules are: QPlogS > -5.7, QPCaco > 22 nm/s, Primary
Metabolites < 7. Compounds with fewer (and preferably no) violations of these rules are more likely to be orally available.
Sequential filter application based upon PASS prediction, Lipinski’s rule and Jorgensen’s rule finalize the seventeen compounds
(6, 8, 12, 17, 18, 38, 45, 46, 47, 48, 49, 50, 51, 54, 55, 60, 73) for animal study.
Human Intestinal Absorption (HIA) and Caco-2 (QPPCaco) permeability are good indicators of drug absorbance in the intestine
and Caco-2 monolayer penetration, respectively. Human Intestinal Absorption data are the sum of bioavailability and absorption
evaluated from the ratio of excretion or cumulative excretion in urine, bile and feces. The predicted percentages of intestinal
absorption are excellent for the virtually screened compounds (80 to 100%). The compounds present good permeability values in
Caco-2 (QPPCaco) cells, ranging from 567 to 3599. Hence, theoretically, all of these virtually screened compounds have good
passive oral absorption. The partition coefficient (QPlogPo/w) and water solubility (QPlogS), critical for estimation of absorption
and distribution of drugs and it is within the body range, between 2.35 to 4.64 and -5.49 to -3.61. Brain/blood partition coefficient
(QPlogBB) predictions are for orally delivered drugs, for example; dopamine and serotonin are CNS negative because they are too
polar to cross the blood-brain barrier. It ranges from -0.57 to 0.33 for virtually screened compounds. All these pharmacokinetic
parameters are within the acceptable range defined for human use (see Table 1S footnote); thereby indicating their potential as a
drug-like molecules.
The anticonvulsant activity and the acute neurotoxicity of the selected virtually screened seventeen compounds (6, 8, 12, 17, 18,
38, 45, 46, 47, 48, 49, 50, 51, 54, 55, 60, and 73) were evaluated. The preliminary screening was performed at 0.5 mmol/kg of all
screened compounds using pentylenetetrazole (PTZ) and MES model of seizures. The MES test is associated with the electrical
induction of the seizure, whereas PTZ methods involve a chemical induction to generate the convulsion.
The initial anticonvulsant evaluation showed that few of these compounds are inactive viz 17,18,38, 45,46, 47, 54, 55, 60, 73;
however, compounds 6, 8, 12, 48, 49, 50 and 51 presented 100% protection against PTZ and MES at 0.5 mmol/kg (Table 1).
As a result of preliminary screening; the most active compounds 6, 8, 12, 48, 49, 50 and 51 were subjected to further investigations
at different doses for quantification of their anticonvulsant activity (indicated by ED50), neurotoxicity (indicated by TD50) and
median lethal dose (indicated by LD50) in mice (Table 2) . The selected compounds 48, 49, 50, 12, 51, 06 and 08 were exhibited
anticonvulsant activity against PTZ-induced seizure with ED50 values of 0.41, 0.53, 0.58, 0.71, 1.50, 1.80, 1.92 mmol/kg,
respectively. Methaqualone and valproate were used as reference drugs and these compounds produced ED50 values of 1.4 and 4.8
mmol/kg, respectively. Interestingly, the ED50 values of the selected compounds were found to be smaller compared to the
reference anticonvulsant drugs at molar doses.
The protective index PI (ED50/TD50) is considered to be an index representing the margin of safety and tolerability between
anticonvulsant doses and doses of anticonvulsant drugs exerting acute adverse effects (e.g., sedation, motor coordination
impairment, ataxia or other neurotoxic manifestations. Evaluation of the acute adverse effect profile (TD50) of compounds 48, 49,
50, and 12 revealed that these agents exerted low neurological deficit (Table 2). The PI values of the selected compounds (12, 48,
49 and 50) were higher than or equal to the reference drugs as compared to 1.14 for methaqualone and 2.0 for valproate. It is
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obvious that the PI values for these selected compounds revealed a difference between the doses producing neurotoxic VaicewtioAnrticle Online
DOI: 10.1039/C6RA01284A
(TD50) and those exerting anti-PTZ (ED50) actions in mice. It is worthwhile to note that the therapeutic index of the selected
compounds (12, 48, 49 and 50) was found to be much higher as compared to the reference anticonvulsant drugs at molar doses
(Table 2).
Structure activity relationship (SAR) study indicated that the different substitution on quinazoline ring, exerted varied
anticonvulsant activities. The electronic nature of the substituent group attached to the quinazoline ring led to a significant
variation in anticonvulsant activity. The anticonvulsant activity of the newly synthesized compounds revealed that compounds
having chloro functional group at 7 position of quinazoline have significant anticonvulsant activity, such as compounds 48, 49, 50
and 51. From the data shown in Table 2, it is clear that the presence of 2-amino phenyl at 3rd position of 7-chloro-2-phenyl
quinazoline results into the most active compound of the series (compound 48). In case of acetyl phenyl substitution at 3rd position
of quinazoline; para substituted is more potent as compare to the ortho and meta (compound 49, 50 and 51) (Fig. 2).
7. Conclusion
New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their anticonvulsant activity in mice using virtual
screening approach. The results of this study demonstrated that compound 48, 3-(2-aminophenyl)-7-chloro-2-phenylquinazolin-
4(3H)-one was found to be the most potent compounds of the series accompanied with relatively low neurotoxicity and low
toxicity in the median lethal dose test as compared to the reference drugs. Structure activity correlation of the investigated
quinazolines proved that; i) the compounds having chloro functional group at 7 position of quinazoline have significant
anticonvulsant activity, ii) presence of 2-amino phenyl at 3rd position of 7-chloro-2-phenyl quinazoline results into the most active
compound of the series, iii) in case of acetyl phenyl substitution at 3rd position of quinazoline; para substituted is more potent as
compare to the ortho and meta. The obtained results showed that compounds 12, 48, 49 and 50 could be useful as a template for
future design, optimization, and investigation to construct more active analogs.
8. Experimental
All the chemicals and solvents were supplied by Sigma-Aldrich and Spectrochem Pvt Ltd. Solvents were distilled and dried before
use if required. The reactions were monitored with the help of thin-layer chromatography using pre-coated aluminum sheets with
GF254 silica gel, 0.2 mm layer thickness (Merck) and the solvent systems of Benzene : Acetone (7:3 and 9:1), Toluene: Ethyl
acetate: Formic acid (5:4:1) and Chloroform: Methanol (9:1) were used. The spots were visualized under UV lamp. Melting points
of the synthesized compounds were determined using one end open capillary tubes on a liquid paraffin bath and are uncorrected.
1
IR spectrum was acquired on Perkin Elmer FT-IR spectrometer. Both H-NMR (DMSO) and 13C NMR (DMSO) spectra of the
synthesized compounds were performed with Bruker Avance-II 400 NMR Spectrometer operating at 400 MHz and 100 MHz
respectively in SAIF, Punjab University (Chandigarh) and their chemical shifts are reported in ppm units with respect to TMS as
internal standard. Mass spectra of the synthesized compounds were recorded at MAT 120 in SAIF, Punjab University.
8.1 2-phenyl-4H-benzo[d][1,3]oxazin-4-one (3a)
It is synthesized as per the reported method. 20
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8.2 General procedure for the synthesis of 3-substituted-2-phenylquinazolin-4(3H)-ones (4-38), except 20 and 38
Equimolar quantity of 2-phenyl-4H-benzo[d][1,3]oxazin-4-one 3 and different primary amino group containing moieties were
°
fused together at 200-250 C in an oil bath for 30 minutes, in such way that reaction mixture should not degraded due to high
heating. The mixture was cooled and ethanol was added to the mixture. The separated solid was collected by filtration, washed
with ethanol, dried and recrystallized multiple times with ethanol to get the pure product.
8.2.1 3-(2-aminoethyl)-2-phenylquinazolin-4(3H)-one (4)
°
Yield 74 %; mp 243-248 C; IR (KBr) ѵmax 3248.56 and 3236.88 (NH2), 3027.82 (Arom.CH strech), 2953.29 (Aliph.CH strech),
1
1671.72 (C=O), 1612.91(NH bend), 1482.74 (C=C), 1456.34 (CH bend) cm-1; H NMR (DMSO-d6) δ 7.12-8.34 (m, 9H, Ar-H),
6.21 (s, 2H, NH2), 4.11 (t, 2H, CH2), 3.60 (t, 2H, CH2); 13C NMR (DMSO-d6) δ 162.95, 158.31, 151.62, 135.91, 133.84, 129.14,
128.55, 128.01, 126.45, 126.04, 125.82, 120.88, 49.53, 36.52. HRMS (EI) m/z calcd for C16H15N3O: 265.1215; found: 265.1221.
8.2.2 3-(1H-benzo[d]imidazol-2-yl)-2-phenylquinazolin-4(3H)-one (5)
°
Yield 62 %; mp above 250 C; IR (KBr) ѵmax 3126.88 (NH strech), 2924.91 (CH strech), 1696.71 (C=O), 1609.45 (NH bend),
1568.46 (C=C), 1385.98 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 12.51 (s, 1H, NH), 6.99-7.96 (m, 13H, Ar-H); 13C NMR (DMSO-
d6) δ 164.75, 156.44, 148.14, 145.98, 138.97, 133.91, 132.65, 132.14, 129.97, 128.73, 128.68, 127.17, 126.94, 126.90, 122.43,
120.28; HRMS (EI) m/z calcd for C21H14N4O: 338.1168; found: 338.1176.
8.2.3 3-(4-acetylphenyl)-2-phenylquinazolin-4(3H)-one (6)
°
Yield 81 %; mp above 250 C; IR (KBr) ѵmax 3026.59 (Arom.CH strech), 2968.37 (Aliph.CH strech), 1712.55 [C=O (ketone)],
1635.78 [C=O (amide)], 1582.12 (C=C), 1445.65 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 7.20-8.36 (m, 13H, Ar-H), 2.57 (s, 3H,
CH3); 13C NMR (DMSO-d6) δ 198.11, 162.30, 158.41, 150.69, 139.39, 138.54, 135.62, 132.13, 130.13, 129.52, 128.68, 128.22,
127.31, 126.67, 125.15, 123.12, 120.63, 24.53. HRMS (EI) m/z calcd for C22H16N2O2: 340.1212; found: 340.1218.
8.2.4 2,2'-diphenyl-4H,4'H-3,3'-biquinazoline-4,4'-dione (7)
°
Yield 85 %; mp above 250 C; IR (KBr) ѵmax 3059.50 (CH strech), 1712.58 (C=O), 1603.43 (C=C), 1447.02 (CH bend) cm-1; 1H
NMR (DMSO-d6) δ 7.20-8.14 (m, 18H, Ar-H); 13C NMR (DMSO-d6) δ 159.83, 153.96, 146.56, 135.54, 132.14, 130.81, 128.30,
128.16, 128.14, 127.85, 127.70, 120.77; HRMS (EI) m/z calcd for C28H18N4O2: 442.1430; found: 442.1435.
8.2.5 3-(3-acetylphenyl)-2-phenylquinazolin-4(3H)-one (8)
°
Yield 65 %; mp 186-189 C; IR (KBr) ѵmax 3126.72 (Arom.CH strech), 2972.82 (Aliph.CH strech), 1718.82 [C=O (ketone)],
1649.88 [C=O (amide)], 1591.17 (C=C), 1468.24 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 7.30-8.21 (m, 13H, Ar-H), 2.48 (s, 3H,
CH3); 13C NMR (DMSO-d6) δ 198.15, 164.63, 158.24, 150.38, 140.35, 135.22, 133.12, 132.66, 131.64, 130.27, 129.71, 129.10,
128.22, 127.31, 126.68, 125.11, 124.30, 120.10, 118.51, 25.15. HRMS (EI) m/z calcd for C22H16N2O2: 340.1212; found: 340.1217.
8.2.6 3-(5-(3,5-dichlorophenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (9)
Yield 42 %; mp 244-248 °C; IR (KBr) ѵmax 3032.93 (CH strech), 1658.64 (C=O), 1568.49 (C=C), 1462.94 (CH bend), 718.18 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 7.16-8.14 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 173.50, 170.11, 162.55, 158.33, 150.18,
138.35, 136.56, 135.36, 132.19, 130.14, 129.51, 129.12, 128.45, 127.67, 127.14, 127.02, 126.10, 121.80. HRMS (EI) m/z calcd for
C22H12Cl2N4OS: 450.0109; found: 450.0104.
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8.2.7 7-chloro-2,2'-diphenyl-4H,4'H-3,3'-biquinazoline-4,4'-dione (10)
Yield 39 %; mp above 250°C; IR (KBr) ѵmax 3047.76 (CH strech), 1724.82 (C=O), 1571.59 (C=C), 1449.29 (CH bend) 764.53 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 7.11-8.31 (m, 17H, Ar-H); 13C NMR (DMSO-d6) δ 158.96, 158.43, 154.65, 153.01, 146.91,
145.88, 141.15, 136.03, 131.37, 131.20, 131.06, 130.87, 128.94, 128.66, 128.29, 128.16, 127.99, 127.60, 127.34, 127.02, 119.87,
118.63; HRMS (EI) m/z calcd for C28H17ClN4O2: 476.1040; found: 477.1044 [M+1].
8.2.8 3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (11)
Yield 31 %; mp 231-234 °C; IR (KBr) ѵmax 3015.87 (Arom.CH strech), 1658.84 (C=O), 1575.89 (C=C), 1461.82 (CH bend) cm-1;
1H NMR (DMSO-d6) δ 6.85-8.05 (m, 13H, Ar-H), 3.84 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 173.17, 170.84, 162.32, 160.62,
158.34, 150.12, 135.10, 132.60, 129.14, 129.00, 128.54, 128.27, 127.11, 126.12, 126.50, 124.35, 121.38, 118.18, 55.94. HRMS
(EI) m/z calcd for C23H16N4O2S: 412.0994; found: 412.0999.
8.2.9 3-(2-aminophenyl)-2-phenylquinazolin-4(3H)-one (12)
°
Yield 28 %; mp above 250 C; IR (KBr) ѵmax 3226.21 and 3208.90 (NH2), 3055.92 (CH strech), 1626.28 (C=O), 1590.91 (NH
bend), 1534.74 (C=C), 1443.34 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 6.99-8.66 (m, 13H, Ar-H), 6.52 (s, 2H, NH2); 13C NMR
(DMSO-d6) δ 159.19, 148.49, 144.37, 134.29, 131.86, 130.98, 129.31, 129.27, 128.37, 128.29, 128.21, 125.61, 124.19, 122.56,
119.96, 118.41, 114.34, 112.4; HRMS (EI) m/z calcd for C16H9Cl2N3S: 313.1215; found: 313.1219
8.2.10 2-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzoic acid (13)
°
Yield 34 %; mp above 250 C; IR (KBr) ѵmax 3062.92 (CH strech), 2530.35 [OH (acid)], 1713.72 [C=O (acid)], 1651.10 [C=O
(amide)], 1565.36 (C=C), 1449.76 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 10.72 (s, 1H, COOH), 7.20-8.23 (m, 13H, Ar-H); 13C
NMR (DMSO-d6) δ 169.80, 164.51, 142.24, 141.71, 138.97, 133.91, 132.65, 132.14, 129.97, 128.73, 128.68, 127.17, 126.94,
126.90, 122.43, 120.28, 119.00, 114.4; HRMS (EI) m/z calcd for C21H14N2O3: 342.1004; found: 342.1009.
8.2.11 N-(4-oxo-2-phenylquinazolin-3(4H)-yl) hydrazine carbothioamide (14)
°
Yield 31 %; mp 183-185 C; IR (KBr) ѵmax 3358.28 (NH strech), 3282.74 and 3245.83 (NH2), 3058.45 (CH strech), 1672.65
(C=O), 1628.84 (NH bend), 1591.55 (C=C), 1438.29 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 10.12 (s, 1H, NH), 9.46 (s, 1H, NH),
7.12-8.25 (m, 9H, Ar-H), 5.12 (s, 2H, NH2); 13C NMR (DMSO-d6) δ 182.11, 163.18, 159.35, 152.19, 135.87, 132.55, 129.85,
129.66, 128.33, 127.17, 126.55, 125.38, 122.37. HRMS (EI) m/z calcd for C15H13N5OS: 311.0841; found: 311.0846.
8.2.12 3-(5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (15)
°
Yield 69 %; mp above 250 C; IR (KBr) ѵmax 3098.12 (Arom.CH strech), 2918.68 (Aliph.CH strech), 1671.12 (C=O), 1561.11
(C=C), 1465.48 (CH bend), 731.12 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.11-8.14 (m, 12H, Ar-H), 2.45 (s, 3H, CH3); 13C NMR
(DMSO-d6) δ 175.14, 170.15, 164.18, 158.28, 150.15, 140.16, 135.67, 134.16, 132.89, 132.67, 131.65, 130.86, 129.68, 128.50,
128.00, 127.66, 127.00, 126.86, 126.00, 122.14, 24.36. HRMS (EI) m/z calcd for C22H13ClN4OS: 416.0499; found: 416.0492.
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8.2.13 N-(2-(2-phenylhydrazinecarbonyl) phenyl) benzamide (16)
°
Yield 56 %; mp 190-194 C; IR (KBr) ѵmax 3279.17 (NH strech), 3029.40 (CH strech), 1683.71 (C=O), 1601.01 (NH bend),
1559.31 (C=C), 1446.22 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 11.80 (s, 1H, NHCO), 11.20 (s, 1H, CONH), 10.72 (s, 1H, NH),
6.64-7.82 (m, 14H, Ar-H); 13C NMR (DMSO-d6) δ 167.80, 164.74, 147.18, 134.92, 133.77, 130.20, 129.26, 129.18, 128.00,
127.92, 127.10, 126.88, 122.32, 121.14, 114.09; HRMS (EI) m/z calcd for C20H17N3O2: 331.1321; found: 331.1321.
8.2.14 3-(3-chloro-4-fluorophenyl)-2-phenylquinazolin-4(3H)-one (17)
Yield 68 %; mp 168-170 °C; IR (KBr) ѵmax 3060.36 (CH strech), 1680.53 (C=O), 1604.96 (C=C), 1445.27 (CH bend), 1084.23 (C-
F), 770.71 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.92-8.23 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 162.06, 158.88, 156.38, 154.59,
134.92, 134.09, 134.05, 131.52, 129.15, 129.08, 128.88, 128.35, 127.86, 127.69, 121.65, 120.64, 116.92; HRMS (EI) m/z calcd for
C20H12ClFN2O: 350.0622; found: 350.0629.
8.2.15 3-(2-acetylphenyl)-2-phenylquinazolin-4(3H)-one (18)
°
Yield 39 %; mp 210-212 C; IR (KBr) ѵmax 3101.34 (Arom.CH strech), 2981.46 (Aliph.CH strech), 1710.38 [C=O (ketone)],
1672.47 [C=O (amide)], 1568.19 (C=C), 1458.38 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 7.09-8.08 (m, 13H, Ar-H), 2.31 (s, 3H,
CH3); 13C NMR (DMSO-d6) δ 198.61, 163.78, 158.89, 156.12, 140.25, 138.46, 136.12, 135.38,132.78, 130.34, 129.12, 128.72,
128.61, 128.28, 127.32,126.68, 126.12, 124.12, 120.82, 26.26. HRMS (EI) m/z calcd for C22H16N2O2: 340.1212; found: 340.1217.
8.2.16 2-benzamido-N-(4-sulfamoylphenyl) benzamide (19)
°
Yield 85 %; mp above 250 C; IR (KBr) ѵmax 3337.55 (NH strech), 3237.55 and 3193.26 (NH2), 3101.98 (CH strech), 1666.16
1
(C=O), 1605.26 (NH bend), 1585.55 (C=C), 1404.88 (CH bend), 1321.15 and 1160.06 [SO (sulphonamide)] cm-1; H NMR
(DMSO-d6) δ 12.84 (s, 1H, NHCO), 12.42 (s, 1H, CONH), 6.83-8.69 (m, 13H, Ar-H), 4.81 (s, 2H, NH2); 13C NMR (DMSO-d6) δ
167.19, 164.21, 148.49, 144.37, 134.29, 131.86, 130.98, 129.31, 129.27, 128.37, 128.29, 128.21, 125.61, 124.19, 122.56, 119.96,
118.41; HRMS (EI) m/z calcd for C20H17N3O4S: 395.0940; found: 395.0946.
8.2.17 N-(2-carbamoylphenyl) benzamide (20)
A compound 3 (0.01 mol) was stirred with concentrated ammonia solution (20 ml) at room temperature for 5 h, the solvent was
evaporated under reduced pressure, the solid was filtered, washed with water, dried and crystallized from ethanol; yield 66 %; mp
°
218-221 C; IR (KBr) ѵmax 3389.76 (NH strech), 3229.72 and 3188.36 (NH2), 3055.79 (CH strech), 1661.09 (C=O), 1619.53 (NH
bend), 1591.05 (C=C), 1451.47 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 13.03 (s, 1H, NHCO), 7.12-8.77 (m, 9H, Ar-H), 3.41 (s,
2H, NH2); 13C NMR (DMSO-d6) δ 171.22, 164.31, 140.22, 134.61, 132.28, 131.67, 128.59, 126.89, 122.27, 119.94, 118.93;
HRMS (EI) m/z calcd for C14H12N2O2: 240.0899; found: 240.0899.
8.2.18 3-(3,4-dichlorophenyl)-2-phenylquinazolin-4(3H)-one (21)
Yield 59 %; mp 165-168 °C; IR (KBr) ѵmax 3063.93 (CH strech), 1675.95 (C=O), 1594.46 (C=C), 1387.93 (CH bend), 771.00 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 6.97-8.34 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 160.19, 156.73, 149.14, 142.00, 131.65,
129.89, 129.55, 127.75, 127.66, 125.92, 125.35, 124.61, 123.64, 123.27, 123.19, 122.65; HRMS (EI) m/z calcd for C20H12Cl2N2O:
366.0327; found: 366.0332.
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8.2.19 N-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzamide (22)
°
Yield 46 %; mp 198-201 C; IR (KBr) ѵmax 3169.09 (NH strech), 3056.62 (CH strech), 1711.81 [C=O (ketone)], 1671.89 [C=O
(amide)], 1595.94 (NH bend), 1566.44 (C=C), 1372.93 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 10.72 (s, 1H, NH), 6.98-8.36 (m,
14H, Ar-H); 13C NMR (DMSO-d6) δ 169.92, 159.82, 155.72, 149.23, 147.03, 135.40, 133.95, 133.53, 132.47, 130.42, 129.93,
129.18, 128.66, 128.30, 128.20, 128.08, 127.96, 127.69; HRMS (EI) m/z calcd for C21H15N3O2: 341.1164; found: 341.1169.
8.2.20 4-bromo-N-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzamide (23)
°
Yield 41 %; mp 221-224 C; IR (KBr) ѵmax 3282.34 (NH strech), 3083.26 (CH strech), 1728.72 [C=O (ketone)], 1672.38 [C=O
(amide)], 1626.84 (NH bend), 1568.26 (C=C), 1452.97 (CH bend), 601.83 (C-Br) cm-1; 1H NMR (DMSO-d6) δ 11.31 (s, 1H, NH),
6.82-7.98 (m, 13H, Ar-H); 13C NMR (DMSO-d6) δ 166.37, 162.15, 158.36, 152.32, 135.98, 132.84, 131.86, 130.68, 129.65,
128.94, 128.47, 128.00, 127.80, 126.5, 126.37, 126.00, 120.90. HRMS (EI) m/z calcd for C21H14BrN3O2: 419.0269; found:
419.0274.
8.2.21 3-(5-benzyl-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (24)
°
Yield 52 %; mp 248-250 C; IR (KBr) ѵmax 3092.54 (Arom.CH strech), 2926.28 (Aliph.CH strech), 1658.26 (C=O), 1542.25
(C=C), 1465.46 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 6.45-7.89 (m, 14H, Ar-H), 4.21 (s, 2H, CH2); 13C NMR (DMSO-d6) δ
172.87, 164.55, 162.36, 158.37, 150.85, 138.88, 135.86, 133.78, 130.19, 129.65, 129.57, 129.00, 128.31, 127.47, 126.35, 126.00,
125.38, 120.11, 36.30. HRMS (EI) m/z calcd for C23H16N4OS: 396.1045; found: 396.1051.
8.2.22 2-phenyl-3-(5-phenyl-1,3,4-thiadiazol-2-yl)quinazolin-4(3H)-one (25)
Yield 49 %; mp above 250 °C; IR (KBr) ѵmax 3034.85 (Arom.CH strech), 1678.28 (C=O), 1534.95 (C=C), 1471.83 (CH bend) cm-
1; 1H NMR (DMSO-d6) δ 6.54-7.92 (m, 14H, Ar-H); 13C NMR (DMSO-d6) δ 172.88, 170.36, 162.35, 158.68, 150.37, 135.68,
135.05, 132.87, 132.55, 131.34, 129.87, 129.75, 129.37, 128.25, 127.63, 126.37, 126.03, 120.90. HRMS (EI) m/z calcd for
C22H14N4OS: 382.0888; found: 382.0894.
8.2.23 3-(3,5-dichlorophenyl)-2-phenylquinazolin-4(3H)-one (26)
Yield 56 %; mp 188-190 °C; IR (KBr) ѵmax 3051.48 (CH strech), 1662.89 (C=O), 1584.53 (C=C), 1482.89 (CH bend), 742.79 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 6.38-8.11 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 164.27, 158.30, 150.15, 138.24, 135.35,
133.14, 132.85, 131.33, 130.67, 130.35, 130.07, 127.65, 126.36, 126.08, 125.35, 120.67. HRMS (EI) m/z calcd for C20H12Cl2N2O:
366.0327; found: 366.0332.
8.2.24 3-(3,4-difluorophenyl)-2-phenylquinazolin-4(3H)-one (27)
Yield 58 %; mp 243-246 °C; IR (KBr) ѵmax 3088.16 (CH strech), 1651.61 (C=O), 1603.15 (C=C), 1427.48 (CH bend), 1209.02 (C-
1
F) cm-1; H NMR (DMSO-d6) δ 7.17-8.70 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 164.74, 150.36, 148.06, 147.48, 145.06,
134.52, 132.46, 131.81, 128.76, 128.68, 127.02, 122.65, 121.25, 120.96, 117.01, 116.89, 116.72, 110.37, 110.16; HRMS (EI) m/z
calcd for C20H12F2N2O: 334.0918; found: 334.0923.
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8.2.25 4-hydroxy-N-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzamide (28)
°
Yield 38 %; mp 241-244 C; IR (KBr) ѵmax 3415.36 (OH strech), 3309.69 (NH strech), 3023.88 (CH strech), 1712.58 [C=O
(ketone)], 1688.59 [C=O (amide)], 1603.43 (NH bend), 1594.26 (C=C), 1447.02 (CH bend) cm-1; 1H NMR (DMSO-d6) δ 12.03 (s,
1H, NH), 7.03-8.25 (m, 13H, Ar-H), 4.22 (s, 1H, OH); 13C NMR (DMSO-d6) δ 164.34, 161.05, 155.30, 150.23, 146.67, 134.65,
133.86, 129.46, 129.30, 127.26, 127.23, 126.34, 125.92, 123.46, 121.86, 115.97; HRMS (EI) m/z calcd for C21H15N3O3: 357.1113;
found: 357.1117.
8.2.26 3-(2-fluorophenyl)-2-phenylquinazolin-4(3H)-one (29)
Yield 71 %; mp 145-148 °C; IR (KBr) ѵmax 3028.38 (CH strech), 1662.82 (C=O), 1592.28 (C=C), 1462.82 (CH bend), 1019.62 (C-
1
F) cm-1; H NMR (DMSO-d6) δ 6.59-7.98 (m, 13H, Ar-H); 13C NMR (DMSO-d6) δ 164.37, 161.35, 160.22, 150.66, 135.37,
132.36, 132.05, 131.3, 129.67, 129.44, 129.00, 128.45, 127.43, 127.07, 126.31, 125.25, 120.32, 118.40. HRMS (EI) m/z calcd for
C20H13FN2O: 316.1012; found: 316.1017.
8.2.27 3-(5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (30)
°
Yield 38 %; mp above 250 C; IR (KBr) ѵmax 3082.89 (CH strech), 1660.72 (C=O), 1482.89 (C=C), 1468.28 (CH bend), 1548.24
and 1342.68 (NO2) cm-1; 1H NMR (DMSO-d6) δ 6.14-7.78 (m, 13H, Ar-H); 13C NMR (DMSO-d6) δ 72.87, 170.14, 162.34, 158.35,
150.32, 150.08, 139.47, 136.35, 135.36, 132.45, 132.00, 129.87, 129.65, 128.46, 127.35, 126.67, 126.56, 123.85, 122.64, 120.61.
HRMS (EI) m/z calcd for C22H13N5O3S: 427.0739; found: 427.0743.
8.2.28 3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (31)
°
Yield 81 %; mp 224-228 C; IR (KBr) ѵmax 3068.74 (Arom.CH strech), 2973.01 (Aliph.CH strech), 1677.32 (C=O), 1560.25
1
(C=C), 1468.23 (CH bend) cm-1; H NMR (DMSO-d6) δ 7.17-8.88 (m, 9H, Ar-H), 1.08-2.34 (m, 5H, cyclopropyl); 13C NMR
(DMSO-d6) δ 175.41, 170.90, 159.15, 146.90, 140.84, 134.81, 134.45, 131.99, 129.45, 128.83, 127.42, 123.22, 121.44, 117.58,
11.09, 10.65; HRMS (EI) m/z calcd for C19H14N4OS: 346.0888; found: 347.0882 [M+1].
8.2.29 3,4-dinitro-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)benzamide (32)
°
Yield 31 %; mp 160-164 C; IR (KBr) ѵmax 3302.26 (NH strech), 3066.10 (CH strech), 1692.86 (C=O), 1594.25 (NH bend),
1472.34 (C=C), 1432.85 (CH bend), 1516.63 and 1339.35 (NO2) cm-1; 1H NMR (DMSO-d6) δ 11.80 (s, 1H, NH), 7.20-8.23 (m,
12H, Ar-H); 13C NMR (DMSO-d6) δ 164.74, 158.18, 155.74, 147.18, 145.20, 134.92, 133.77, 130.20, 129.26, 129.18, 128.00,
127.92, 127.10, 126.88, 122.32, 121.14, 114.09; HRMS (EI) m/z calcd for C21H13N5O6: 431.0866; found: 431.0872.
8.2.30 3-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (33)
°
Yield 41 %; mp above 250 C; IR (KBr) ѵmax 3087.18 (CH strech), 1673.73 (C=O), 1604.03 (C=C), 1449.81 (CH bend), 1531.33
1
and 1349.73 (NO2) cm-1; H NMR (DMSO-d6) δ 7.23-8.24 (m, 13H, Ar-H); 13C NMR (DMSO-d6) δ 174.23, 170.46, 164.46,
159.20, 146.52, 138.42, 134.85, 134.58, 131.34, 129.98, 129.92, 129.78, 129.23, 129.14, 127.93, 127.91, 127.30, 127.13, 121.46;
HRMS (EI) m/z calcd for C22H13N5O3S: 427.0739; found: 427.0744.
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8.2.31 2-phenyl-3-(3,4,5-trichlorophenyl)quinazolin-4(3H)-one (34)
Yield 48 %; mp 152-156 °C; IR (KBr) ѵmax 3037.97 (CH strech), 1714.91 (C=O), 1611.53 (C=C), 1449.28 (CH bend), 764.78 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 7.47-8.23 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 159.53, 157.04, 150.41, 146.91, 142.11,
136.54, 132.59, 130.16, 128.71, 128.55, 128.27, 128.22, 127.19, 126.21, 125.87, 121.14, 116.95; HRMS (EI) m/z calcd for
C20H11Cl3N2O: 399.9937; found: 399.9942.
8.2.32 2-phenyl-3-(2,4,5-trichlorophenyl)quinazolin-4(3H)-one (35)
Yield 41 %; mp 196-201 °C; IR (KBr) ѵmax 3083.56 (CH strech), 1678.45 (C=O), 1578.67 (C=C), 1488.28 (CH bend), 732.67 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 7.42-8.23 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 164.62, 158.37, 150.65, 137.34, 135.49,
132.39, 132.07, 131.45, 130.18, 129.84, 129.65, 129.43, 128.45, 127.65, 126.30, 126.04, 124.35, 120.68. HRMS (EI) m/z calcd for
C20H11Cl3N2O: 344.9894; found: 344.9899.
8.2.33 4-methyl-N-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzamide (36)
°
Yield 36 %; mp 234-237 C; IR (KBr) ѵmax 3282.18 (NH strech), 3081.82 (Arom.CH strech), 2964.89 (Aliph.CH strech), 1708.28
[C=O (ketone)], 1668.95 [C=O (amide)], 1621.82 (NH bend), 1582.92 (C=C), 1472.82 (CH bend) cm-1; 1H NMR (DMSO-d6) δ
11.69 (br s, 1H, NH), 7.23-8.24 (m, 13H, Ar-H), 2.37 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 165.33, 159.65, 156.19, 146.70,
142.43, 134.68, 133.42, 129.79, 128.79, 128.45, 128.38, 127.53, 127.46, 126.91, 126.42, 120.86, 21.09; HRMS (EI) m/z calcd for
C22H17N3O2: 355.1321; found: 355.1326.
8.2.34 N-(4-oxo-2-phenylquinazolin-3(4H)-yl) acetamide (38)
A compound 3 (0.01 mol) was melted in beaker and excess of hydrazine hydrate was added and heated further for 30 minutes. The
mixture was cooled and water was added to the mixture. The separated solid of 37 was collected by filtration, washed with water,
dried and recrystallized from ethanol; it is further acylated with acetic anhydride by refluxing for 4 h. The solvent was removed
under reduced pressure. The residue was triturated with petroleum ether 40-60. The separated solid was collected by filtration,
washed with petroleum ether 40-60, dried and recrystallized from toluene; yield 31 %; mp 154-158 °C; IR (KBr) ѵmax 3198.38 (NH
strech), 3047.28 (Arom.CH strech), 2948.74 (Aliph.CH strech), 1713.84 (C=O), 1629.73 (NH bend), 1572.52 (C=C), 1462.45 (CH
1
bend) cm-1; H NMR (DMSO-d6) δ 11.81 (s, 1H, NH), 6.88-7.61 (m, 9H, Ar-H), 2.34 (s, 3H, CH3); 13C NMR (DMSO-d6) δ
169.23, 162.78, 159.82, 152.56, 134.85, 130.26, 128.76, 128.62, 128.20, 126.47, 125.46, 124.85, 122.54, 23.56. HRMS (EI) m/z
calcd for C16H13N3O2: 279.1008; found: 279.1002.
8.3 7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one (4a)
It is synthesized as per the reported method [20].
8.4 7-chloro-3-hydroxy-2-phenylquinazolin-4(3H)-one (41)
Equimolar quantity of 7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 40 and hydroxylamine hydrochloride in dry pyridine (30
ml) was heated under reflux for 8 h. The reaction mixture was poured into cold 5 % dilute HCl, solution (100 ml). The separated
°
solid was filtered, washed with water and recrystallized with ethanol; yield 33 %; mp 210-214 C; IR (KBr) ѵmax 3416.26 (OH
strech), 3026.96 (CH strech), 1662.87 (C=O), 1582.86 (C=C), 1422.76 (CH bend), 708.82 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ
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10.41 (s, 1H, OH), 6.99-7.88 (m, 8H, Ar-H); C NMR (DMSO-d6) δ 158.32, 157.33, 154.37, 137.48, 132.45, 132.05, 1V2i9ew.6A3r,ticle Online
DOI: 10.1039/C6RA01284A
129.45, 129.08, 127.64, 123.61, 120.11. HRMS (EI) m/z calcd for C14H9ClN2O2: 272.0353; found: 272.0358.
8.5 7-chloro-2-phenylquinazoline-4(3H)-thione (43)
7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 40 (0.01 mol) and excess of formamide were fused together at 200-250 °C in an
oil bath for 15 minutes. The mixture was cooled and ethanol was added to the mixture. The separated solid of 42 was collected by
filtration, washed with ethanol, dried and recrystallized from ethanol; it is further refluxed with P2S5 in xylene for 1h. The solution
was cooled and the product precipitated. The solid was collected and recrystallized from methanol; yield 34 %; mp 235-238 °C; IR
(KBr) ѵmax 3202.46 (NH), 2928.53 (CH strech), 1593.29 (NH bend), 1560.57 (C=C), 1448.72 (CH bend), 756.47 (C-Cl) cm-1; 1H
NMR (DMSO-d6) δ 13.80 (s, 1H, NH), 7.54-8.60 (m, 8H, Ar-H); 13C NMR (DMSO-d6) δ 152.56, 145.43, 140.45, 131.83, 131.54,
131.15, 128.44, 128.31, 127.90, 127.82, 127.19, 126.60; HRMS (EI) m/z calcd for C14H9ClN2S: 272.0175; found: 272.0175.
8.6 N-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl) acetamide (45)
7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 40 (0.01 mol) (0.01 mol) was melted in beaker and excess of hydrazine hydrate
was added and heated further for 30 minutes. The mixture was cooled and water was added to the mixture. The separated solid of
44 was collected by filtration, washed with water, dried and recrystallized from ethanol; it is further acylated with acetic anhydride
by refluxing for 4 h. The solvent was removed under reduced pressure. The residue was triturated with petroleum ether 40-60. The
separated solid was collected by filtration, washed with petroleum ether 40-60, dried and recrystallized from toluene; yield 38 %;
°
mp 217-221 C; IR (KBr) ѵmax 3314.96 (NH strech), 3020.48 (Arom.CH strech), 2939.21 (Aliph.CH strech), 1724.15 [C=O
1
(ketone)], 1701.30 [C=O (amide)], 1559.53 (C=C), 1615.75 (NH bend), 1444.48 (CH bend), 772.87 (C-Cl) cm-1; H NMR
(DMSO-d6) δ 9.47 (s, 1H, NH), 7.27-8.26 (m, 8H, Ar-H), 2.30 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 169.95, 158.90, 156.25,
147.73, 142.03, 132.34, 130.95, 128.85, 128.78, 128.58, 127.9, 127.57, 119.45, 24.65; HRMS (EI) m/z calcd for C16H12ClN3O2:
313.0618; found: 313.0623.
8.7 General procedure for the synthesis of 3-substituted-7-chloro-2-phenylquinazolin-4(3H)-ones (46-105), except 91
Equimolar quantity of 7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 40 and different primary amino group containing moieties
were fused together at 200-250 °C in an oil bath for 30 minutes. The mixture was cooled and ethanol was added to the mixture. The
separated solid was collected by filtration, washed with ethanol, dried and recrystallized multiple times with ethanol and dioxane to
get the pure product.
8.7.1 7-chloro-2-phenyl-3-(phenylamino) quinazolin-4(3H)-one (46)
°
Yield 54 %; mp above 250 C; IR (KBr) ѵmax 3261.17 (NH strech), 3059.11 (CH strech), 1677.70 (C=O), 1599.72 (NH bend),
1571.23 (C=C), 1445.26 (CH bend), 693.88 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 12.64 (s, 1H, NH), 7.47-8.21 (m, 13H, Ar-H); 13
C
NMR (DMSO-d6) δ 161.80, 156.74, 150.37, 147.18, 134.92, 133.77, 130.20, 129.18, 129.00, 128.00, 127.92, 127.10, 126.88,
122.32, 121.14, 114.09; HRMS (EI) m/z calcd for C20H14ClN3O: 347.0825; found: 348.0830 [M+1]
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8.7.2 4-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl) benzene sulfonamide (47)
°
Yield 82 %; mp above 250 C; IR (KBr) ѵmax 3318.51 and 3280.87 (NH2), 3118.55 (CH strech), 1667.94 (C=O), 1640.68 (NH
bend), 1582.35 (C=C), 1400.47 (CH bend), 1342.67 and 1161.73 [SO (sulphonamide)], 695.45 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ
6.77-8.70 (m, 12H, Ar-H), 4.79 (s, 2H, NH2); 13C NMR (DMSO-d6) δ 161.49, 155.82, 149.65, 148.30, 141.35, 136.48, 135.06,
130.01, 129.07, 128.67, 128.44, 128.21, 127.49, 123.51, 119.06, 118.67; HRMS (EI) m/z calcd for C20H14ClN3O3S: 411.0444;
found: 412.0442 [M+1].
8.7.3 3-(2-aminophenyl)-7-chloro-2-phenylquinazolin-4(3H)-one (48)
°
Yield 62 %; mp above 250 C; IR (KBr) ѵmax 3171.26 and 3131.98 (NH2), 3065.33 (CH strech), 1671.48 (C=O), 1602.48 (NH
bend), 1569.04 (C=C), 1444.24 (CH bend), 693.14 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.14-8.21 (m, 12H, Ar-H), 6.65 (s, 2H,
NH2); 13C NMR (DMSO-d6) δ 161.67, 151.26, 149.21, 143.67, 134.91, 130.08, 129.49, 128.55, 126.35, 122.27, 121.47, 121.23,
118.63, 118.09, 114.92, 114.64, 111.08, 110.55; HRMS (EI) m/z calcd for C20H14ClN3O: 347.0825; found: 348.0831 [M+1].
8.7.4 3-(4-acetylphenyl)-7-chloro-2-phenylquinazolin-4(3H)-one (49)
°
Yield 63 %; mp 244-249 C; IR (KBr) ѵmax 3042.34 (Arom.CH strech), 2912.78 (Aliph.CH strech), 1705.43 [C=O (ketone)],
1662.78 [C=O (amide)], 1598.23 (C=C), 1461.24 (CH bend), 749.23 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.08-8.18 (m, 12H, Ar-
H), 2.98 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 198.17, 164.68, 160.35, 156.33, 141.65, 141.56, 140.66, 134.35, 134.06, 132.66,
129.66, 129.57, 129.35, 128.47, 125.65, 122.63, 120.60, 24.30. HRMS (EI) m/z calcd for C22H15ClN2O2: 374.0822; found:
374.0828.
8.7.5 3-(3-acetylphenyl)-7-chloro-2-phenylquinazolin-4(3H)-one (50)
°
Yield 54 %; mp above 250 C; IR (KBr) ѵmax 3082.87 (Arom.CH strech), 2978.45 (Aliph.CH strech), 1712.87 [C=O (ketone)],
1642.89 [C=O (amide)], 1543.68 (C=C), 1446.47 (CH bend), 724.87 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.81-8.01 (m, 12H, Ar-
H), 2.69 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 198.45, 162.62, 158.33, 154.45, 139.45, 138.66, 135.64, 134.67, 134.38, 132.60,
132.49, 128.64, 128.42, 128.02, 127.45, 124.46, 122.76, 120.60, 118.41, 25.30. HRMS (EI) m/z calcd for C22H15ClN2O2:
374.0822; found: 374.0828.
8.7.6 3-(2-acetylphenyl)-7-chloro-2-phenylquinazolin-4(3H)-one (51)
°
Yield 32 %; mp 192-194 C; IR (KBr) ѵmax 3111.20 (Arom.CH strech), 2924.66 (Aliph.CH strech), 1681.55 [C=O (ketone)],
1645.32 [C=O (amide)], 1606.71 (C=C), 1421.30 (CH bend), 759.92 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.23-8.38 (m, 12H, Ar-
H), 2.74 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 199.14, 164.94, 160.01, 141.35, 139.60, 138.65, 134.81, 133.88, 131.72, 131.66,
128.39, 128.33, 126.82, 123.09, 122.79, 122.03, 120.58, 120.47, 118.13, 28.16; HRMS (EI) m/z calcd for C22H15ClN2O2:
374.0822; found: 375.0828[M+1].
8.7.7 N-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl) benzamide (52)
°
Yield 41 %; mp above 250 C; IR (KBr) ѵmax 3314.96 (NH strech), 3020.48 (CH strech), 1724.15 [C=O (ketone)], 1701.12 [C=O
(amide)], 1595.89 (NH bend), 1559.53 (C=C), 1444.48 (CH bend), 707.70 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 9.60 (s, 1H, NH),
7.26-8.13 (m, 13H, Ar-H); 13C NMR (DMSO-d6) δ 170.92, 160.82, 155.72, 149.23, 147.03, 133.53, 132.47, 130.42, 129.93,
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129.18, 128.66, 128.30, 128.20, 128.08, 127.96, 127.69, 127.39, 123.96, 121.33; HRMS (EI) m/z calcd for C21H14ClN3O2:
375.0775; found: 375.0775.
8.7.8 N-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl)-4-methylbenzamide (53)
°
Yield 52 %; mp 241-246 C; IR (KBr) ѵmax 3238.76 (NH strech), 3120.75 (Arom.CH strech), 2933.48 (Aliph.CH strech), 1708.24
[C=O (ketone)], 1682.32 [C=O (amide)], 1609.34 (NH bend), 1538.93 (C=C), 1489.23 (CH bend), 734.92 (C-Cl) cm-1; 1H NMR
(DMSO-d6) δ 10.31 (s, 1H, NH), 6.11-7.68 (m, 12H, Ar-H), 2.58 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 169.55, 162.64, 158.377,
154.66, 143.43, 140.45, 134.37, 134.22, 132.65, 132.12, 128.65, 128.47, 128.02, 127.62, 126.33, 124.55, 120.15, 23.40. HRMS
(EI) m/z calcd for C22H16ClN3O2: 389.0931; found: 389.0936.
8.7.9 7-chloro-2-phenyl-3-(pyridin-2-yl) quinazolin-4(3H)-one (54)
Yield 88 %; mp 211-215 °C; IR (KBr) ѵmax 3089.78 (CH strech), 1662.89 (C=O), 1586.21 (C=C), 1462.45 (CH bend), 721.68 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 6.12-7.98 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 158.28, 154.27, 150.37, 149.37, 138.48,
137.45, 132.57, 130.45, 129.45, 129.12, 127.47, 126.45, 123.49, 122.73, 120.47, 118.34. HRMS (EI) m/z calcd for C19H12ClN3O:
333.0669; found: 333.0675.
8.7.10 7-chloro-2-phenyl-3-(pyridin-3-yl) quinazolin-4(3H)-one (55)
Yield 81 %; mp 230-235 °C; IR (KBr) ѵmax 3063.52 (CH strech), 1684.71 (C=O), 1598.68 (C=C), 1421.88 (CH bend), 702.79 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 7.25-8.50 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 161.49, 155.82, 149.65, 149.34, 148.30,
141.35, 136.48, 134.42, 134.34, 130.01, 129.07, 128.67, 128.44, 128.21, 127.49, 123.51, 119.06; HRMS (EI) m/z calcd for
C19H12ClN3O: 333.0669; found: 334.0671[M+1].
8.7.11 7-chloro-3-(naphthalen-1-yl)-2-phenylquinazolin-4(3H)-one (56)
Yield 83 %; mp 156-160 °C; IR (KBr) ѵmax 3060.29 (CH strech), 1689.09 (C=O), 1593.69 (C=C), 1421.60 (CH bend), 769.65 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 7.00-8.30 (m, 15H, Ar-H); 13C NMR (DMSO-d6) δ 161.70, 157.45, 148.60, 141.10, 134.83,
134.20, 133.92, 130.28, 129.65, 129.63, 128.82, 128.64, 127.99, 127.44, 127.66, 127.45, 127.34, 126.56, 125.08, 122.12, 119.26;
HRMS (EI) m/z calcd for C24H15ClN2O: 382.0873; found: 383.0876 [M+1].
8.7.12 7-chloro-3-(3,4-difluorophenyl)-2-phenylquinazolin-4(3H)-one (57)
Yield 80 %; mp 227-230 °C; IR (KBr) ѵmax 3111.18 (CH strech), 1651.78 (C=O), 1601.07 (C=C), 1427.61 (CH bend), 1280.08 (C-
F), 705.42 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.96-7.53 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 161.51, 155.86, 148.23, 141.33,
134.62, 130.09, 129.01, 128.81, 128.68, 128.39, 128.21, 127.47, 127.40, 125.65, 125.55, 119.12, 118.93, 117.63; HRMS (EI) m/z
calcd for C20H11ClF2N2O: 368.0528; found: 368.0532.
8.7.13 7-chloro-3-(2-methoxyphenyl)-2-phenylquinazolin-4(3H)-one (58)
Yield 71 %; mp 198-202 °C; IR (KBr) ѵmax 3029.65 (CH strech), 1648.23 (C=O), 1543.69 (C=C), 1462.23 (CH bend), 771.38 (C-
Cl) cm-1; 1H NMR (DMSO-d6) δ 7.06-7.88 (m, 12H, Ar-H), 3.89 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 164.35, 160.30, 158.65,
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156.66, 141.67, 134.65, 134.26, 128.68, 128.45, 128.35, 127.62, 126.37, 125.35, 123.66, 120.10, 119.60, 118.38, 116.66, 55.31.
HRMS (EI) m/z calcd for C21H15ClN2O2: 362.0822; found: 362.0828.
8.7.14 7-chloro-3-(3-methoxyphenyl)-2-phenylquinazolin-4(3H)-one (59)
Yield 66 %; mp 201-205 °C; IR (KBr) ѵmax 3073.27 (CH strech), 1689.24 (C=O), 1578.36 (C=C), 1458.68 (CH bend), 734.87 (C-
Cl) cm-1; 1H NMR (DMSO-d6) δ 6.88-8.10 (m, 12H, Ar-H), 3.83 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 163.67, 160.65, 158.33,
154.35, 139.69, 135.46, 132.65, 132.46, 130.42, 130.27, 129.65, 129.46, 127.45, 122.72, 120.40, 119.65, 118.42, 112.65, 55.15.
HRMS (EI) m/z calcd for C21H15ClN2O2: 362.0822; found: 362.0828.
8.7.15 7-chloro-3-(4-methoxyphenyl)-2-phenylquinazolin-4(3H)-one (60)
Yield 62 %; mp 200-204 °C; IR (KBr) ѵmax 3056.62 (CH strech), 1711.81 (C=O), 1595.94 (C=C), 1446.28 (CH bend), 771.14 (C-
Cl) cm-1; 1H NMR (DMSO-d6) δ 6.68-7.52 (m, 12H, Ar-H), 3.78 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 65.89, 160.23, 156.12,
150.04, 138.41, 134.13, 132.29, 130.12, 129.94, 128.92, 127.95, 127.46, 123.05, 121.70, 119.34, 113.16, 55.44; HRMS (EI) m/z
calcd for C21H15ClN2O2: 362.0822; found: 363.0825 [M+1].
8.7.16 4-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl) benzoic acid (61)
°
Yield 81 %; mp 169-174 C; IR (KBr) ѵmax 3315.78 (OH strech), 3063.95 (CH strech), 1755.52 [C=O (acid)], 1665.51 [C=O
(amide)], 1576.49 (C=C), 1312.75 (C-H bend), 775.31 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 10.94 (s, 1H, COOH), 7.17-8.69 (m,
12H, Ar-H); 13C NMR (DMSO-d6) δ 169.44, 164.75, 145.98, 142.24, 138.97, 133.91, 132.65, 132.14, 129.97, 128.73, 128.68,
127.17, 126.94, 126.90, 122.43, 120.28, 119.00; HRMS (EI) m/z calcd for C21H13ClN2O3: 376.0615; found: 377.0621 [M+1].
8.7.17 7-chloro-3-(4-hydroxyphenyl)-2-phenylquinazolin-4(3H)-one (62)
Yield 29 %; mp above 250 °C; IR (KBr) ѵmax 3346.05 (OH strech), 3062.81 (CH strech), 1672.95 (C=O), 1595.74 (C=C), 1431.36
(C-H bend), 698.14 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.79-8.85 (m, 12H, Ar-H), 4.86 (s, 1H, OH); 13C NMR (DMSO-d6) δ
164.93, 158.68, 154.65, 140.99, 137.54, 134.19, 131.98, 129.89, 129.36, 128.69, 127.10, 127.06, 123.52, 122.28, 120.15, 119.03,
115.20; HRMS (EI) m/z calcd for C20H13ClN2O2: 348.0666; found: 348.0666.
8.7.18 2-benzamido-4-chloro-N-(4-nitrophenyl) benzamide (63)
°
Yield 38 %; mp 206-208 C; IR (KBr) ѵmax 3221.82 (NH strech), 3012.29 (CH strech), 1669.23 (C=O), 1612.27 (NH bend),
1
1529.18 (C=C), 1443.21 (C-H bend), 701.28 (C-Cl), 1542.01 and 1348.23 (NO2) cm-1; H NMR (DMSO-d6) δ 12.31 (s, 1H,
NHCO), 11.68 (s, 1H, CONH), 7.39-8.26 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 167.58, 164.35, 148.33, 147.54, 144.67,
142.68, 138.35, 136.65, 132.16, 128.66, 127.50, 124.34, 124.25, 121.65, 120.67, 118.62. HRMS (EI) m/z calcd for C20H14ClN3O4:
395.0673; found: 395.0679.
8.7.19 2-benzamido-4-chloro-N-(3,4-dichlorophenyl)benzamide (64)
°
Yield 52 %; mp 181-184 C; IR (KBr) ѵmax 3285.46 (NH strech), 3020.48 (CH strech), 1726.14 (C=O), 1638.99 (NH bend),
1597.05 (C=C), 1411.46 (C-H bend), 703.99 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 12.03 (s, 1H, NHCO), 10.71 (s, 1H, CONH),
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7.03-8.25 (m, 11, Ar-H); 13C NMR (DMSO-d6) δ 167.80, 164.74, 139.47, 135.35, 135.32, 135.26, 135.23, 134.52, 132.46, 1V3i1ew.8A1r,ticle Online
DOI: 10.1039/C6RA01284A
128.76, 128.68, 127.02, 122.65, 121.25, 120.96, 117.10, 116.89; HRMS (EI) m/z calcd for C20H13Cl3N2O2: 418.0043; found:
418.0049.
8.7.20 2-benzamido-4-chloro-N-(3,5-dichlorophenyl)benzamide (65)
°
Yield 58 %; mp 202-205 C; IR (KBr) ѵmax 3292.46 (NH strech), 3102.21 (CH strech), 1678.31 (C=O), 1601.24 (NH bend),
1563.27 (C=C), 1429.83 (C-H bend), 746.73 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 11.39 (s, 1H, NHCO), 10.31 (s, 1H, CONH),
7.54-8.38 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 167.64, 164.13, 144.34, 143.65, 142.17, 138.65, 136.62, 133.15, 130.66,
129.30, 128.65, 125.30, 125.11, 122.42, 121.34, 120.66. HRMS (EI) m/z calcd for C20H13Cl3N2O2: 418.0043; found: 418.0049.
8.7.21 2-benzamido-4-chloro-N-(2,5-dichlorophenyl)benzamide (66)
°
Yield 51 %; mp 221-225 C; IR (KBr) ѵmax 3239.68 (NH strech), 3078.67 (CH strech), 1681.89 (C=O), 1615.29 (NH bend),
1591.03 (C=C), 1463.38 (C-H bend), 719.28 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 11.88 (s, 1H, NHCO), 11.21 (s, 1H, CONH),
7.21-8.13 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 167.34, 164.24, 144.36, 142.63, 139.65, 138.32, 136.33, 136.02, 132.63,
129.64, 129.44, 128.42, 126.35, 124.57, 122.30, 122.42, 120.10. HRMS (EI) m/z calcd for C20H13Cl3N2O2: 418.0043; found:
418.0051.
8.7.22 7-chloro-3-(3-chloro-4-fluorophenyl)-2-phenylquinazolin-4(3H)-one (67)
Yield 65 %; mp 209-213 °C; IR (KBr) ѵmax 3068.79 (CH strech), 1685.11 (C=O), 1597.20 (C=C), 1398.17 (CH bend), 1148.97 (C-
F), 709.23 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.02-8.09 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 159.06, 156.73, 149.14, 142.00,
137.65, 131.65, 129.89, 129.55, 127.75, 127.66, 125.92, 125.35, 124.61, 123.64, 123.27, 123.19, 122.65, 118.14; HRMS (EI) m/z
calcd for C20H11Cl2FN2O: 384.0232; found: 384.0238.
8.7.23 2-benzamido-4-chloro-N-(3,4,5-trichlorophenyl)benzamide (68)
°
Yield 61 %; mp 204-208 C; IR (KBr) ѵmax 3112.42 (NH strech), 3064.92 (CH strech), 1675.32 (C=O), 1600.78 (NH bend),
1570.29 (C=C), 1425.86 (C-H bend), 759.75 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 12.19 (s, 1H, NHCO), 10.72 (s, 1H, CONH),
7.30-8.87 (m, 10H, Ar-H); 13C NMR (DMSO-d6) δ 166.53, 164.04, 146.91, 143.05, 139.04, 136.54, 132.59, 130.16, 128.71,
128.55, 128.27, 128.22, 127.19, 124.04, 121.15, 116.95; HRMS (EI) m/z calcd for C20H12Cl4N2O2: 451.9653; found: 451.9659.
8.7.24 7-chloro-2-phenyl-3-(2,4,5-trichlorophenyl)quinazolin-4(3H)-one (69)
Yield 41 %; mp 184-186 °C; IR (KBr) ѵmax 3123.86 (CH strech), 1662.38 (C=O), 1592.49 (C=C), 1484.38 (CH bend), 762.38 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 7.14-8.23 (m, 10H, Ar-H); 13C NMR (DMSO-d6) δ 162.32, 158.35, 154.33, 139.41, 137.68,
132.35, 132.05, 131.25, 130.03, 129.44, 128.35, 128.06, 127.47, 127.12, 126.47, 124.85, 122.36, 120.13. HRMS (EI) m/z calcd for
C20H10Cl4N2O: 433.9547; found: 433.9553.
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8.7.25 2-benzamido-4-chloro-N-(3,4-dimethylphenyl)benzamide (70)
Yield 71 %; mp 168-172 °C; IR (KBr) ѵmax 3264.39 (NH strech), 3060.76 (Arom.CH strech), 2917.88 (Aliph.CH strech), 1684.52
1
(C=O), 1582.41 (NH bend), 1511.88 (C=C), 1413.59 (C-H bend), 693.66 (C-Cl) cm-1; H NMR (DMSO-d6) δ 12.67 (s, 1H,
NHCO), 10.16 (s, 1H, CONH), 7.02-8.90 (m, 11H, Ar-H), 2.33 (s, 3H, CH3), 2.24 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 167.18,
164.65, 141.19, 137.53, 136.03, 134.62, 133.95, 132.49, 131.79, 130.91, 129.82, 128.49, 126.84, 126.70, 126.58, 122.17, 119.81,
117.87, 20.59, 17.71; HRMS (EI) m/z calcd for C22H19ClN2O2: 378.1135; found: 378.1139.
8.7.26 2-benzamido-4-chloro-N-(2,4-dimethylphenyl)benzamide (71)
°
Yield 69 %; mp 206-210 C; IR (KBr) ѵmax 3212.28 (NH strech), 3028.24 (Arom.CH strech), 2958.42 (Aliph.CH strech), 1658.82
1
(C=O), 1612.56 (NH bend), 1538.28 (C=C), 1468.28 (C-H bend), 684.28 (C-Cl) cm-1; H NMR (DMSO-d6) δ 10.39 (s, 1H,
NHCO), 9.88 (s, 1H, CONH), 7.21-8.38 (m, 11H, Ar-H), 2.68 (s, 3H, CH3), 2.39 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 167.47,
164.28, 146.355, 144.29, 142.38, 138.35, 136.38, 134.39, 133.67, 133.55, 130.67, 129.65, 128.56, 127.62, 125.60, 122.30, 120.65,
118.67, 116.35, 24.36, 20.10. HRMS (EI) m/z calcd for C22H19ClN2O2: 378.1135; found: 378.1141.
8.7.27 7-chloro-2-phenyl-3-p-tolylquinazolin-4(3H)-one (72)
°
Yield 83 %; mp above 250 C; IR (KBr) ѵmax 3098.12 (Arom.CH strech), 2967.29 (Aliph.CH strech), 1642.26 (C=O), 1581.29
(C=C), 1428.16 (CH bend), 718.22 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.16-8.01 (m, 12H, Ar-H), 2.62 (s, 3H, CH3); 13C NMR
(DMSO-d6) δ 164.33, 160.35, 156.37, 141.35, 140.31, 134.37, 134.26, 130.15, 130.03, 129.67, 129.45, 128.52, 128.38, 127.45,
122.76, 120.67, 24.33. HRMS (EI) m/z calcd for C21H15ClN2O: 346.0873; found: 346.0878.
8.7.28 7-chloro-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (73)
°
Yield 68 %; mp 243-247 C; IR (KBr) ѵmax 3064.98 (Arom.CH strech), 2923.34 (Aliph.CH strech), 1686.93 (C=O), 1590.32
(C=C), 1462.36 (CH bend), 724.38 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.74-7.81 (m, 8H, Ar-H), 2.81 (s, 3H, CH3); 13C NMR
(DMSO-d6) δ 171.31, 163.43, 158.44, 154.35, 146.32, 138.43, 132.62, 130.65, 129.62, 129.20, 129.01, 128.60, 124.62, 120.33,
22.30. HRMS (EI) m/z calcd for C17H11ClN4OS: 354.0342; found: 354.0347.
8.7.29 2-benzamido-4-chloro-N-phenylbenzamide (74)
°
Yield 72 %; mp 187-190 C; IR (KBr) ѵmax 3246.73 (NH strech), 3023.46 (CH strech), 1682.62 (C=O), 1612.42 (NH bend),
1582.42 (C=C), 1462.23 (C-H bend), 678.79 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 12.31 (s, 1H, NHCO), 10.40 (s, 1H, CONH),
7.14-8.87 (m, 13H, Ar-H); 13C NMR (DMSO-d6) δ 167.55, 164.33, 143.61, 141.64, 139.67, 136.35, 134.22, 131.43, 130.63,
130.25, 130.00, 128.65, 126.32, 124.63, 124.25, 120.65. HRMS (EI) m/z calcd for C20H15ClN2O2: 350.0822; found: 350.0828.
8.7.30 7-chloro-2-phenyl-3-(5-phenyl-1,3,4-thiadiazol-2-yl)quinazolin-4(3H)-one (75)
°
Yield 45 %; mp above 250 C; IR (KBr) ѵmax 3023.98 (CH strech), 1668.84 (C=O), 1568.47 (C=C), 1472.62 (CH bend), 710.23
(C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.89-8.34 (m, 13H, Ar-H); 13C NMR (DMSO-d6) δ 172.35, 170.14, 162.34, 158.35, 156.35,
139.43, 135.65, 132.64, 132.15, 130.25, 129.63, 128.62, 128.43, 126.45, 126.14, 124.35, 122.34, 120.35. HRMS (EI) m/z calcd for
C22H13ClN4OS: 416.0499; found: 416.0493.
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DOI: 10.1039/C6RA01284A
8.7.31 3-(5-benzyl-1,3,4-thiadiazol-2-yl)-7-chloro-2-phenylquinazolin-4(3H)-one (76)
°
Yield 51 %; mp 235-238 C; IR (KBr) ѵmax 3012.73 (Arom.CH strech), 2998.46 (Aliph.CH strech), 1662.83 (C=O), 1586.38
(C=C), 1448.89 (CH bend), 678.93 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.63-8.16 (m, 13H, Ar-H), 4.01 (s, 2H, CH2); 13C NMR
(DMSO-d6) δ 169.45, 164.35, 162.33, 158.34, 154.38, 139.45, 138.62, 132.30, 132.15, 130.35, 130.12, 130.05, 129.35, 129.06,
127.36, 126.33, 123 .69, 120.66, 36.35. HRMS (EI) m/z calcd for C23H15ClN4OS: 430.0655; found: 430.0659.
8.7.32 7-chloro-2-phenyl-3-(5-m-tolyl-1,3,4-thiadiazol-2-yl)quinazolin-4(3H)-one (77)
°
Yield 55 %; mp above 250 C; IR (KBr) ѵmax 3081.77 (Arom.CH strech), 2968.89 (Aliph.CH strech), 1684.87 (C=O), 1594.46
(C=C), 1462.98 (CH bend), 682.87 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.39-7.69 (m, 12H, Ar-H), 2.68 (s, 3H, CH3); 13C NMR
(DMSO-d6) δ 172.14, 169.35, 162.36, 158.35, 154.35, 140.37, 138.45, 136.32, 132.63, 132.37, 130.60, 129.45, 129.04, 128.85,
128.67, 128.05, 126.35, 126.06, 124.32, 120.15, 23.65. HRMS (EI) m/z calcd for C23H15ClN4OS: 430.0655; found: 430.0659.
8.7.33 7-chloro-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (78)
°
Yield 68 %; mp 222-226 C; IR (KBr) ѵmax 3123.35 (Arom.CH strech), 2956.32 (Aliph.CH strech), 1665.87 (C=O), 1543.76
(C=C), 1446.87 (CH bend), 678.92 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.31-8.21 (m, 8H, Ar-H), 1.10-2.61 (m, 5H, cyclopropyl);
13C NMR (DMSO-d6) δ 171.36, 166.37, 162.35, 158.37, 154.48, 139.45, 132.66, 132.37, 130.89, 130.67, 130.25, 128.65, 124.66,
120.37, 11.25, 10.86. HRMS (EI) m/z calcd for C19H13ClN4OS: 380.0499; found: 380.0493.
8.7.34 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (79)
°
Yield 63 %; mp above 250 C; IR (KBr) ѵmax 3046.38 (CH strech), 1658.24 (C=O), 1572.82 (C=C), 1462.83 (CH bend), 756.32
1
(C-Cl) cm-1; H NMR (DMSO-d6) δ 6.81-8.12 (m, 12H, Ar-H), 3.85 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 172.67, 169.45,
162.36, 160.37, 158.85, 156.36, 139.47, 132.66, 132.17, 130.67, 130.35, 128.52, 128.40, 127.64, 126.35, 124.68, 120.66, 118.33,
55.67. HRMS (EI) m/z calcd for C23H15ClN4O2S: 446.0604; found: 446.0609.
8.7.35 3-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-7-chloro-2-phenylquinazolin-4(3H)-one (80)
°
Yield 73 %; mp above 250 C; IR (KBr) ѵmax 3189.28 (NH strech), 3011.45 (CH strech), 1681.68 (C=O), 1624.95 (NH bend),
1586.78 (C=C), 1485.35 (CH bend), 679.56 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 11.31 (s, 1H, NH), 6.31-8.34 (m, 16H, Ar-H); 13
C
NMR (DMSO-d6) δ 162.64, 158.62, 154.35, 152.54, 142.33, 138.65, 136.62, 132.37, 130.12, 129.42, 128.64, 128.35, 128.02,
127.63, 127.33, 124.34, 122.60, 121.65, 118.64, 116.42. HRMS (EI) m/z calcd for C27H17ClN4O: 448.1091; found: 448.1097.
8.7.36 3-(1H-benzo[d]imidazol-2-yl)-7-chloro-2-phenylquinazolin-4(3H)-one (81)
°
Yield 61 %; mp above 250 C; IR (KBr) ѵmax 3234.54 (NH strech), 3032.68 (CH strech), 1656.82 (C=O), 1612.65 (NH bend),
1545.76 (C=C), 1398.28 (CH bend), 681.99 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 10.11 (s, 1H, NH), 6.81-8.12 (m, 12H, Ar-H); 13
C
NMR (DMSO-d6) δ 163.64, 158.34, 154.65, 151.33, 139.68, 136.35, 134.22, 130.64, 130.47, 130.27, 128.65, 128.26, 126.45,
124.64, 122.87, 120.82. HRMS (EI) m/z calcd for C21H13ClN4O: 372.0778; found: 372.0783.
8.7.37 7-chloro-3-(5-(3,5-dichlorophenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (82)
Yield 38 %; mp 255-258 °C; IR (KBr) ѵmax 3068.34 (CH strech), 1648.34 (C=O), 1572.87 (C=C), 1481.78 (CH bend), 724.28 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 6.21-7.95 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 170.15, 168.25, 162.65, 158.36, 154.37,
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DOI: 10.1039/C6RA01284A
140.46, 138.67, 136.32, 132.82, 132.62, 131.61, 130.64, 130.21, 130.01, 128.64, 126.60, 124.35, 120.46. HRMS (EI) m/z calcd for
C22H11Cl3N4OS: 483.9719; found: 483.9724.
8.7.38 7-chloro-3-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (83)
°
Yield 31 %; mp above 250 C; IR (KBr) ѵmax 3034.28 (CH strech), 1679.24 (C=O), 1589.28 (C=C), 1454.28 (CH bend), 1546.28
and 1351.48 (NO2), 711.28(C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.13-8.39 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 171.38, 168.76,
164.35, 160.36, 156.33, 151.35, 144.28, 141.32, 134.24, 134.11, 129.84, 129.67, 129.22, 128.23, 127.46, 126.65, 124.20, 120.62.
HRMS (EI) m/z calcd for C22H12ClN5O3S: 461.0349; found: 461.0353.
8.7.39 7-chloro-3-(5-(3-nitrophenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one (84)
°
Yield 35 %; mp above 250 C; IR (KBr) ѵmax 3128.47 (CH strech), 1652.84 (C=O), 1572.92 (C=C), 1462.28 (CH bend), 1538.29
1
and 1341.28 (NO2), 688.99 (C-Cl) cm-1; H NMR (DMSO-d6) δ 7.39-8.52 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 170.67,
169.85,162.65, 158.66, 156.34, 150.60, 142.61, 140.34, 138.27, 134.64, 134.22, 134.03, 130.80,130.67, 130.04, 128.44, 126.84,
124.37, 123.84, 120.84. HRMS (EI) m/z calcd for C22H12ClN5O3S: 461.0349; found: 461.0353.
8.7.40 7-chloro-3-(3,4-dinitrophenylamino)-2-phenylquinazolin-4(3H)-one (85)
°
Yield 38 %; mp 185-188 C; IR (KBr) ѵmax 3267.28 (NH strech), 3078.66 (CH strech), 1662.58 (C=O), 1601.48 (NH bend),
1582.38 (C=C), 1468.34 (C-H bend), 1544.38 and 1342.88 (NO2), 721.38 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 11.21 (s, 1H, NH),
7.39-8.43 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 164.37, 160.38, 158.24, 156.34, 150.38, 146.36, 142.65, 140.82, 140.28,
132.80, 132.61, 132.04, 130.46, 128.38, 126.79, 124.90, 120.21, 116.84. HRMS (EI) m/z calcd for C20H12ClN5O5: 437.0527;
found: 437.0527.
8.7.41 2-benzamido-4-chloro-N-(4-fluorophenyl) benzamide (86)
°
Yield 73 %; mp 245-248 C; IR (KBr) ѵmax 3264.62 (NH strech), 3150.42 (CH strech), 1651.20 (C=O), 1601.11 (NH bend),
1550.26 (C=C), 1408.83 (C-H bend), 1223.84 (C-F), 702.43 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 12.03 (s, 1H, NHCO), 10.71(s,
1H, CONH), 6.83-8.69 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 166.76, 164.01, 159.28, 140.56, 139.04, 134.03, 132.41, 128.97,
128.08, 127.42, 123.07, 122.79, 122.71, 121.67, 119.28, 116.04, 115.82; HRMS (EI) m/z calcd for C20H14ClFN2O2: 368.0728;
found: 391.0735 [M+Na].
8.7.42 N-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl)-4-hydroxybenzamide (87)
°
Yield 58 %; mp 212-218 C; IR (KBr) ѵmax 3412.78 (OH strech), 3214.88 (NH strech), 3035.79 (CH strech), 1708.18 [C=O
1
(ketone)], 1672.34 [C=O (amide)], 1609.67 (NH bend), 1528.89 (C=C), 1412.36 (CH bend), 716.87 (C-Cl) cm-1; H NMR
(DMSO-d6) δ 10.31 (s, 1H, NH), 6.38-8.19 (m, 12H, Ar-H), 5.12 (s, 1H, OH); 13C NMR (DMSO-d6) δ 166.82, 164.33, 162.30,
158.34, 154.35, 139.46, 132.67, 132.50, 130.90, 130.64, 130.45, 128.22, 127.42, 124.61, 122.71, 120.60, 118.60. HRMS (EI) m/z
calcd for C21H14ClN3O3: 391.0724; found: 391.0729.
8.7.43 4-bromo-N-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl)benzamide (88)
°
Yield 62 %; mp 220-224 C; IR (KBr) ѵmax 3261.84 (NH strech), 3056.68 (CH strech), 1711.78 [C=O (ketone)], 1658.56 [C=O
(amide)], 1595.89 (NH bend), 1559.53 (C=C), 1468.78 (CH bend), 735.78 (C-Cl), 645.84 (C-Br) cm-1; 1H NMR (DMSO-d6) δ
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11.01 (s, 1H, NH), 7.11-8.19 (m, 12H, Ar-H); C NMR (DMSO-d6) δ 168.55, 164.34, 160.37, 158.39, 152.45, 140.88, 1V3i9ew.3A7r,ticle Online
DOI: 10.1039/C6RA01284A
134.35, 132.46, 131.62, 130.60, 130.44, 130.00, 129.34, 128.35, 124.35, 120.39. HRMS (EI) m/z calcd for C21H13BrClN3O2:
452.9880; found: 452.9886.
8.7.44 7-chloro-2'-methyl-2-phenyl-4H,4'H-3,3'-biquinazoline-4,4'-dione (89)
°
Yield 76 %; mp 254-256 C; IR (KBr) ѵmax 3134.56 (Arom.CH strech), 2936.28 (Aliph.CH strech), 1665.87 (C=O), 1545.59
(C=C), 1449.29 (CH bend), 761.98 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.81-8.13 (m, 12H, Ar-H), 2.33 (s, 3H, CH3); 13C NMR
(DMSO-d6) δ 164.62, 160.81, 158.64, 156.55, 150.30, 141.32, 137.86, 134.38, 134.09, 130.85, 130.65, 130.01, 129.44, 129.34,
128.67, 128.45, 124.49, 122.68, 120.60, 23.40. HRMS (EI) m/z calcd for C23H15ClN4O2: 414.0884; found: 414.0889.
8.7.45 N-(7-chloro-4-oxo-2-phenylquinazolin-3(4H)-yl) propionamide (91)
7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 40 (0.01 mol) (0.01 mol) was melted in beaker and excess of hydrazine hydrate
was added and heated further for 30 minutes. The mixture was cooled and water was added to the mixture. The separated solid of
90 was collected by filtration, washed with water, dried and recrystallized from ethanol; it is further refluxed for 4 h with propionic
anhydride. The solvent was removed under reduced pressure. The residue was triturated with petroleum ether 40-60. The separated
solid was collected by filtration, washed with petroleum ether 40-60, dried and recrystallized from toluene; yield 33 %; mp 134-
°
136 C; IR (KBr) ѵmax 3256.67 (NH strech), 3034.64 (Arom.CH strech), 2912.45 (Aliph.CH strech), 1708.34 [C=O (ketone)],
1689.74 [C=O (amide)], 1567.12 (C=C), 1601.43 (NH bend), 1463.75 (CH bend), 712.54 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ
10.12 (s, 1H, NH), 7.01-8.23 (m, 8H, Ar-H), 1.67-2.54 (m, 5H, N-CH2-CH3); 13C NMR (DMSO-d6) δ 166.12, 160.12, 152.53,
146.12, 140.67, 132.56, 130.22, 128.64, 128.13, 127.64, 127.32, 126.57, 120.23, 28.12, 14.24. HRMS (EI) m/z calcd for
C17H14ClN3O2: 327.0775; found: 327.0779.
8.7.46 2-benzamido-4-chloro-N-propylbenzamide (92)
Yield 91 %; mp 162-165 °C; IR (KBr) ѵmax 3248.38 (NH strech), 3089.28 (Arom.CH strech), 2976.89 (Aliph.CH strech), 1676.91
1
(C=O), 1623.12 (NH bend), 1587.37 (C=C), 1461.67 (C-H bend), 691.76 (C-Cl) cm-1; H NMR (DMSO-d6) δ 12.18 (s, 1H,
NHCO), 11.38 (s, 1H, CONH), 6.51-8.85 (m, 8H, Ar-H), 1.00-3.47 (m, 7H, N-CH2-CH2-CH3); 13C NMR (DMSO-d6) δ 69.40,
166.81, 142.34, 140.46, 136.66, 134.35, 131.36, 130.84, 129.68, 126.64, 124.30, 122.30, 38.41, 24.65, 15.60. HRMS (EI) m/z
calcd for C17H17ClN2O2: 316.0979; found: 316.0984.
8.7.47 2-benzamido-N-benzyl-4-chlorobenzamide (93)
°
Yield 68 %; mp 200-205 C; IR (KBr) ѵmax 3257.31 (NH strech), 3111.10 (CH strech), 1652.02 (C=O), 1600.85 (NH bend),
1561.87 (C=C), 1413.34 (C-H bend), 705.37 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 11.57 (s, 1H, NHCO), 10.14 (s, 1H, CONH),
6.91-8.84 ((m, 13H, Ar-H), 4.63 (s, 2H, CH2); 13C NMR (DMSO-d6) δ 167.43, 165.78, 140.93, 138.81, 137.36, 134.30, 132.19,
128.92, 128.89, 127.87, 127.80, 127.42, 122.86, 121.33, 118.37, 44.16; HRMS (EI) m/z calcd for C21H17ClN2O2: 364.0979; found:
364.0973.
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8.7.48 7-chloro-3-(3-chlorophenyl)-2-phenylquinazolin-4(3H)-one (94)
Yield 71 %; mp 194-200 °C; IR (KBr) ѵmax 3069.99 (CH strech), 1686.80 (C=O), 1580.47 (C=C), 1447.27 (CH bend), 701.77 (C-
1
Cl) cm-1; H NMR (DMSO-d6) δ 6.77-8.70 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 161.48, 155.96, 141.21, 138.41, 134.67,
134.65, 129.94, 129.88, 129.42, 128.97, 128.93, 128.89, 128.67, 128.26, 128.10, 127.41, 127.38, 119.20; HRMS (EI) m/z calcd for
C20H12Cl2N2O: 366.0327; found: 367.0321 [M+1].
8.7.49 2-benzamido-4-chloro-N-o-tolylbenzamide (95)
Yield 48 %; mp 210-214 °C; IR (KBr) ѵmax 3246.35 (NH strech), 3078.89 (Arom.CH strech), 2945.67 (Aliph.CH strech), 1664.43
1
(C=O), 1624.89 (NH bend), 1531.56 (C=C), 1468.28 (C-H bend), 691.34 (C-Cl) cm-1; H NMR (DMSO-d6) δ 10.38 (s, 1H,
NHCO), 10.01 (s, 1H, CONH), 7.12-8.31 (m, 12H, Ar-H), 2.34 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 167.40, 164.34, 144.74,
142.65, 138.61, 138.02, 134.22, 133.43, 132.14, 130.30, 130.14, 129.89, 128.58, 126.98, 125.35, 122.30, 120.81, 118.30, 24.39.
HRMS (EI) m/z calcd for C21H17ClN2O2: 364.0979; found: 364.0984.
8.7.50 3-(2-aminoethyl)-7-chloro-2-phenylquinazolin-4(3H)-one (96)
°
Yield 89 %; mp 223-228 C; IR (KBr) ѵmax 3268.12 and 3214.78 (NH2), 3087.21 (Arom.CH strech), 2912.98 (Aliph.CH strech),
1656.12 (C=O), 1601.78 (NH bend), 1491.23 (C=C), 1438.12 (CH bend), 712.98 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.98-7.97
(m, 8H, Ar-H), 6.11 (s, 2H, NH2,), 2.91 (t, 2H, CH2); 13C NMR (DMSO-d6) δ 160.11, 158.25, 154.34, 139.30, 132.26, 132.05,
130.87, 130.24, 130.00, 129.45, 124.84, 120.87, 50.14, 36.39. HRMS (EI) m/z calcd for C16H14ClN3O: 299.0825; found: 299.0829.
8.7.51 2-benzamido-N-(4-bromophenyl)-4-chlorobenzamide (97)
°
Yield 71 %; mp 234-238 C; IR (KBr) ѵmax 3212.12 (NH strech), 3021.89 (CH strech), 1662.72 (C=O), 1588.23 (NH bend),
1554.89 (C=C), 1442.98 (C-H bend), 713.34 (C-Cl), 623.89 (C-Br) cm-1; 1H NMR (DMSO-d6) δ 11.34 (s, 1H, NHCO), 10.65 (s,
1H, CONH), 7.38-8.31 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 167.64, 164.31, 144.37, 142.60, 140.31, 138.22, 136.23, 135.24,
130.10, 129.31, 128.62, 125.60, 123.44, 122.45, 121.38, 119.44. HRMS (EI) m/z calcd for C20H14BrClN2O2: 427.9927; found:
427.9932.
8.7.52 2-benzamido-4-chloro-N-(2,4-dimethylphenyl)benzamide (98)
°
Yield 48 %; mp 184-188 C; IR (KBr) ѵmax 3212.78 (NH strech), 3012.86 (Arom.CH strech), 2962.78 (Aliph.CH strech),
1668.21(C=O), 1612.68 (NH bend), 1578.45 (C=C), 1442.78 (C-H bend), 734.89 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 10.88 (s, 1H,
NHCO), 10.31 (s, 1H, CONH), 6.98-8.18 (m, 11H, Ar-H), 2.98 (s, 3H, CH3), 2.64 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 167.11,
164.02, 146.42, 144.31, 142.39, 138.25, 136.34, 135.34, 133.43, 132.42, 130.18, 129.64, 128.40, 127.35, 125.64, 122.32, 120.86,
116.80, 24.35, 21.35. HRMS (EI) m/z calcd for C22H19ClN2O2: 378.1135; found: 379.1139[M+1].
8.7.53 2-benzamido-4-chloro-N-(2-fluorophenyl) benzamide (99)
°
Yield 64 %; mp 225-228 C; IR (KBr) ѵmax 3289.21 (NH strech), 3078.23 (CH strech), 1678.68 (C=O), 1609.14 (NH bend),
1581.31 (C=C), 1478.56 (C-H bend), 1089.21 (C-F), 712.48 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 11.39 (s, 1H, NHCO), 10.92 (s,
1H, CONH), 7.08-8.37 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 167.36, 164.25, 162.37, 144.35, 142.34, 138.23, 136.35, 134.32,
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133.85, 130.15, 129.62, 128.52, 125.35, 124.38, 122.35, 120.10, 119.40, 118.43. HRMS (EI) m/z calcd for C20H14ClFN2O2:
368.0728; found: 369.0734[M+1].
8.7.54 2-benzamido-N-butyl-4-chlorobenzamide (100)
Yield 85 %; mp 189-191 °C; IR (KBr) ѵmax 3223.21 (NH strech), 3038.29 (Arom.CH strech), 2964.99 (Aliph.CH strech), 1671.21
1
(C=O), 1623.10 (NH bend), 1571.90 (C=C), 1459.21 (C-H bend), 692.90 (C-Cl) cm-1; H NMR (DMSO-d6) δ 10.65 (s, 1H,
NHCO), 10.21 (s, 1H, CONH), 7.31-8.13 (m, 8H, Ar-H), 1.03-3.49 (m, 9H, N-CH2-CH2-CH2-CH3); 13C NMR (DMSO-d6) δ
168.36, 164.35, 142.35, 141.30, 136.38, 134.25, 131.34, 130.35, 129.34, 128.62, 126.35, 120.34, 39.43, 28.65, 14.32. HRMS (EI)
m/z calcd for C18H19ClN2O2: 330.1135; found: 331.1141[M+1].
8.7.55 3-(2-benzamido-4-chlorobenzamido) benzoic acid (101)
Yield 46 %; mp 191-193 °C; IR (KBr) ѵmax 3242.45 (NH strech), 3098.87 (CH strech), 2634.21 [OH (acid)], 1721.56 [C=O (acid)],
1668.34 [C=O (amide)], 1600.89 (NH bend), 1543.22 (C=C), 1439.28 (CH bend), 681.32 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ
12.31(s, 1H, COOH), 11.68(s, 1H, NHCO), 11.21 (s, 1H, CONH), 7.34-8.64 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 169.32,
167.39, 164.35, 143.34, 141.55, 137.88, 136.34, 134.38, 130.14, 129.85, 129.60, 128.45, 126.38, 125.34, 125.22, 124.38, 122.34,
121.32, 120.30. HRMS (EI) m/z calcd for C21H15ClN2O4: 394.0720; found: 395.0726 [M+1].
8.7.56 2-benzamido-4-chloro-N-(2,6-dichlorophenyl)benzamide (102)
°
Yield 38 %; mp 175-178 C; IR (KBr) ѵmax 3145.12 (NH strech), 3015.89 (CH strech), 1662.78 (C=O), 1618.23 (NH bend),
1578.90 (C=C), 1478.34 (C-H bend), 722.65 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 10.48 (s, 1H, NHCO), 10.11 (s, 1H, CONH),
7.31-8.43 (m, 11H, Ar-H); 13C NMR (DMSO-d6) δ 167.38, 164.25, 143.39, 141.35, 136.37, 135.55, 134.32, 131.23, 130.45,
128.42, 128.08, 127.35, 126.43, 124.30, 121.48, 120.37. HRMS (EI) m/z calcd for C20H13Cl3N2O2: 418.0043; found: 419.0048
[M+1].
8.7.57 2-(2-benzamido-4-chlorobenzamido) benzoic acid (103)
Yield 46 %; mp 186-190 °C; IR (KBr) ѵmax 3211.89 (NH strech), 3021.54 (CH strech), 2611.98 [OH (acid)], 1722.11 [C=O (acid)],
1678.90 [C=O (amide)], 1634.99 (NH bend), 1589.21 (C=C), 1421.56 (CH bend), 738.24 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ
11.98 (s, 1H, COOH), 11.39 (s, 1H, NHCO), 11.09 (s, 1H, CONH), 7.11-8.39 (m, 12H, Ar-H); 13C NMR (DMSO-d6) δ 169.35,
167.31, 164.15, 143.30, 142.32, 141.56, 138.39, 136.37, 134.24, 132.32, 129.70, 128.67, 127.40, 124.35, 124.00, 121.25, 120.34,
118.25, 116.27. HRMS (EI) m/z calcd for C21H15ClN2O4: 394.0720; found: 395.0726 [M+1].
8.7.58 7-chloro-2'-(furan-2-yl)-2-phenyl-4H,4'H-3,3'-biquinazoline-4,4'-dione (104)
°
Yield 58 %; mp above 250 C; IR (KBr) ѵmax 3134.21 (CH strech), 1712.67 (C=O), 1589.59 (C=C), 1478.78 (CH bend), 734.89
(C-Cl) cm-1; 1H NMR (DMSO-d6) δ 6.30-8.13 (m, 15H, Ar-H); 13C NMR (DMSO-d6) δ 162.34, 158.24, 154.35, 148.24, 144.20,
143.74, 139.45, 135.35, 132.36, 132.10, 130.30, 130.11, 130.05, 128.44, 128.06, 126.45, 126.25, 124.39, 122.41, 120.41, 111.32,
110.20. HRMS (EI) m/z calcd for C26H15ClN4O3: 466.0833; found: 467.0838 [M+1].
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8.7.59 7,7'-dichloro-2-methyl-2'-phenyl-4H,4'H-3,3'-biquinazoline-4,4'-dione (105)
°
Yield 53 %; mp above 250 C; IR (KBr) ѵmax 3101.21 (Arom.CH strech), 2988.11 (Aliph.CH strech), 1701.21 (C=O), 1564.34
(C=C), 1462.99 (CH bend), 706.12 (C-Cl) cm-1; 1H NMR (DMSO-d6) δ 7.11-8.36 (m, 11H, Ar-H), 3.18 (s, 3H, CH3); 13C NMR
(DMSO-d6) δ 162.30, 158.36, 154.84, 150.32, 139.45, 138.34, 134.28, 132.35, 130.14, 129.38, 128.85, 126.37, 124.36, 120.30,
23.45. HRMS (EI) m/z calcd for C23H14Cl2N4O2: 448.0494; found: 449.0499 [M+1].
8.7.60 Synthesis of Compounds 106-129
It is synthesized as per the reported method [20].
9.8 Anticonvulsant Activity
The anticonvulsant activity of all synthesized compounds was evaluated by pentylenetetrazole (PTZ), and maximal electroshock
(MES) models .26, 27 The test compounds were dissolved in 10% DMSO and injected intraperitoneally (i. p.) at a dose of 0.5
mmol/kg 30 min before seizure induction. Sodium valproate (1.5 mmol/kg) and methaqualone (1.4 mmol/kg) were used as
26, 27
reference drugs.
In the MES test, seizures were elicited with a 75-Hz alternating current of 99 mA intensity in mice. The
current was applied via ear electrodes for 2 s. Protection against the spread of MES induced seizures was defined as the abolition
of the hind leg and tonic maximal extension component of the seizure. 26,27 The PTZ test was carried out by the i. p. injection of a
convulsant dose of PTZ (100 mg/kg). Seizures and tonic-clonic convulsions were recorded. Five of the most promising
compounds (8, 9, 11, 19, and 25) at different doses were further evaluated in the PTZ model to determine their protective and
therapeutic indexes. Groups of ten mice each were given a range of i. p. doses of the selected drug until at least four points were
established in the range of 10–90% seizure protection or minimal observed neurotoxicity. From the plots of these data, the
respective ED50 and TD50 values, slopes of the regression line, and the standard error were calculated using a computer program
based on the method described by Finney. 27 The dose of tested compounds that prevented 50% of the treated animals from PTZ-
induced clonic convulsion was calculated (ED50). Observation time with all convulsants was 60 min for convulsions and death.
26,27
The animals that showed no convulsion within 1 h after convulsive drug administration were considered to be protected.
9.9 Neurological Toxicity
The acute neurotoxicity of the selected compounds was evaluated in mice using the chimney test.28 Here, motor impairment was
indicated by the inability of the mice to climb backward up the tube within 30s. Tested animals were given an i.p. injection of the
selected compounds in various doses 30 min before the test. The neurotoxic effects of the tested compounds were expressed as
their median toxic doses (TD50 values), representing the doses at which the investigated compounds impaired motor coordination
in 50% of the animals.
9.10 Protective and Therapeutic Indexes
The protective index for the selected compounds was calculated by dividing the TD50 value, as determined in the chimney test, by
the respective ED50 value, as determined in the PTZ test. The protective index is considered to be an index representing the margin
of safety and tolerability between ED50 and TD50. 29 The median lethal dose (LD50), the dose of the selected compounds that causes
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50% mortality in mice, was determined from dose-response curves with at least four doses by the method of Litchfield and
29
Wilcoxon. The therapeutic index, the ratio of the dose producing toxicity in 50% of animals to the dose needed to produce the
desired 50% therapeutic response, was then calculated.
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References
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and H.I. Al-Subbagh. Med. Chem. Res., 2013, 22, 2815-2827.
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17 G. Saravanan, V. Alagarsamy and R.C. Prakash, Bioorg. Med. Chem. Lett. 2012, 22, 3072-3078.
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19 M. F. Zayed, H. E. A. Ahmed, A. S. M. Omar, A. S. Abdelrahim and K. El-Adl. Med Chem Res. 2013, 22, 5823-5831.
20 M. N. Noolvi and H. M. Patel. Arab J. Chem.2013, 6, 35-48.
21 V. V. Poroikov, D. A. Filimonov, T. A. Gloriozova, T.A., A. A. Lagunin, D. S. Druzhi- lovsky and A. V. Stepanchikova,
The Herald of Vavilov Society for Geneticists and Breeding Scientists, 2009, 13,137–143.
22 V. Poroikov, D. Filimonov, A. Lagunin, T. Gloriozova and A. Zakharov, SAR QSAR Environ Res., 2007, 18, 101-110.
23 G. Vistoli, A. Pedretti and B. Testa, Drug Discov. Today, 2008, 13, 285-294.
24 C. A. Lipinski, F. Lombardo, B.W. Dominy and P. Feeney, J. Adv. Drug Deliv. Rev., 2001, 46, 3-26.
25 P. Ertl, B. Rohde and P. Selzer, J. Med. Chem. 2000, 43, 3714-3717.
26 H. G. Vogel In: Vogel HG, Vogel WH (eds) Drug Discovery and Evaluation, Pharmacological assays, 2nd edn. Springer
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27 H. S. White, J. H. Woodhead, M. R. Franklin, E. A. Swinyard, H. H. Wolf In: Levy RH, Mattson RH, Meldrum BS (eds)
Antiepileptic drugs, 4th edn. Raven, New York, 1995, p 99.
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Fig. 1 Reported and proposed compounds
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Fig. 2 Structure activity relationship (SAR)
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Fig. 2 Virtual screening protocol for anti-convulsant screening
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Table 1. Preliminary anticonvulsant activity of the new synthesized compounds (0.5 mmol/kg), valproate (1.5 mmol/kg)
and methaqualone (1.4 mmol/kg)
Compound
Code
Standard
Structure
Valproate
PTZ (% protection)
MES (% protection)
100
100
100
100
Standard
06
Methaqualone
100
100
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08
100
100
12
17
100
66
100
50
18
38
45
50
50
33
33
66
100
46
47
66
66
30
50
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