Anti-convulsant potential of quinazolinones

Abstract

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.

---

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, and social and frightening manifestations.² A global campaign against epilepsy conducted by the World Health Organization (WHO) in partnership with the International Bureau for Epilepsy (IBE) and the International League Against Epilepsy (ILAE) suggests that around 1% of the world’s population at any time (about 50 million people worldwide) is afflicted with this neurological disorder.^3–6

Methaqualone (a quinazoline analog) is an important landmark in the field of synthetic anticonvulsants; its chloro analog (mecloqualone) has been found to possess marked anticonvulsant potency, being 1.5 times more potent than phenytoin sodium against electroshock-induced convulsions and 10 times more active than troxidone against pentylenetetrazol (PTZ)-induced seizures.^7–12 A persistent problem with these compounds arises from the fact that nearly every derivative exhibits 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 aimed at finding new structure leads with potential anticonvulsant activities,¹⁵ a new series of the 4(3H)-quinazoline pharmacophore was designed with substituted moieties possessing different electronic environments in the hope of developing potent and safe new effective compounds.

2. Rationale

Various reported facts were analyzed before the chemical synthesis of our target compounds. The first fact was that modifications at the 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). The second was that the presence of a phenyl group at the second position of quinazolin-4(3H)-one was more significant than a methyl and yielded more potent CNS active agents.^16,17 The third fact explained that substitution of the quinazolinone ring with halogens or an electron rich group at the sixth, seventh or eighth positions greatly enhanced the anticonvulsant activity and these compounds were reported to possess better activity, a longer duration and lower toxicity than phenytoin.^18,19 Fig. 1 represents the structural similarities and pharmacophoric features of some reported anticonvulsant quinazolinones and our designed compounds. Fig. 1 shows that the structure of the title final compounds fulfilled all of the pharmacophoric structural requirements. These requirements include: a quinazolin-4(3H)-one moiety as the hydrophobic portion, the N of the quinazoline ring as an electron donor system, the carbonyl group as a hydrogen bonding site and the phenyl ring at the 2-position as a hydrophobic domain responsible for controlling the pharmacokinetic properties of the antiepileptic activity. Based on the previously mentioned facts,^16–18 the current study was carried out in the hope of developing potent, safe, new and effective anticonvulsant agents with low dose related toxicity and without idiosyncratic side effects.

Fig. 1 Reported and proposed compounds.

3. Chemistry

Anthranilic acid 1 and 4-chloro 2-amino benzoic acid 39, reacting with benzoyl chloride 2, yielded 2-phenyl-4H-3,1-benzoxazin-4-one 3 and 7-chloro 2-phenyl-4H-3,1-benzoxazin-4-one 40 by N-acylation via a dehydrative cyclization mechanism.²⁰ The reaction of different primary amines containing anilines, sulphonamides, thiadiazoles and hydrazides with 2-phenyl-4H-3,1-benzoxazin-4-one 3 and 7-chloro 2-phenyl-4H-3,1-benzoxazin-4-one 40 in dry pyridine yielded the corresponding quinazoline-4-one derivatives as shown in Scheme 1 and 2. Further reaction of 40 with hydrazine hydrate afforded compounds 107 and 108, which on further condensation with appropriate aromatic aldehydes in glacial acetic acid afforded the arylidene derivatives 109–129 (Scheme 3).

Scheme 1

Scheme 2

Scheme 3

4. Computational study

The current in silico study was carried out using PASS software (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). The 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 activity.^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 their 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 certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans.^23,24 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 a good indicator of drug absorbance in the intestine. MDCK cells and log BB are good markers to determine the blood–brain barrier crossing ability of compounds. PlogKhsa shows the prediction of binding to human serum albumin. Similarly, we studied a number of violations of Jorgensen’s rule of three. The three rules are: QPlogS > −5.7, QPCaco > 22 nm s⁻¹, and 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. 3. First of all, in silico prediction of the anti-convulsant activity was carried out, and the molecules which were showing more than 50% anti-convulsant activity were considered for the next filter of Lipinski’s rule of five and ADME prediction, which becomes an essential tool to facilitate drug discovery. As part of our study, the compliance of the compounds with Lipinski’s rule of five was evaluated. As discussed by Lipinski, molecular properties are closely related to the oral bioavailability of a drug. QikProp 3.2 was used for analyzing drug likeness (Lipinski’s Rule of Five) and in silico ADME evaluation; the results are given in Table 1S (ESI†) 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 their ADME (absorption, distribution, metabolism and excretion) properties. The results for ADME prediction are shown in Table 1S.† We similarly studied a number of violations of Jorgensen’s rule of three. The three rules are: QPlogS > −5.7, QPCaco > 22 nm s⁻¹, primary metabolites < 7. Compounds with fewer (and preferably no) violations of these rules are more likely to be orally available. The application of sequential filters based upon PASS prediction, Lipinski’s rule and Jorgensen’s rule finalized the seventeen compounds (6, 8, 12, 17, 18, 38, 45, 46, 47, 48, 49, 50, 51, 54, 55, 60, 73) selected for animal study.

Fig. 2 Structure activity relationship (SAR).

Fig. 3 Virtual screening protocol for anti-convulsant screening.

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 the estimation of the absorption and distribution of drugs, is within range for the body, between 2.35 and 4.64 and −5.49 to −3.61, respectively. 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. The values range from −0.57 to 0.33 for the virtually screened compounds. All of these pharmacokinetic parameters are within the acceptable range defined for human use (see Table 1S† footnote); thereby indicating their potential as 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⁻¹ of all the screened compounds using pentylenetetrazole (PTZ) and the MES model of seizures. The MES test is associated with the electrical induction of a seizure, whereas PTZ methods involve 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, and 73. However, compounds 6, 8, 12, 48, 49, 50 and 51 presented 100% protection against PTZ and MES at 0.5 mmol kg⁻¹ (Table 1).

Table 1 Preliminary anticonvulsant activity of the new synthesized compounds (0.5 mmol kg⁻¹), valproate (1.5 mmol kg⁻¹) and methaqualone (1.4 mmol kg⁻¹)

Compound code	Structure	PTZ (% protection)	MES (% protection)
Standard	Valproate	100	100
Standard	Methaqualone	100	100
6		100	100
8		100	100
12		100	100
17		66	50
18		50	33
38		50	33
45		100	66
46		66	30
47		66	50
48		100	100
49		100	100
50		100	100
51		100	100
54		50	30
55		66	33
60		66	50
73		50	33

---

As a result of the preliminary screening, the most active compounds (6, 8, 12, 48, 49, 50 and 51) were subjected to further investigations at different doses for the 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, 6 and 8 exhibited anticonvulsant activity against PTZ-induced seizure with ED₅₀ values of 0.41, 0.53, 0.58, 0.71, 1.50, 1.80, and 1.92 mmol kg⁻¹, respectively. Methaqualone and valproate were used as reference drugs and these compounds produced ED₅₀ values of 1.4 and 4.8 mmol kg⁻¹, respectively. Interestingly, the ED₅₀ values of the selected compounds were found to be smaller compared to the reference anticonvulsant drugs at molar doses.

Table 2 Comparison of the anticonvulsant activity (ED₅₀), acute neurotoxic effects (TD₅₀), median lethal dose (LD₅₀), therapeutic and protective indexes of the most promising anticonvulsant synthesized compounds, valproate, and methaqualone in mice^a

Compound code	Structure	ED50 (mmol kg^−1)	TD50 (mmol kg^−1)	LD50 (mmol kg^−1)	Therapeutic index	Protective index
a ED50 = median effective dose providing anticonvulsant protection in 50% of mice against pentylenetetrazole (PTZ) induced seizures, TD50 = median toxic dose producing minimal neurological toxicity in 50% of mice subjected to the chimney test, LD50 = median lethal dose that causes 50% mortality in mice, therapeutic index = LD50/ED50, protective index = TD50/ED50.
	Valproate	4.8	9.6	11.9	2.48	2.00
	Methaqualone	1.40	1.60	2.00	1.40	1.14
6		1.80	1.88	2.78	1.54	1.04
8		1.92	1.98	2.99	1.55	1.03
12		0.71	0.89	2.49	3.5	1.25
48		0.41	0.95	2.24	5.46	2.31
49		0.53	0.96	2.70	5.09	1.81
50		0.58	0.91	2.88	4.96	1.56
51		1.50	1.65	2.56	1.56	1.1

---

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 obvious that the PI values for these selected compounds revealed a difference between the doses producing neurotoxic action (TD₅₀) and those exerting anti-PTZ (ED₅₀) actions in mice. It is worthwhile to note that the therapeutic index of compounds 12, 48, 49 and 50 was found to be much higher as compared to the reference anticonvulsant drugs at molar doses (Table 2).

A structure activity relationship (SAR) study indicated that the different substitutions on the 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 a chloro functional group at the 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 a 2-amino phenyl at the 3^rd position of 7-chloro-2-phenyl quinazoline results into the most active compound of the series (compound 48). In the case of acetyl phenyl substitution at the 3^rd 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 a virtual screening approach. The results of this study demonstrated that compound 48, 3-(2-aminophenyl)-7-chloro-2-phenylquinazolin-4(3H)-one, was the most potent compound of the series accompanied by 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 a chloro functional group at the 7 position of the quinazoline have significant anticonvulsant activity, (ii) the presence of 2-amino phenyl at the 3^rd position of 7-chloro-2-phenyl quinazoline results in the most active compound of the series, and (iii) in the case of acetyl phenyl substitution at the 3^rd position of quinazoline, para substitution is more advantageous as compared to ortho and meta. The obtained results showed that compounds 12, 48, 49 and 50 could be useful as templates 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 using thin-layer chromatography on aluminum sheets pre-coated with GF₂₅₄ silica gel (0.2 mm layer thickness, Merck), and 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 a UV lamp. The melting points of the synthesized compounds were determined using one end open capillary tubes on a liquid paraffin bath and are uncorrected. IR spectra were acquired using a Perkin Elmer FT-IR spectrometer. Both ¹H-NMR (DMSO) and ¹³C NMR (DMSO) spectra of the synthesized compounds were obtained using a 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 an internal standard. Mass spectra of the synthesized compounds were recorded at MAT 120 in SAIF, Punjab University. The animal experimentations have been carried out according to the guidelines of the Institutional Animal Ethical Committee at Shree Dhanvantari Pharmacy College, (Kim) Surat, Gujarat (India).

8.1 2-Phenyl-4H-benzo[d][1,3]oxazin-4-one (3a)

Synthesized as per the reported method.²⁰

8.2 General procedure for the synthesis of 3-substituted-2-phenylquinazolin-4(3H)-ones (4–38), except 20 and 38

Equimolar amounts 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 a way that the reaction mixture should not be 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 obtain the pure product.

8.2.1 3-(2-Aminoethyl)-2-phenylquinazolin-4(3H)-one (4). Yield 74%; mp 243–248 °C; IR (KBr) ν_max 3248.56 and 3236.88 (NH₂), 3027.82 (arom. CH strech), 2953.29 (aliph. CH strech), 1671.72 (C=O), 1612.91 (NH bend), 1482.74 (C=C), 1456.34 (CH bend) cm⁻¹; ¹H 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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) ν_max 3032.93 (CH strech), 1658.64 (C=O), 1568.49 (C=C), 1462.94 (CH bend), 718.18 (C–Cl) cm⁻¹; ¹H 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.

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) ν_max 3047.76 (CH strech), 1724.82 (C=O), 1571.59 (C=C), 1449.29 (CH bend) 764.53 (C–Cl) cm⁻¹; ¹H 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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.

8.2.13 N-(2-(2-Phenylhydrazinecarbonyl)phenyl)benzamide (16). Yield 56%; mp 190–194 °C; IR (KBr) ν_max 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) ν_max 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) ν_max 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) ν_max 3337.55 (NH strech), 3237.55 and 3193.26 (NH₂), 3101.98 (CH strech), 1666.16 (C=O), 1605.26 (NH bend), 1585.55 (C=C), 1404.88 (CH bend), 1321.15 and 1160.06 [SO (sulphonamide)] cm⁻¹; ¹H 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). 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, and the solid was filtered, washed with water, dried and crystallized from ethanol. Yield 66%; mp 218–221 °C; IR (KBr) ν_max 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) ν_max 3063.93 (CH strech), 1675.95 (C=O), 1594.46 (C=C), 1387.93 (CH bend), 771.00 (C–Cl) cm⁻¹; ¹H 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.

8.2.19 N-(4-Oxo-2-phenylquinazolin-3(4H)-yl)benzamide (22). Yield 46%; mp 198–201 °C; IR (KBr) ν_max 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) ν_max 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) ν_max 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) ν_max 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) ν_max 3051.48 (CH strech), 1662.89 (C=O), 1584.53 (C=C), 1482.89 (CH bend), 742.79 (C–Cl) cm⁻¹; ¹H 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) ν_max 3088.16 (CH strech), 1651.61 (C=O), 1603.15 (C=C), 1427.48 (CH bend), 1209.02 (C–F) cm⁻¹; ¹H 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.

8.2.25 4-Hydroxy-N-(4-oxo-2-phenylquinazolin-3(4H)-yl)benzamide (28). Yield 38%; mp 241–244 °C; IR (KBr) ν_max 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) ν_max 3028.38 (CH strech), 1662.82 (C=O), 1592.28 (C=C), 1462.82 (CH bend), 1019.62 (C–F) cm⁻¹; ¹H 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) ν_max 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) ν_max 3068.74 (arom. CH strech), 2973.01 (Aliph. CH strech), 1677.32 (C=O), 1560.25 (C=C), 1468.23 (CH bend) cm⁻¹; ¹H 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) ν_max 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) ν_max 3087.18 (CH strech), 1673.73 (C=O), 1604.03 (C=C), 1449.81 (CH bend), 1531.33 and 1349.73 (NO₂) cm⁻¹; ¹H 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.

8.2.31 2-Phenyl-3-(3,4,5-trichlorophenyl)quinazolin-4(3H)-one (34). Yield 48%; mp 152–156 °C; IR (KBr) ν_max 3037.97 (CH strech), 1714.91 (C=O), 1611.53 (C=C), 1449.28 (CH bend), 764.78 (C–Cl) cm⁻¹; ¹H 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) ν_max 3083.56 (CH strech), 1678.45 (C=O), 1578.67 (C=C), 1488.28 (CH bend), 732.67 (C–Cl) cm⁻¹; ¹H 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) ν_max 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). Compound 3 (0.01 mol) was melted in a beaker, excess hydrazine hydrate was added and it was heated further for 30 minutes. The mixture was cooled and water was added. The separated solid 37 was collected by filtration, washed with water, dried and recrystallized from ethanol; it was 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) ν_max 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 bend) cm⁻¹; ¹H 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 (40)

Synthesized as per the reported method.²⁰

8.4 7-Chloro-3-hydroxy-2-phenylquinazolin-4(3H)-one (41)

Equimolar amounts of 7-chloro-2-phenyl-4H-benzo[d][1,3]oxazin-4-one 40 and hydroxylamine hydrochloride in dry pyridine (30 ml) were 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) ν_max 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 10.41 (s, 1H, OH), 6.99–7.88 (m, 8H, Ar-H); ¹³C NMR (DMSO-d₆) δ 158.32, 157.33, 154.37, 137.48, 132.45, 132.05, 129.63, 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 formamide were fused together at 200–250 °C in an oil bath for 15 minutes. The mixture was cooled and ethanol was added. The separated solid 42 was collected by filtration, washed with ethanol, dried and recrystallized from ethanol; it was further refluxed with P₂S₅ in xylene for 1 h. The solution was cooled and the product precipitated. The solid was collected and recrystallized from methanol; yield 34%; mp 235–238 °C; IR (KBr) ν_max 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) was melted in a beaker, excess hydrazine hydrate was added, and it was heated further for 30 minutes. The mixture was cooled and water was added. The separated solid 44 was collected by filtration, washed with water, dried and recrystallized from ethanol. It was 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) ν_max 3314.96 (NH strech), 3020.48 (arom. CH strech), 2939.21 (aliph. CH strech), 1724.15 [C=O (ketone)], 1701.30 [C=O (amide)], 1559.53 (C=C), 1615.75 (NH bend), 1444.48 (CH bend), 772.87 (C–Cl) cm⁻¹; ¹H 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 amounts 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. 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) ν_max 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); ¹³C 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].

8.7.2 4-(7-Chloro-4-oxo-2-phenylquinazolin-3(4H)-yl)benzene sulfonamide (47). Yield 82%; mp above 250 °C; IR (KBr) ν_max 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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, 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) ν_max 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) ν_max 3089.78 (CH strech), 1662.89 (C=O), 1586.21 (C=C), 1462.45 (CH bend), 721.68 (C–Cl) cm⁻¹; ¹H 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) ν_max 3063.52 (CH strech), 1684.71 (C=O), 1598.68 (C=C), 1421.88 (CH bend), 702.79 (C–Cl) cm⁻¹; ¹H 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) ν_max 3060.29 (CH strech), 1689.09 (C=O), 1593.69 (C=C), 1421.60 (CH bend), 769.65 (C–Cl) cm⁻¹; ¹H 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) ν_max 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) ν_max 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, 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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) ν_max 3221.82 (NH strech), 3012.29 (CH strech), 1669.23 (C=O), 1612.27 (NH bend), 1529.18 (C=C), 1443.21 (C–H bend), 701.28 (C–Cl), 1542.01 and 1348.23 (NO₂) cm⁻¹; ¹H 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) ν_max 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), 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, 131.81, 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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) ν_max 3123.86 (CH strech), 1662.38 (C=O), 1592.49 (C=C), 1484.38 (CH bend), 762.38 (C–Cl) cm⁻¹; ¹H 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.

8.7.25 2-Benzamido-4-chloro-N-(3,4-dimethylphenyl)benzamide (70). Yield 71%; mp 168–172 °C; IR (KBr) ν_max 3264.39 (NH strech), 3060.76 (arom. CH strech), 2917.88 (aliph. CH strech), 1684.52 (C=O), 1582.41 (NH bend), 1511.88 (C=C), 1413.59 (C–H bend), 693.66 (C–Cl) cm⁻¹; ¹H 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) ν_max 3212.28 (NH strech), 3028.24 (arom. CH strech), 2958.42 (aliph. CH strech), 1658.82 (C=O), 1612.56 (NH bend), 1538.28 (C=C), 1468.28 (C–H bend), 684.28 (C–Cl) cm⁻¹; ¹H 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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.

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) ν_max 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 0.69, 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) ν_max 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) ν_max 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) ν_max 3046.38 (CH strech), 1658.24 (C=O), 1572.82 (C=C), 1462.83 (CH bend), 756.32 (C–Cl) cm⁻¹; ¹H 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) ν_max 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); ¹³C 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) ν_max 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); ¹³C 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) ν_max 3068.34 (CH strech), 1648.34 (C=O), 1572.87 (C=C), 1481.78 (CH bend), 724.28 (C–Cl) cm⁻¹; ¹H 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, 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) ν_max 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) ν_max 3128.47 (CH strech), 1652.84 (C=O), 1572.92 (C=C), 1462.28 (CH bend), 1538.29 and 1341.28 (NO₂), 688.99 (C–Cl) cm⁻¹; ¹H 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) ν_max 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) ν_max 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) ν_max 3412.78 (OH strech), 3214.88 (NH strech), 3035.79 (CH strech), 1708.18 [C=O (ketone)], 1672.34 [C=O (amide)], 1609.67 (NH bend), 1528.89 (C=C), 1412.36 (CH bend), 716.87 (C–Cl) cm⁻¹; ¹H 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) ν_max 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 11.01 (s, 1H, NH), 7.11–8.19 (m, 12H, Ar-H); ¹³C NMR (DMSO-d₆) δ 168.55, 164.34, 160.37, 158.39, 152.45, 140.88, 139.37, 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) ν_max 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) was melted in a beaker, excess hydrazine hydrate was added, and it was heated further for 30 minutes. The mixture was cooled and water was added. The separated solid 90 was collected by filtration, washed with water, dried and recrystallized from ethanol; it was 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) ν_max 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) ν_max 3248.38 (NH strech), 3089.28 (arom. CH strech), 2976.89 (aliph. CH strech), 1676.91 (C=O), 1623.12 (NH bend), 1587.37 (C=C), 1461.67 (C–H bend), 691.76 (C–Cl) cm⁻¹; ¹H 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) ν_max 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.

8.7.48 7-Chloro-3-(3-chlorophenyl)-2-phenylquinazolin-4(3H)-one (94). Yield 71%; mp 194–200 °C; IR (KBr) ν_max 3069.99 (CH strech), 1686.80 (C=O), 1580.47 (C=C), 1447.27 (CH bend), 701.77 (C–Cl) cm⁻¹; ¹H 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) ν_max 3246.35 (NH strech), 3078.89 (arom. CH strech), 2945.67 (aliph. CH strech), 1664.43 (C=O), 1624.89 (NH bend), 1531.56 (C=C), 1468.28 (C–H bend), 691.34 (C–Cl) cm⁻¹; ¹H 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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, 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) ν_max 3223.21 (NH strech), 3038.29 (arom. CH strech), 2964.99 (aliph. CH strech), 1671.21 (C=O), 1623.10 (NH bend), 1571.90 (C=C), 1459.21 (C–H bend), 692.90 (C–Cl) cm⁻¹; ¹H 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) ν_max 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) ν_max 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) ν_max 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) ν_max 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].

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) ν_max 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. Synthesized as per the reported method.²⁰

8.8 Anticonvulsant activity

The anticonvulsant activity of all the 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⁻¹ 30 min before seizure induction. Sodium valproate (1.5 mmol kg⁻¹) and methaqualone (1.4 mmol kg⁻¹) were used as reference drugs.^26,27 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⁻¹). 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. The animals that showed no convulsion within 1 h after convulsive drug administration were considered to be protected.^26,27

8.9 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 30 s. 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.

8.10 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 50% mortality in mice, was determined from dose–response curves with at least four doses by the method of Litchfield and Wilcoxon.²⁹ 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.

References

1. A. S. El-Azab and K. E. H. Eltahir, Bioorg. Med. Chem. Lett., 2012, 22, 327–333.
2. N. D. Amnerkar and K. P. Bhusari, Eur. J. Med. Chem., 2010, 45, 149–159.
3. www.who.int/entity/mediacentre/factsheets/fs999/en.
4. A. S. El-Azab, K. E. H. ElTahir and S. M. Attia, Monatsh. Chem., 2011, 142, 837–848.
5. H. Stefan and T. Feuerstein, Pharmacol. Ther., 2007, 113, 165–183.
6. E. J. Donner and O. C. Snead, NeuroRx, 2006, 3, 170–180.
7. A. S. El-Azab and K. E. H. ElTahir, Med. Chem. Res., 2012, 21, 3785–3796.
8. W. Löscher and D. Schmidt, Epilepsy Res., 2002, 50, 3–16.
9. W. Löscher and D. Schmidt, Epilepsy Res., 2006, 69, 183–272.
10. R. S. Greenwood, Epilepsia, 2000, 41, S42–S52.
11. J. F. Wolfe, T. L. Rathman, M. C. Sleevi, J. A. Campbell and T. D. Greenwood, J. Med. Chem., 1990, 33, 161–166.
12. M. A. A. Aziza, J. Pharm. Sci., 1997, 19, 129–135.
13. A. S. El-azab and K. E. H. ElTahir, Bioorg. Med. Chem. Lett., 2012, 22, 1879–1885.
14. A. S. El-azab, S. G. Abdel Hamid, M. M. Sayed Ahmed, G. H. Hassan, T. M. El-Hadiyah, O. A. Al-Shabanah, O. A. Al-Deeb and H. I. Al-Subbagh, Med. Chem. Res., 2013, 22, 2815–2827.
15. V. Ugale, H. M. Patel and S. G. Wadodkar, Eur. J. Med. Chem., 2012, 53, 107–113.
16. P. Kumar, B. Shrivastava, S. N. Pandeya and J. P. Stables, Eur. J. Med. Chem., 2011, 46, 1006–1018.
17. G. Saravanan, V. Alagarsamy and R. C. Prakash, Bioorg. Med. Chem. Lett., 2012, 22, 3072–3078.
18. M. K. Ibrahim, K. El-Adl and A. A. Al-Karmalawy, Bull. Fac. Pharm., 2015, 53, 101–116.
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, Arabian J. Chem., 2013, 6, 35–48.
21. V. V. Poroikov, D. A. Filimonov, T. A. Gloriozova, A. A. Lagunin, D. S. Druzhi- lovsky and A. V. Stepanchikova, The Herald of Vavilov Society for Geneticists and Breeding Scientists, 2009, vol. 13, pp. 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 Discovery Today, 2008, 13, 285–294.
24. C. A. Lipinski, F. Lombardo, B. W. Dominy and P. Feeney, Adv. Drug Delivery 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 Drug Discovery and Evaluation, Pharmacological assays, ed. H. G. Vogel and W. H. Vogel, Springer Verlag, Berlin, 2nd edn, 2002, p. 422.
27. H. S. White, J. H. Woodhead, M. R. Franklin, E. A. Swinyard and H. H. Wolf, in Antiepileptic drugs, ed. R. H. Levy, R. H. Mattson and B. S. Meldrum, Raven, New York, 4th edn, 1995, p. 99.
28. J. R. Boissier, J. Tardy and J. C. Diverres, Med. Exp., 1960, 3, 81–84.
29. J. Litchfield and F. Wilcoxon, J. Pharmacol. Exp. Ther., 1949, 96, 99–113.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra01284a

---