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Design, Synthesis, Computer Modeling and Analgesic Activity of Some New Quinazoline Derivatives | OMICS International
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Medicinal Chemistry

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Design, Synthesis, Computer Modeling and Analgesic Activity of Some New Quinazoline Derivatives

Helmy Sakr M*

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt

*Corresponding Author:
Helmy Sakr M
Department of Pharmaceutical Chemistry
Faculty of Pharmacy, Al-Azhar University
Nasr City, 11884, Cairo, Egypt
Tel: 00201065565461
E-mail: [email protected]

Received date: August 21, 2016; Accepted date: August 27, 2016; Published date: August 31, 2016

Citation: Helmy Sakr M (2016) Design, Synthesis, Computer Modeling and Analgesic Activity of Some New Quinazoline Derivatives. Med Chem (Los Angeles) 6:550-556. doi:10.4172/2161-0444.1000398

Copyright: © 2016 Helmy Sakr M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Some new 2-(substituted)-N-(6-bromo-4-oxo-2-phenylquinazolin-3(3H)-yl) acetamides (4.1-9), 2-(substituted)- N-(6,8-dibromo-4-oxo-2-phenylquinazolin-3(3H)-yl) acetamides (4.10-18), 2-(substituted)-N-(6-chloro-4-oxo-2- phenylquinazolin-3(3H)-yl) acetamides (4.19-27) and 2-(substituted)-N-(6,8-dichloro-4-oxo-2-phenylquinazolin- 3(3H)-yl) acetamides (4.28-36) were synthesized in good yield and investigated for analgesic activity. Computer aided drug design (CADD) studies were performed to rationalize the best fitting value of the prepared compounds. All the test compounds exhibited significant analgesic activity compared to reference standard diclofenac sodium. The compounds with aliphatic group (CH3 or C2H5) (4.1, 2, 10, 11, 19, 20, 28 and 29) showed most potent analgesic activity of the series and it is moderately more potent compared to the reference standard diclofenac sodium.

Keywords

Analgesic; Anti-inflammatory; Quinazoline; Diclofenac sodium

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of acute and chronic inflammation, pain, and fever. The most of NSAIDs act via inhibition of cyclooxygenase, thus preventing prostaglandin biosynthesis. However, this mechanism of action is also responsible for their main undesirable effects, gastrointestinal (GI) ulceration, and, less frequently, nephrotoxicity. The increase in hospitalization and deaths due to GI-related disorders parallels the increased use of NSAIDs. Therefore, the discovery of new safer anti-inflammatory drugs represents a challenging goal for such a research area. In medicinal chemistry research program, I found that quinazolines and condensed quinazolines exhibit potent central nervous system activities including analgesic [1-7], anti-inflammatory [8-11], and anticonvulsant [12,13]. Quinazolin-4(3H)-ones with C-2 and N-3 substitution are reported to possess significant analgesic, antiinflammatory [14,15], and anticonvulsant activities [16]. In the present work a series of 2-(substituted)-N-(4-oxo-2-phenylquinazolin-3(3H)- yl) acetamides were synthesized and tested for their analgesic activity. For synthesizing the target compounds 4.1-36 the following scheme is adopted Scheme 1.

medicinal-chemistry-target-compounds

Scheme 1: Synthesizing the target compounds 4.1-36.

Experimental

All melting points were measured in capillary tube on a Graffin melting point apparatus and are uncorrected. The chemical structures of the synthesized compounds were confirmed on the basis of their spectral data (IR, 1H NMR and mass spectra) and the purity was ascertained by microanalysis. The IR spectra were recorded on Pye Unicam SP 1000 IR spectrophotometer using KBr discs (λmax in cm-1). 1H NMR spectra were performed either on Gemini 300BB (300 MHz) or (500 MHz) and (300 MHz) for 13C NMR), spectrometer, using TMS as internal standard and DMSO-d6 as solvent; the chemical shifts are reported in ppm (δ) and coupling constant (J) values are given in Hertz (Hz). Signal multiplicities are represented by s (singlet), d (doublet), t (triplet), q (quadruplet), and m (multiplet). All of the new compounds were analyzed for C, H and N and agreed with the proposed structures within ± 0.4% of the theoretical values by the automated CHN analyzer. Mass spectra were recorded on Hewlett Packard 5988 spectrometer at the RCMB. The purity of the compounds was checked by Thin Layer Chromatography (TLC) on Merck silica gel 60 F254 precoated sheets. All analyses were performed at the Micro-analytical Unit of Cairo University, Cairo, Egypt.

Synthesis of 2-Phenyl-3,1-benzoxazin-4-one derivatives (1)

Anthranilic acid derivatives [17-19] (0.1 mol) were dissolved in pyridine (60 mL), benzoyl chloride (1.40 g, 0.2 mol) was added. The reaction mixture was stirred for an hour followed by treatment with 15 mL. of 5% sodium bicarbonate. The solid product was obtained filtered off and recrystallized from ethanol.

6-Bromo-2-Phenyl-3,1-benzoxazin-4-one (1.1): Yield: 85%; MP: 136-138°C; IR (KBr, ν, cm-1): 3330 (NH), 1760 (C=O), 1600 (C=N). 1H NMR (300 MHz, [D6] DMSO): δ = 7.31-7.34 (m, 3H, Ar-H), 7.50-7.52 (d, 1H, Ar-H), 7.71-7.74 (m, 2H, Ar-H), 7.84-7.86 (d, 1H, Ar-H), 7.90–7.92 (d, 1H, Ar-H). 13C NMR (300 MHz, [D6] DMSO): δ = 118.7, 121.6, 124.49], 128.2, 128.3, 128.4, 128.5, 129.9, 131.2, 135.3, 138.4, 145.4, 156.5, 159.6. MS (m/z): 301/303/302, M+, 100/95/20%). Anal. Calcd. For C14H8NO2Br: C, 55.62; H, 2.64; N, 4.63. Found: C, 55.83; H, 2.41; N, 4.65.

6,8-Dibromo-2-Phenyl-3,1-benzoxazin-4-one (1.2): Yield: 80%; MP: 145-147°C; IR (KBr, ν, cm-1): 3360 (NH), 1740 (C=O), 1620 (C=N).1H NMR (300 MHz, [D6] DMSO): δ = 7.48-7.50 (m, 3H, Ar- H), 7.86-7.88 (m, 2H, Ar-H), 7.92–7.94 (d, 1H, Ar-H), 8.00-8.10 (d, 1H, Ar-H).13C NMR (300 MHz, [D6] DMSO): δ = 113.2, 120.7, 121.9, 128.2, 128.2, 128.9, 128.9, 129.9 131.2, 134.2, 141.4, 156.4, 157.2, 159.5. MS (m/z): (381/383, M+, 100/42%). Anal. Calcd. for C14H7NO2Br2: C, 44.09; H, 1.83; N, 3.67. Found: C, 44.36; H, 1.91; N, 3.71.

6-Chloro-2-Phenyl-3,1-benzoxazin-4-one (1.3): Yield: 78%; MP: 124-126°C; IR (KBr, ν, cm-1): 3330 (NH), 1720 (C=O), 1630 (C=N). 1H NMR (300 MHz, [D6] DMSO): δ = 7.40-7.43 (m, 4H, Ar-H), 7.61-7.63 (d, 1H, Ar-H), 7.76-7.78 (m, 2H, Ar-H), 7.94-7.96 (d, 1H, Ar-H).13C NMR (300 MHz, [D6] DMSO): δ = 117.8, 127.6, 128.2, 128.3, 128.8, 128.9, 129.8, 131.3, 131.6, 132.8, 135.4, 144.3, 156.4, 159.5. MS (m/z): (257/259, M+, 100/30%). Anal. Calcd. For C14H8NO2Cl: C 65.24; H, 3.10; N, 5.44. Found: C, 65.41; H, 3.26; N, 5.61.

6,8-Dichloro-2-Phenyl-3,1-benzoxazin-4-one (1.4): Yield: 70%; MP: 130-132°C; IR (KBr, ν, cm-1): 3340 (NH), 1730 (C=O), 1610 (C=N).1H NMR (300 MHz, [D6] DMSO): δ = 7.48-7.50 (m, 3H, Ar- H), 7.76-7.78 (m, 3H, Ar-H), 7.84-7.87 (d, 2H, Ar-H). 13C NMR (300 MHz, [D6] DMSO): δ = 119.3, 128.2, 128.3, 128.9, 128.9, 129.3, 129.8, 129.9, 131.2, 134.2, 136.9, 156.4, 159.5, 166.3. MS (m/z): (291/293, M+, 100/60%). Anal. Calcd. for C14H7NO2Cl2: C, 57.53; H, 2.40; N, 4.79. Found: C, 57.70; H, 2.44; N, 4.86.

Synthesis of 3-Amino-2-phenylquinazolin-4-(3H)-one derivatives (2)

A mixture of 2-phenyl-3,1-benzoxazin-4-one (1) (0.05 mol) and hydrazine hydrate (0.30 mL, 0.05 mol) in ethanol was refluxed for 3 hours. The solid product was obtained after cooling is filtered off and recrystallized from ethanol.

3-Amino-6-bromo-2-phenylquinazolin-4-(3H)-one (2.1): Yield: 80%; MP: 172-174°C; IR (KBr, ν, cm-1): 3300 (NH2), 1680 (C=O), 1620 (C=N) and 1600 (C=C). 1H NMR (300 MHz, [D6] DMSO): δ = 4.70 (s, 2H, NH2, D2O exchangeable), 7.21-7.23 (m, 3H, Ar- H), 7.40- 7.42 (d, 1H, Ar-H), 7.63-7.66 (m, 2H, Ar-H), 7.86-7.88 (d, 1H, Ar-H), 7.94-7.96 (d, 1H, Ar-H).13C NMR (300 MHz, [D6] DMSO): δ = 121.9, 123.2, 124.8, 128.2, 128.4, 128.8, 128.9, 129.0, 130.3, 132.5, 136.3, 147.8, 156.4, 160.8. MS (m/z): (315/317/316, M+, 100/90/20%). Anal. Calcd. for C14H10N3OBr: C, 53.16; H, 3.16; N, 13.29. Found: C, 53.34; H, 3.28; N, 13.43.

3-Amino-6,8-dibromo-2-phenylquinazolin-4-(3H)-one (2.2): Yield: 72%; MP: 186-188°C; IR (KBr, ν, cm-1): 3310 (NH2), 1700 (C=O), 1630 (C=N) and 1610 (C=C). 1H NMR (300 MHz, [D6] DMSO): δ = 4.60 (s, 2H, NH2, D2O exchangeable), 7.26-7.28 (m, 3H, Ar- H), 7.46- 7.48 (m, 2H, Ar-H), 7.90-7.92 (d, 1H, Ar-H), 7.96-7.89 (d, 1H, Ar- H).13C NMR (300 MHz, [D6] DMSO): δ = 113.2, 122.1, 125.4, 128.3, 128.4, 128.8, 128.9, 129.9 130.2, 131.2, 139.5, 154.5, 156.4, 160.8. MS (m/z): (395/397, M+, 100/50%). Anal. Calcd. for C14H9N3OBr2: C, 42.53; H, 2.28; N, 10.63. Found: C, 42.70; H, 2.43; N, 10.41.

3-Amino-6-chloro-2-phenylquinazolin-4-(3H)-one (2.3): Yield: 85%; MP: 154-156°C; IR (KBr, ν, cm-1): 3320 (NH2), 1690 (C=O), 1610 (C=N) and 1600 (C=C). 1H NMR (300 MHz, [D6] DMSO): δ = 4.81 (s, 2H, NH2, D2O exchangeable), 7.31-7.34 (m, 4H, Ar- H), 7.45-7.47 (d, 1H, Ar-H), 7.60-7.62 (m, 2H, Ar-H), 7.71-7.73 (d, 1H, Ar-H).13C NMR (300 MHz, [D6] DMSO): δ = 122.4, 127.8, 127.9, 128.3, 128.4, 128.7, 128.9, 128.3, 130.1, 132.9, 133.6, 146.8, 156.3, 160.6. MS (m/z): (271/273, M+, 100/34%). Anal. Calcd. For C14H10N3OCl: C 61.88; H, 3.68; N, 15.47. Found: C, 61.97; H, 3.54; N, 15.58.

3-Amino-6,8-dichloro-2-phenylquinazolin-4-(3H)-one (2.4): Yield: 76%; MP: 161-163°C; IR (KBr, ν, cm-1): 3300 (NH2), 1720 (C=O), 1620 (C=N) and 1600 (C=C). 1H NMR (300 MHz, [D6] DMSO): δ = 4.62 (s, 2H, NH2, D2O exchangeable), 7.43-7.45 (m, 3H, Ar- H), 7.62- 7.64 (m, 3H, Ar-H), 7.81-7.83 (d, 1H, Ar-H). 13C NMR (300 MHz, [D6] DMSO): δ = 123.8., 125.9, 128.3, 128.4, 128.7, 128.9, 128.9, 129.4, 130.2, 134.4, 135.3, 156.4, 160.75], 163.4. MS (m/z): (305/307, M+, 100/40%). Anal. Calcd. for C14H9N3OCl2: C 54.90; H, 2.94; N, 13.72. Found: C, 54.93; H, 2.97; N, 13.74.

Synthesis of 2-Chloro-N-(4-oxo-2-phenylquinazolin-3(3H)- yl)acetamide (3)

3-Amino-2-phenylquinazoline derivatives 2 (0.01 mol) was dissolved in dioxane (20 mL), triethylamine (1.01 gm., 0.01 mol) and chloroacetyl chloride (1.12 gm., 0.01 mol) were added and the reaction mixture was stirred at room temperature for 1 hour. The stirring was continued for 2 hours with heating. Then the reaction mixture was poured into ice water and extracted with ether. The ether extract was washed with 3% sodium bicarbonate solution and dried over anhydrous magnesium sulfate; the ether was distilled off to yield 3.

N-(6-bromo-4-oxo-2-phenylquinazolin-3(3H)-yl)-2- chloroacetamide (3.1): Yield: 78%; MP: 172-174°C; IR (KBr, ν, cm- 1): 3200 (NH), 1710 (C=O), 1680 (C=O), 1610 (C=N). 1H NMR (300 MHz, [D6] DMSO): δ = 4.10 (s, 2H, CH2), 7.45-7.47 (m, 3H, Ar- H), 7.52-7.54 (d, 1H, Ar-H), 7.60-7.62 (m, 2H, Ar-H), 7.81-7.83 (d, 1H, Ar-H), 7.96-7.98 (d, 1H, Ar-H), 9.24 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 40.6, 121.8, 123.1, 124.7, 128.3, 128.4, 128.7, 128.9, 128.09130.2, 132.4, 136.4, 147.8, 156.3, 160.7, 166.38]. MS (m/z): 393/395, M+, 100/28%). Anal. Calcd. for C16H11N3O2BrCl: C, 48.91; H, 2.80; N, 10.70. Found: C, 48.99; H, 2.97; N, 10.87.

N-(6,8-Dibromo-4-oxo-2-phenylquinazolin-3(3H)-yl)-2- chloroacetamide (3.2): Yield: 70%; MP: 191-193°C; IR (KBr, ν, cm-1): 3190 (NH), 1690 (C=O), 1670 (C=O), 1607 (C=N), 700 (C–Cl). 1H NMR (300 MHz, [D6] DMSO): δ = 4.00 (s, 2H, CH2), 7.46-7.48 (m, 3H, Ar- H), 7.57-7.59 (m, 2H, Ar-H), 7.68-7.70 (d, 1H, Ar-H), 7.94-7.96 (d, 1H, Ar-H), 9.12 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 40.6, 113.3, 122.1, 125.3, 128.3, 128.4, 128.7, 128.8, 128.9, 128.9, 130.2, 139.5, 154.4, 156.3, 160.6, 166.9. MS (m/z): 471/473, M+, 100/60%). Anal. Calcd. for C16H10N3O2Br2Cl: C, 40.72; H, 2.12; N, 8.91. Found: C, 40.61; H, 2.19; N, 8.84.

N-(6-Chloro-4-oxo-2-phenylquinazolin-3(3H)-yl)-2- chloroacetamide (3.3): Yield: 75%; MP: 165-167°C; IR (KBr, ν, cm-1): 3189 (NH), 1689 (C=O), 1660 (C=O), 1607 (C=N), 700 (C–Cl). 1H NMR (300 MHz, [D6] DMSO): δ = 4.20 (s, 2H, CH2), 7.40-7.42 (m, 4H, Ar- H), 7.61-7.63 (d, 1H, Ar-H), 7.70-7.72 (m, 2H, Ar-H), 7.84-7.86 (d, 1H, Ar-H), 9.38 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 40.6, 122.3, 127.8, 127.9, 128.3, 128.4, 128.7, 128.8, 128.9, 130.2, 132.98, 133.6, 146.9, 156.3, 160.9, 166.4. MS (m/z): (347/349, M+, 100/38%). Anal. Calcd. For C16H11N3O2Cl2: C 55.17; H, 3.16; N, 12.07. Found: C, 55.31; H, 3.31; N, 12.33.

N-(6,8-Dichloro-4-oxo-2-phenylquinazolin-3(3H)-yl)-2- chloroacetamide (3.4): Yield: 68%; MP: 181-183°C; IR (KBr, ν, cm-1): 3200 (NH2), 1700 (C=O), 1620 (C=N) and 1600 (C=C), 700 (C–Cl).. 1H NMR (300 MHz, [D6] DMSO): δ = 3.98 (s, 2H, CH2), 7.42-7.44 (m, 3H, Ar- H), 7.65-7.67 (m, 3H, Ar-H), 7.80-7.82 (d, 1H, Ar-H), 9.41 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 40.5, 123.6, 125.8, 128.3, 128.4, 128.6, 128.8, 128.9, 129.4, 130.2, 134.4, 135.1, 156.3, 160.9, 163.5, 166.4. MS (m/z): (381/383/385, M+, 100/90/32%). Anal. Calcd. for C16H10N3O2Cl3: C 50.22; H, 2.61; N, 10.98. Found: C, 50.37; H, 2.69; N, 11.07.

Synthesis of N-(4-Oxo-2-phenylquinazolin-3(3H)-yl) acetamide derivative (4)

A mixture of 2-chloro-N-(4-oxo-2-phenylquinazolin-3(3H)-yl) acetamide (3) (0.01 mol), anhydrous potassium carbonate (200 mg), and amine derivatives (0.01 mol) in dioxane (15 mL) was refluxed for 12 hours The reaction mixture was then poured into crushed ice. The solid product was obtained filtered off, washed with water, dried, and recrystallized from ethanol (Table 1).

Comp. No. X Y R Yield % m.p. °C Mol. F./Mol. Wt. Elemental analysis
C H N
4.1 Br H -NHCH3 80 178-180 C17H15N4O2Br
387
52.71
52.94
3.87
3.96
14.47
14.62
4.2 Br H -NHC2H5 82 183-185 C18H17N4O2Br
401
53.86
53.89
4.24
4.32
13.96
13.91
4.3 Br H -NHC6H5 78 188-190 C22H17N4O2Br
449
58.80
58.92
3.79
3.96
12.47
12.59
4.4 Br H -NH-4-(Cl)C6H4 75 195-197 C22H16N4O2BrCl
483.50
54.60
54.73
3.31
3.34
11.58
11.70
4.5 Br H -NH-2-(NO2)C6H4 72 208-210 C22H16N5O4Br
494
53.44
53.38
3.24
3.27
14.17
14.24
4.6 Br H -NH-4-(NO2)C6H4 75 212-214 C22H16N5O4Br
494
53.44
53.61
3.24
3.35
14.17
14.30
4.7 Br H -NH-2-(OCH3)C6H4 76 193-195 C23H19N4O3Br
479
57.62
57.68
3.97
3.84
11.69
11.78
4.8 Br H -NH-4-(OCH3)C6H4 74 195-197 C23H19N4O3Br
479
57.62
57.70
3.97
4.08
11.69
11.82
4.9 Br H -NH-2-(CH3)C6H4 75 186-188 C23H19N4O2Br
463
59.61
59.73
4.10
4.33
12.09
12.27
4.10 Br Br -NHCH3 70 223-225 C17H14N4O2Br2
466
43.78
43.90
3.00
3.24
12.02
12.31
4.11 Br Br -NHC2H5 75 233-235 C18H16N4O2Br2
480
45.00
45.08
3.33
3.39
11.66
11.82
4.12 Br Br -NHC6H5 78 237-239 C22H16N4O2Br2
528
50.00
49.91
3.03
3.10
10.60
10.74
4.13 Br Br -NH-4-(Cl)C6H4 76 241-243 C22H15N4O2Br2Cl
562.5
46.93
47.01
2.66
2.90
9.95
9.74
4.14 Br Br -NH-2-(NO2)C6H4 74 253-255 C22H15N5O4Br2
573
46.07
46.21
2.62
2.68
12.22
12.31
4.15 Br Br -NH-4-(NO2)C6H4 75 251-253 C22H15N5O4Br2
573
46.07
46.24
2.62
2.71
12.22
12.38
4.16 Br Br -NH-2-(OCH3)C6H4 78 228-230 C23H18N4O3Br2
558
49.46
49.70
3.23
3.50
10.04
10.08
4.17 Br Br -NH-4-(OCH3)C6H4 80 230-232 C23H18N4O3Br2
558
49.46
49.68
3.23
3.37
10.04
10.12
4.18 Br Br -NH-2-(CH3)C6H4 77 212-214 C23H18N4O2Br2
542
50.92
50.74
3.32
3.38
10.33
10.50
4.19 Cl H -NHCH3 78 152-154 C17H15N4O2Cl
342.5
59.56
59.62
4.38
4.61
16.35
16.40
4.20 Cl H -NHC2H5 82 158-160 C18H17N4O2Cl
356.5
60.59
60.74
4.77
4.82
15.70
15.79
4.21 Cl H -NHC6H5 74 164-166 C22H17N4O2Cl
404.5
65.27
65.38
4.20
4.09
13.84
13.92
4.22 Cl H -NH-4(Cl)C6H4 75 183-185 C22H16N4O2Cl2
439
60.14
60.30
3.64
3.82
12.75
12.91
4.23 Cl H -NH-2(NO2)C6H4 72 191-193 C22H16N5O4Cl
449.5
58.73
58.80
3.56
3.61
15.57
15.41
4.24 Cl H -NH-4(NO2)C6H4 74 190-192 C22H16N5O4Cl
449.5
58.73
58.86
3.56
3.77
15.57
15.60
4.25 Cl H -NH-2(OCH3)C6H4 80 194-196 C23H19N4O3Cl
434.5
63.52
63.74
4.37
4.61
12.88
12.93
4.26 Cl H -NH-4(OCH3)C6H4 78 207-209 C23H19N4O3Cl
434.5
63.52
63.60
4.37
4.56
12.88
12.87
4.27 Cl H -NH-2(CH3)C6H4 80 176-178 C23H19N4O2Cl
418.5
65.95
65.87
4.54
4.66
13.38
13.52
4.28 Cl Cl -NHCH3 78 180-182 C17H14N4O2Cl2
377
54.11
54.20
3.71
3.89
14.85
14.93
4.29 Cl Cl -NHC2H5 85 191-193 C18H16N4O2Cl2
391
55.24
55.49
4.09
4.20
14.32
14.37
4.30 Cl Cl -NHC6H5 78 205-207 C22H16N4O2Cl2
439
60.14
60.22
3.64
3.59
12.75
12.81
4.31 Cl Cl -NH-4-(Cl)C6H4 76 218-220 C22H15N4O2Cl3
473.5
55.76
55.90
3.17
3.41
11.83
11.88
4.32 Cl Cl -NH-2-(NO2)C6H4 75 235-237 C22H15N5O4Cl2
484
54.55
54.70
3.10
3.26
14.46
14.51
4.33 Cl Cl -NH-4-(NO2)C6H4 74 234-236 C22H15N5O4Cl2
484
54.55
54.43
3.10
3.18
14.46
14.58
4.34 Cl Cl -NH-2(-OCH3)C6H4 80 247-249 C23H18N4O3Cl2
469
58.85
58.93
3.84
3.96
11.94
12.10
4.35 Cl Cl -NH-4-(OCH3)C6H4 82 245-247 C23H18N4O3Cl2
469
58.85
58.87
3.84
3.90
11.94
11.98
4.36 Cl Cl -NH-2-(CH3)C6H4 78 234-236 C23H18N4O2Cl2
453
60.93
60.87
3.97
4.13
12.36
12.50

Table 1: The physical data and elemental analysis of compounds (4).

N-(6-Bromo-4-oxo-2-phenylquinazolin-3(3H)-yl)-2-(ethylamino) acetamide (4.2)

IR (KBr, ν, cm-1): 3330 (NH), 3230 (NH), 1710 (C=O), 1680 (C=O), 1610 (C=N).1H NMR (500 MHz, [D6] DMSO): δ = 0.98-1.00 (t, 3H, CH3), 2.50-2.52 (m, 2H, CH2-CH3), 3.30 (s, 2H, CH2-NH) 7.18-7.20 (m, 3H, Ar-H), 7.60-7.62(d, 1H, Ar-H), 7.80-7.83 (m, 2H, Ar-H), 7.98- 8.00 (d, 1H, Ar-H), 8.20-8.22 (d, 1H, Ar-H), 8.42 (s, 1H, NH), 8.65 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 14.3, 19.6, 40.7, 120.8, 121.9, 123.2, 128.2, 128.3, 128.6, 128.8, 128.9, 130.3, 132.4, 136.4, 147.8, 156.6, 160.8, 176.7. MS (m/z): 400/402/403 M+, 100/95 /20%).

N-(6-Bromo-4-oxo-2-phenylquinazolin-3(3H)-yl)-2-(2- nitrophenylamino)acetamide (4.5)

IR (KBr, ν, cm-1): 3380 (NH), 3190 (NH), 1725 (C=O), 1700 (C=O), 1615 (C=N). 1H NMR (500 MHz, [D6] DMSO): δ = 3.60 (s, 2H, CH2- NH) 7.28-7.30 (m, 2H, Ar-H), 7.58-7.62(m, 5H, Ar-H), 7.80-7.82 (m, 2H, Ar-H), 8.00-8.02 (m, 2H, Ar-H), 8.12-8.14 (d, 1H, Ar-H), 8.50 (s, 1H, NH), 8.62 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 56.4, 111.8, 118.5, 121.8, 123.2, 124.7, 125.9, 128.2, 128.2, 128.6, 128.8, 128.9, 130.3, 131.8 132.4, 135.6, 136.3, 145.6, 147.6, 156.4, 160.7, 170.4.. MS (m/z): 493/495/495 M+, 100/90/24%).

N-(6,8-Dibromo-4-oxo-2-phenylquinazolin-3(3H)-yl)-2- (phenylamino)acetamide (4.12)

IR (KBr, ν, cm-1): 3360 (NH), 3240 (NH), 1705 (C=O), 1640 (C=O), 1598 (C=N). 1H NMR (500 MHz, [D6] DMSO): δ = 3.70 (s, 2H, CH2- NH) 6.65-6.68 (m, 3H, Ar-H), 7.16-7.18(m, 2H, Ar-H), 7.48-7.50 (m, 3H, Ar-H), 7.62-7.46 (d, 1H, Ar-H), 7.76-7.78 (m, 2H, Ar-H), 8.10 (d, 1H, Ar-H), 8.51 (s, 1H, NH), 8.62 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 57.4, 113.4, 113.6, 113.7, 120.9, 122.1, 125.4, 128.4, 128.6, 128.9, 128.9, 128.9, 129.6, 130.3, 131.4, 139.7, 147.8, 154.5, 156.5, 160.8, 160.7, 170.6. MS (m/z): (528/526/530, M+, 100/52/46%).

N-(6,8-Dibromo-4-oxo-2-phenylquinazolin-3(3H)-yl)-2-(otolylamino) acetamide (4.18)

IR (KBr, ν, cm-1): 3400 (NH), 3200 (NH), 1700 (C=O), 1660 (C=O), 1590 (C=N). 1H NMR (500 MHz, [D6] DMSO): δ = 2.04(s, 3H, CH3) 3.68 (s, 2H, CH2-NH) 6.62-6.64 (m, 2H, Ar-H), 6.83-6.85(m, 1H, Ar- H), 7.10-7.12 (d, 1H, Ar-H), 7.43-7.45 (m, 3H, Ar-H), 7.66-7.68 (d, 1H, Ar-H), 7.78-7.80 (m, 2H, Ar-H), 8.05-8.07 (d, 1H, Ar-H), 8.40 (s, 1H, NH), 8.60 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 17.8, 57.6, 113.3, 117.2, 121.9, 122.2, 122.3, 125.4, 126.7, 127.2, 128.3, 128.4, 128.4, 128.7, 128.9, 130.3, 131.4, 139.5, 146.7, 154.5, 156.2, 160.7, 170.3. MS (m/z): (542/544/540, M+, 100/50/48%).

N-(6-Chloro-4-oxo-2-phenylquinazolin-3(3H)-yl)-2-(ethylamino) acetamide (4.20)

IR (KBr, ν, cm-1): 3350 (NH), 3228 (NH), 1712 (C=O), 1655 (C=O), 1600 (C=N). 1H NMR (500 MHz, [D6] DMSO): δ = 1.00-1.02 (t, 3H, CH3), 2.48-2.50 (m, 2H, CH2-CH3), 3.34 (s, 2H, CH2-NH) 7.40-7.43 (m, 4H, Ar-H), 7.58-7.60(d, 1H, Ar-H), 7.82-7.84 (m, 2H, Ar-H), 7.94-7.96 (d, 1H, Ar-H), 8.45 (s, 1H, NH), 8.60 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 15.4, 44.5, 54.9, 122.3, 127.8, 127.8, 128.3, 128.4, 128.6, 128.9, 128.9, 130.3, 132.9, 133.6, 146.8, 156.3, 160.8, 170.4. MS (m/z): (356/358, M+, 100/32%).

N-(6-Chloro-4-oxo-2-phenylquinazolin-3(3H)-yl)-2-(4- chlorophenylamino)acetamide (4.22)

IR (KBr, ν, cm-1): 3360 (NH), 3236 (NH), 1730 (C=O), 1675 (C=O), 1590 (C=N). 1H NMR (500 MHz, [D6] DMSO): δ = 3.68 (s, 2H, CH2- NH) 6.48-6.50 (d, 2H, Ar-H), 7.40-7.42(d, 2H, Ar-H), 7.50-7.53 (m, 4H, Ar-H), 7.68-7.70 (d, 1H, Ar-H), 7.85-7.87 (m, 2H, Ar-H), 7.92-7.94 (d, 1H, Ar-H), 8.40 (s, 1H, NH). 8.58 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 57.4, 114.9, 114.9, 122.2, 126.3, 127.8, 127.8, 128.2, 128.3, 128.7, 128.9, 128.9, 129.7, 129.7, 130.3, 132.9, 133.6, 145.7, 146.7, 156.3, 160.9, 170.4. MS (m/z): (438/440/439, M+, 100/60/22%).

N-(6,8-Dichloro-4-oxo-2-phenylquinazolin-3(3H)-yl)-2- (methylamino)acetamide (4.28)

IR (KBr, ν, cm-1): 3345 (NH), 3218 (NH), 1720 (C=O), 1660 (C=O), 1596 (C=N). 1H NMR (500 MHz, [D6] DMSO): δ = 3.20 (s, 2H, CH2-NH) 3.40 (s, 3H, CH3), 7.48-7.50 (m, 4H, Ar-H), 7.82-7.84 (m, 3H, Ar-H), 8.45 (s, 1H, NH). 8.61 (s, 1H, NH).13C NMR (300 MHz, [D6] DMSO): δ = 57.5, 79.1, 123.7, 125.9, 128.3, 128.3, 128.7, 128.9, 128.9, 129.4, 130.2, 134.4, 135.3, 156.3, 160.7, 163.5, 170.4. MS (m/z): (376/378/377, M+, 100/60/20%).

Pharmacology

The synthesized compounds were evaluated for analgesic activity. The test compounds and the standard drugs were administered in the form of a suspension (1% carboxy methyl cellulose as a vehicle) by oral route. Each group consisted of six animals. The animals were maintained in colony cages at 25 ± 2°C, relative humidity of 45-55%, under a 12 hours light and dark cycle; they were fed standard animal feed. All the animals were acclimatized for a week before use.

Analgesic activity

The analgesic activity was performed by the tail-flick technique [20,21] using albino mice (25-35 g) of either sex selected by the random sampling technique. Diclofenac sodium at a dose level of 10 mg/ kg was administered orally as a reference drug for comparison. The test compounds at a dose level of 10 mg/kg were administered orally. The reaction time was recorded at 30 minutes, 1, 2, and 3 hours after the treatment, and cut-off time was 10 seconds. The results are presented in Table 2. The percent analgesic activity (PAA) was calculated by the following formula:

Comp. 4 % Analgesic Activitya
Time (minutes)
180 120 60 30
4.1 30 ± 1.32b 40 ± 1.91c 37 ± 1.41c 34 ± 1.62b
4.2 31 ± 1.53b 53 ± 1.05b 41 ± 1.42c 35 ± 1.28c
4.3 29 ± 1.63b 36 ± 1.51c 33 ± 1.26c 30 ± 1.51b
4.4 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.5 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.6 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.7 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.8 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.9 26 ± 1.73b 30 ± 1.20b 27 ± 1.01b 25 ± 1.11b
4.10 30 ± 1.32b 40 ± 1.91c 37 ± 1.41c 34 ± 1.62b
4.11 31 ± 1.53b 53 ± 1.05b 41 ± 1.42c 35 ± 1.28c
4.12 29 ± 1.63b 36 ± 1.51c 33 ± 1.26c 30 ± 1.51b
4.13 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.14 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.15 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.16 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.17 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.18 26 ± 1.73b 30 ± 1.20b 27 ± 1.01b 25 ± 1.11b
4.19 30 ± 1.32b 40 ± 1.91c 37 ± 1.41c 34 ± 1.62b
4.20 31 ± 1.53b 53 ± 1.05b 41 ± 1.42c 35 ± 1.28c
4.21 29 ± 1.63b 36 ± 1.51c 33 ± 1.26c 30 ± 1.51b
4.22 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.23 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.24 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.25 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.26 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.27 26 ± 1.73b 30 ± 1.20b 27 ± 1.01b 25 ± 1.11b
4.28 30 ± 1.32b 40 ± 1.91c 37 ± 1.41c 34 ± 1.62b
4.29 31 ± 1.53b 53 ± 1.05b 41 ± 1.42c 35 ± 1.28c
4.30 29 ± 1.63b 36 ± 1.51c 33 ± 1.26c 30 ± 1.51b
4.31 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.32 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.33 22 ± 1.44b 32 ± 1.06c 29 ± 1.21b 28 ± 1.13b
4.34 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.35 28 ± 1.32c 36 ± 1.41b 31 ± 1.30b 29 ± 1.51b
4.36 26 ± 1.73b 30 ± 1.20b 27 ± 1.01b 25 ± 1.11b
Control 2 ± 0.51 4 ± 0.29 4 ± 0.30 2 ± 0.23
Diclofenac 35 ± 1.15b 46 ± 1.08c 43 ± 1.42c 38 ± 1.23c

Table 2: The analgesic effect of diclofenac sodium and test compounds (4) in mice.

PAA=[T2-T1/10-T1] × 100

Where T1 is the reaction time (s) before treatment and T2 is the reaction time (s) after treatment.

Molecular modeling

Docking studies were carried out to examine the analgesic effect of compounds 4.1-36.

Preparation of the target protein

The protein target needs to be prepared and modeled according to the format requirements of the docking algorithms used. Thus the required protein was downloaded from protein data bank (PDB) (code 4COX) using Discovery Studio 2.5 software. Water molecules were removed from downloaded protein. Crystallographic disorders and unfilled valence atoms were corrected using alternate conformations and valence monitor options. Protein was subjected to energy minimization by applying CHARMM force fields for charge, and MMFF94 force field for partial charge. Inflexibility of structure is obtained by creating fixed atom constraint. The binding site of the protein was defined and prepared for docking.

Tested compounds preparation

The designed compounds 2D structures were sketched using ChemBioDraw Ultra 14.0 and saved in MDL-SDfile format. SDfile opened, 3D structures were protonated and energy minimized by applying CHARMM force fields for charge, and MMFF94 force field for partial charge, then prepared for docking by optimization of the parameters.

Results and Discussion

The synthetic route depicted in Scheme 1 outlines the chemistry part of the present work. The key intermediate 3-amino-2- phenylquinazoline-4-(3H)-one (2) was synthesized by a straightforward method; 5-bromoanthranilic acid, 3,5-dibromoanthranilic acid, 5-chloroanthranilic acid and 3,5-dichloroanthranilic acid was treated with benzoyl chloride in the presence of pyridine to give benzoxazin- 4-one (1) which was condensed with hydrazine hydrate in ethanol to yield the desired 3-amino-2-phenylquinazoline-4-(3H)-one (2). The 2-chloro-N-(4-oxo-2-phenylquinazolin-3(3H)-yl)acetamide (3) was prepared by the reaction between 3-amino-2-phenylquinazoline-4- (3H)-one (2) and chloroacetyl chloride in dioxane in the presence of triethylamine. The IR spectrum of 3 showed intense peaks at 3200 cm-1 for NH, 1710 1680, cm-1 for carbonyl (C = O), 1610 cm-1 for (C = N). The 1H NMR spectrum of 3 showed a singlet at δ=3.98-4.20 ppm due to a CH2 group and for aromatic protons in the range δ=7.40–7.98 ppm and there is a singlet around 9.12-9.41 due to NH.

The target compounds, 2-(substituted)-N-(4-oxo-2- phenylquinazolin-3(3H)-yl)acetamide 4.1-36, were obtained in a good yield through the nucleophilic displacement of the chloride substituted of 3 with a variety of amines, using dioxane as solvent. The formation of target compounds is indicated by the disappearance of the C–Cl stretching peak of the starting material and the appearance of NH at 3380-3330 cm-1 in the IR spectra of the compounds. The 1H NMR spectra showed signals for substituents at C-3 and a two singlet around δ=8.4 and 8.5 ppm due to two NH groups, and a multiplet at δ=6.62–7.94 ppm was observed for aromatic protons. The mass spectra of the title compounds showed molecular ion peaks corresponding to their molecular formulae. In the mass spectrum of compounds 4.1- 36, a common peak at m/z=144 corresponding to a quinazolin-4-one moiety appeared. The 35Cl/37Cl isotope peaks were observed in the mass spectra of all the compounds containing Cl, confirming the presence of a chlorine atom in the compounds. The relative intensities of these 35Cl/37Cl peaks in comparison with the molecular ion peak were in the ratio of 1:3. Elemental (C, H, N) analyses satisfactorily confirmed elemental composition and purity of the synthesized compounds.

The analgesic activity was performed by the tail-immersion technique using albino mice (Table 2). The results of analgesic testing indicate that the test compounds exhibited moderate analgesic activity at 30 minutes of reaction time and an increase in activity at 1 hour which reached a peak level at 2 hours, and declining activity was observed at 3 hours (Tables 2 and 3). Compounds 4.2, 11, 20 and 29 with ethyl substituent showed good activity, when the ethyl group was replaced by aryl substituents showed a decrease in activity compared to the aliphatic as methyl and ethyl groups.

Comp. âG Comp. âG
4.1 -45.42 4.19 -44.05
4.2 -43.32 4.20 -43.26
4.3 -44.19 4.21 -44.08
4.4 -50.01 4.22 -54.01
4.5 -49.29 4.23 -43.31
4.6 -51.25 4.24 -48.55
4.7 -49.91 4.25 -47.88
4.8 -47.09 4.26 -42.17
4.9 -40.14 4.27 -50.31
4.10 -55.91 4.28 -55.14
4.11 -54.50 4.29 -48.59
4.12 -51.05 4.30 -49.49
4.13 -48.17 4.31 -41.68
4.14 -53.12 4.32 -42.29
4.15 -43.87 4.33 -50.44
4.16 -43.55 4.34 -40.39
4.17 -40.94 4.35 -44.56
4.18 -52.32 4.36 -43.52

Table 3: ΔG for ligands 4.1-4.36.

The obtained results indicated that all studied ligands have similar position and orientation inside the putative binding site of the COX II enzyme. The selected compounds (4.10, 4.28 and 4.11) showed good binding energies ranging from –40.14 to -55.91 kcal/mol. The proposed binding mode of compound 4.10 (affinity value of –55.91 kcal/mol and 2 H-bonds) is shown in Figure 1. It formed two hydrogen bonds with a distance of 1.79 and 2.35 A° with Lue352 and Ser353 respectively. Furthermore, the compound formed Pi-Pi interaction with Phe518. The proposed binding mode of compound 4.28 (affinity value of –55.14 kcal/mol and 2 H-bonds) is shown in Figure 2. It formed two hydrogen bonds with a distance of 2.15 and 2.45 A° with Lue352 and Ser353 respectively. Furthermore, the compound formed Pi-Pi interaction with Phe518. The proposed binding mode of compound 4.11 (affinity value of –54.50 kcal/mol and 1 H-bonds) is shown in Figure 3. It formed a hydrogen bond with a distance of 2.43 A° with Ser353. Furthermore, the compound formed Pi-Pi interaction with Phe518.

medicinal-chemistry-Binding-mode

Figure 1: Binding mode of compound 4.10.

medicinal-chemistry-compound

Figure 2: Binding mode of compound 4.28.

medicinal-chemistry-Binding

Figure 3: Binding mode of compound 4.11.

Conclusion

In the present study, the synthesis of a new series of 2-(substituted)- N-(4-oxo-2-phenylquinazolin-3(3H)-yl)acetamides (4.1-36) has been described. The results of the analgesic activity showed a moderate enhancement of activity. The compounds with ethyl side chain (4.2, 11, 20 and 29) emerged as the most active compound. Hence this series could be developed as a novel class of analgesic agents. Further structural modification is planned to obtain compounds with increased analgesic and anti-inflammatory activities with minimal ulcerogenic behavior.

References

 

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