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Design, Synthesis, Computer Modeling and Analgesic Activity of Some New Disubstituted Quinazolin-4(3H)-ones | OMICS International
ISSN: 2161-0444
Medicinal Chemistry

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Design, Synthesis, Computer Modeling and Analgesic Activity of Some New Disubstituted Quinazolin-4(3H)-ones

Rezk A Ayyad1,3, Helmy M Sakr1 and Kamal M El-Gamal2,3*

1Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Al-Azhar University, Nasr City 11884, Cairo, Egypt

2Faculty of Pharmacy, Department of Organic Chemistry, Al-Azhar University, Nasr City 11884, Cairo, Egypt

3Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Delta University, Gamsa, Dakahlia, Egypt

*Corresponding Author:
Kamal M El-Gamal
Faculty of Pharmacy, Department of Organic Chemistry
Al-Azhar University
Nasr City 11884, Cairo, Egypt
E-mail: [email protected]

Received date: April 20, 2016; Accepted date: April 28, 2016; Published date: May 04, 2016

Citation: Ayyad RA, Sakr HM, El-Gamal KM (2016) Design, Synthesis, Computer Modeling and Analgesic Activity of Some New Disubstituted Quinazolin-4(3H)-ones. Med chem (Los Angeles) 6:299-305. doi:10.4172/2161-0444.1000360

Copyright: © 2016 Ayyad RA, et al. 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

A series of substituted quinazolin-4(3H)-ones (VIII1-12) have been synthesized by treating 3-amino-2- benzylamino-substituted- quinazolin-4(3H)-one VII1-4, with different aldehydes. The starting material 3-amino-2- benzylamino substituted- quinazolin-4(3H)-one VII1-4 was synthesized by nucleophilic substitution of thiomethyl group of 3-amino-2-methylthio-substituted- quinazolin-4(3H)-one VI1-4 with benzylamine. The synthesized compounds VIII1-12 was investigated for analgesic activity. All the test compounds exhibited significant analgesic activity in comparison with paracetamol.

Keywords

2,3-disubstituted quinazolin-4(3H)-one; Paracetamol; Modeling; Analgesic activity

Abbreviations

NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; COX: Cyclooxygenase; DMSO: N,N-Dimethylformamide; PDB: Protein Data Bank; MOE: Molecular Operating Environment; MP: Melting Point.

Introduction

Quinazolines derivatives exhibited a vital role in many pharmacological activities [1-8] including anti-inflammatory, [9] antibacterial, [10] and anticonvulsant, [11] activities. Schiff 's bases have generated a great deal of attention due to their interesting pharmaceutical activities include possess potent analgesic and antiinflammatory activities [12]. In the view of these facts and to develop earlier reporting [6] quinazoline-4(3H)-ones series that drawn great attention in the field of synthetic medicinal chemistry because it shown good analgesic and anti-inflammatory activities therefore, our aim was oriented to design derivatives of existing clinically used NSAIDs that has ability to inhibit the cyclooxygenase (COX) and as a result in safety when taking paracetamol [13] because it used in medication to treat pain and fever [14] through acting by inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX- 2 [15]. As part of our ongoing medicinal chemistry research program we found that quinazolines [6] especially quinazolin-4(3H)-ones with 2, 3-disubstitution that reported [16] to possess significant analgesic, anti-inflammatory activities. Based on these findings it is rationalized to synthesis and design new substituted quinazolin-4(3H)-ones and screen their anti-inflammatory and analgesic activities (Scheme 1).

medicinal-chemistry-Synthesis-compounds

Scheme 1: Synthesis of compounds I-VIII.

Experimental

General

Chemistry: Melting points were measured in capillary tube on a Graffin melting point apparatus and are uncorrected. The IR spectra were recorded on Pye Unicam SP 1000 IR spectrophotometer using KBr discs (λmax in cm-1). 1HNMR 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 Microanalytical Unit of Cairo University, Cairo, Egypt. Starting Compounds 1-3 was prepared according to reported procedures [17-19].

Synthesis of substituted 3-Amino-2-mercapto Quinazolin- 4(3H)-one (V)

To a vigorously stirred solution of III1-4 derivatives (0.02 mol) in and hydrazine hydrate 95% (8.6 g, 0.2 mol) that was added drop wise under cold condition. After the completion of addition, stirring was continued for 1.5 h at 50°C and the mixture was poured into icewater. The solid obtained was filtered, washed with water, then washed with absolute ethanol and crystallized from dimethylformamide then washed with ethanol to produce compound V.

3-amino-6-bromo-2-mercaptoquinazolin-4(3H)-one (V1): Yield: 68%; MP: 228-230°C; IR (KBr, ν, cm-1): 3300 (NH2), 2560(SH), 1700 (C=O quinazoline ring), 1570 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.02 (s, 1H, C5-H), 7.76 (d, 1H, J = 8.30 Hz, C7-H), 7.43 (s, 1H, J = 16.52 Hz, C8-H), 5.21 (s, 2H, NH2, D2O exchangeable), 3.29 (s, 1H, SH). 13C NMR (300 MHz, [D6] DMSO): δ = 121.6, 123.2, 124.7, 132.5, 136.8, 146, 159.7, 160.7. MS (m/z): 274 (M+2, 34.58%), 272 (M+, 35, 11%). Anal. Calcd. for C8H6BrN3OS: C, 35.31; H, 2.22; N, 15.44. Found: C, 35.17; H, 2.36; N, 15.62.

3-amino-6, 8-dibromo-2-mercaptoquinazolin-4(3H)-one (V2): Yield: 60%; mp 237-239°C; IR (KBr, ν, cm-1): 3320 (NH2), 2567 (SH), 1690 (C=O quinazoline ring), 1573 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 7.93 (s, 1H, C5-H), 7.71 (s, 1H, C7-H), 5.41(s, 2H, NH2, D2O exchangeable), 3.21 (s, 1H, SH). 13C NMR (300 MHz, [D6] DMSO): δ = 122, 125.2, 130.2, 131.4, 139.5, 150.2, 159.4, 160.4. MS (m/z): 350 (M+4, 14.12%), 348 (M+2, 28.44%), 272 (M+, 13.89%). Anal. Calcd. for C8H6Br2N3OS: C, 27.37; H, 1.44; N, 11.97. Found: C, 27.48; H, 1.66; N, 11.72.

3-amino-6-chloro-2-mercaptoquinazolin-4(3H)-one (V3): Yield: 75%; MP: 204-206°C; IR (KBr, ν, cm-1): 3280 (NH2), 2570 (SH), 1700 (C=O quinazoline ring), 1560 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 7.93 (s, 1H, C5-H), 7.74 (d, 1H, J = 7.50 Hz, C7-H), 7.61 (d, 1H, J = 8.60 Hz, C8-H), 5.41 (s, 2H, NH2, D2O exchangeable), 3.34 (s, 1H, SH). 13C NMR (300 MHz, [D6] DMSO): δ = 122.3, 127.8, 127.8, 133, 133.5, 145, 159.4, 160.6. MS (m/z): 229 (M+2, 32%), 227 (M+, 7.1%). Anal. Calcd. for C8H6ClN3OS: C, 42.20; H, 2.66; N, 18.46. Found: C, 42.46; H, 2.61; N, 18.51.

3-amino-6, 8-dichloro-2-mercaptoquinazolin-4(3H)-one (V4): Yield: 68%; MP: 218-220°C; IR (KBr, ν, cm-1): 3300 (NH2), 2562 (SH), 1700(C=O quinazoline ring), 1572 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 7.93 (s, 1H, C5-H), 7.70(s, 1H, C7-H), 5.69 (s, 2H, NH2, D2O exchangeable), 3.20 (s, 1H, SH). 13C NMR (300 MHz, [D6] DMSO): δ = 123.7, 125.9, 129.4, 134.4, 135.2, 159.2, 159.4, 160.7. MS (m/z): 265 (M+4, 1.94%), 263 (M+2, 7.67%), 261 (M+, 10.2%). Anal. Calcd. for C8H5Cl2N3OS: C, 36.66; H, 1.92; N, 16.03. Found: C, 36.71; H, 1.74; N, 16.17.

Synthesis of substituted 3-Amino-2-methylthio Quinazolin- 4(3H)-one (VI)

A solution of 3-amino-2-mercaptoquinazolin-4(3H)-one 1.93 g (0.01 mol) in sodium hydroxide 10 ml (20% w/v) was obtained by warming on a water bath. It was clarified by filtration while in warm condition, cooled and treated with dimethyl sulphate 1.26 g (0.01 mol) under constant stirring. The solution was stirred at room temperature for 12 h. The solid obtained was filtered off, washed with cold water, dried and recrystallized from chloroform/ethanol.

3-amino-6-bromo-2-(methylthio) quinazolin-4(3H)-one (VI1): Yield: 80%; MP: 172-174°C; IR (KBr, ν, cm-1): 3320 (NH2), 1700 (C=O quinazoline ring), 1565 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 8.20 (s, 1H, C5-H), 7.82 (d, 1H, J = 8.0 Hz, C7-H), 7.60 (d, 1H, J = 8.0 Hz, C8-H), 6.70 (s, 2H, NH2, D2O exchangeable), 2.51 (s, 3H, SH3). MS (m/z): 286 (M+2, 21.12%), 284 (M+, 22.19%). Anal. Calcd. for C9H8BrN3OS: C, 37.78; H, 2.82; N, 14.68. Found: C, 37.92; H, 2.90; N, 14.74.

3-amino-6, 8-dibromo-2-(methylthio) quinazolin-4(3H)-one (VI2): Yield: 72%; MP: 186-188°C; IR (KBr, ν, cm-1): 3325 (NH2), 1680 (C=O quinazoline ring), 1570 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 8.20 (s, 1H, C5-H), 8.10 (s, 1H, C7-H), 6.62 (s, 2H, NH2, D2O exchangeable), 2.55 (s, 3H, SH3). MS (m/z): 366 (M+4, 10.12%), 364 (M+2, 20.44%), 362 (M+, 10.09%). Anal. Calcd. for C9H7Br2N3OS: C, 29.61; H, 1.93; N, 11.51. Found: C, 29.72; H, 1.98; N, 11.42.

3-amino-6-chloro-2-(methylthio) quinazolin-4(3H)-one (VI3): Yield: 82%; MP: 154-156°C; IR (KBr, ν, cm-1): 3305 (NH2), 1720 (C=O quinazoline ring), 1575 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 7.90 (s, 1H, C5-H), 7.69 (d, 1H, J = 7.60 Hz, C7-H), 7.40 (s, 1H, J = 8.60 Hz, C8-H), 6.72 (s, 2H, NH2, D2O exchangeable), 2.50 (s, 3H, SH3). MS (m/z): 243 (M+2, 6.1%), 241 (M+, 17.9%). Anal. Calcd. for C9H8ClN3OS: C, 44.72; H, 3.34; N, 17.39. Found: C, 44.91; H, 3.52; N, 17.56.

3-amino-6, 8-dichloro-2-(methylthio) quinazolin-4(3H)-one (VI4): Yield: 76%; MP: 171-173°C; IR (KBr, ν, cm-1): 3300 (NH2), 1725 (C=O quinazoline ring), 1570 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 7.90 (s, 1H, C5-H), 7.80 (s, 1H, C7-H), 6.61 (s, 2H, NH2, D2O exchangeable), 2.56 (s, 3H, SH3). MS (m/z): 278 (M+4, 1.11%), 276 (M+2, 4.31%), 274 (M+, 5.20%). Anal. Calcd. for C9H7Cl2N3OS: C, 39.15; H, 2.56; N, 15.22. Found: C, 39.41; H, 2.63; N, 15.39.

Synthesis of 3-Amino-2-substituted-benzylamino Quinazolin- 4(3H)-one VII1-4

A mixture of benzyl amine 5.35 g (0.05 mol) and 3-amino-2- methylthio substituted-quinazolin-4(3H)-one VI1-4 (0.01 mol) was heated under reflux at 80°C for 36 h then the reaction mixture was cooled and treated with petroleum ether. The solid product was obtained crystallized from ethanol 95% to afford the desired products VII1-4.

3-amino-2-(benzylamino)-6-bromoquinazolin-4(3H)-one (VII1): Yield: 78%; MP: 172-174°C; IR (KBr, ν, cm-1): 3400 (NH2), 1680 (C=O quinazoline ring), 1555 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 8.40 (s, 1H, C5-H), 8.05 (d, 1H, J = 8.0 Hz, C7-H), 7.75 (d, 1H, J = 7.50 Hz, C8-H), 7.4-6.81 (m, 5H, aromatic protons), 5.80 (s, 2H, NH2, D2O exchangeable), 4.87 (s, 2H, CH2), 4.70 (t, 1H, NH, D2O exchangeable). Anal. Calcd. for C15H13BrN4O: C, 52.19; H, 3.80; N, 16.23. Found: C, 52.36; H, 3.56; N, 16.41.

3-amino-2-(benzylamino)-6, 8-dibromoquinazolin-4(3H)-one (VII2): Yield: 70%; MP: 191-193°C; IR (KBr, ν, cm-1): 3395 (NH2), 1690(C=O quinazoline ring), 1560 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 8.1-7.2 (m, 7H, aromatic protons), 5.60 (s, 2H, NH2, D2O exchangeable), 4.90 (s, 2H, CH2), 4.40 (t, 1H, NH, D2O exchangeable). Anal. Calcd. for C15H12Br2N4O: C, 42.48; H, 2.85; N, 13.21. Found: C, 42.66; H, 2.96; N, 13.39.

3-amino-2-(benzylamino)-6-chloroquinazolin-4(3H)-one (VII3): Yield: 75%; MP: 160-162°C; IR (KBr, ν, cm-1): 3390 (NH2), 1688 (C=O quinazoline ring), 1540 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 8.20 (s, 1H, C5-H), 8.0 (d, 1H, J = 7.0 Hz, C7-H), 7.75 (d, 1H, J = 7.0 Hz, C8-H), 7.71-7.2 (m, 5H, aromatic protons), 5.40 (s, 2H, NH2, D2O exchangeable), 4.60 (s, 2H, CH2), 4.60 (t, 1H, NH, D2O exchangeable). MS (m/z): 302 (M+2, 3.2%), 300 (M+, 3.3%). Anal. Calcd. for C15H13ClN4O: C, 59.91; H, 4.36; N, 18.63. Found: C, 60.01; H, 4.46; N, 18.91.

3-amino-2-(benzylamino)-6, 8-dichloroquinazolin-4(3H)-one (VII4): Yield: 68%; MP: 168-170°C; IR (KBr, ν, cm-1): 3370 (NH2), 1694(C=O quinazoline ring), 1558 (C=N). 1HNMR (500 MHz, [D6] DMSO): δ = 8.23-7.50 (m, 7H, aromatic protons), 5.80 (s, 2H, NH2, D2O exchangeable), 4.80 (t, 1H, NH, D2O exchangeable), 4.60 (s, 2H, CH2). MS (m/z): 338 (M+4, 1.8%), 336 (M+2, 7.2%), 334 (M+, 9.01%). Anal. Calcd. for C15H12Cl2N4O: C, 53.75; H, 3.61; N, 16.72. Found: C, 53.86; H, 3.76; N, 16.86.

Synthesis of substituted- 2-Benzylamino-3-(substituted benzylidene amino) quinazolin-4(3H)-one VIII1-12

General procedure: A mixture of 3-amino-2-benzylamino substituted quinazolin-4(3H)-one VII1-4 (0.01 mol) and different aromatic aldehydes derivative (0.01 mol) in acetic acid was refluxed for 30 hrs. After completion of reaction (TLC) the reaction mixture was poured into crushed ice and the solid obtained was crystallized from ethanol 95% to obtain pure compounds VIII1-12.

2-(benzylamino)-3-(benzylideneamino)-6-bromoquinazolin-4 (3H)-one (VIII1): Yield: 82%; MP: 165-167°C; IR (KBr, ν, cm-1): 3015 (CH-aromatic), 1688 (C=O quinazoline ring), 1550 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.65 (s, 1H, CH), 8.20-7.20 (m, 13H, aromatic protons), 4.90 (s, 1H, NH, D2O exchangeable), 4.10 (s, 2H, CH2). 13C NMR (300 MHz, [D6] DMSO): δ = 45, 121.8, 123.1, 124.7, 126.8, 126.9, 126.9, 128.5, 128.5, 128.8, 128.8, 129.3, 129.3, 131.2, 132.2, 133.7, 136.5, 137, 146, 153.4, 154.2, 162.3. MS (m/z): 434 (M+2, 2.5%), 432 (M+, 2.51%). Anal. Calcd. for C22H17BrN4O: C, 60.98; H, 3.95; N, 12.93. Found: C, 60.84; H, 3.84; N, 12.97.

2-(benzylamino)-6-bromo-3-(2-chlorobenzylide neamino) quinazolin-4(3H)-one (VIII2): Yield: 72%; MP: 187-189°C; IR (KBr, ν, cm-1): 3010 (CH-aromatic), 1690 (C=O quinazoline ring), 1550 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.50 (s, 1H, CH), 8.30-7.20 (m, 12H, aromatic protons), 4.70 (s, 1H, NH, D2O exchangeable), 3.90 (s, 2H, CH2). MS (m/z): 469(M+2, 7.4%), 467(M+, 12.3%). Anal. Calcd. for C22H16BrClN4O: C, 56.49; H, 3.45; N, 11.98. Found: C, 56.71; H, 3.67; N, 11.84.

2-(benzylamino)-6-bromo-3-(2,4-dimethoxybenzylideneamino)- quinazolin-4(3H)-one (VIII3): Yield: 68%; MP: 205-207°C; IR (KBr, ν, cm-1): 3012 (CH-aromatic), 1685 (C=O quinazoline ring), 1551 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.90 (s, 1H, CH), 8.00-7.20 (m, 11H, aromatic protons), 4.68(s, 1H, NH, D2O exchangeable), 3.92(s, 2H, CH2), 3.74 (s, 6H, OCH3). MS (m/z): 494 (M+2, 34.2%), 496(M+, 34.3%). Anal. Calcd. for C24H21BrN4O3: C, 58.43; H, 4.29; N, 11.36. Found: C, 58.57; H, 4.37; N, 11.54.

2-(benzylamino)-3-(benzylideneamino)-6, 8-dibromoquinazolin- 4(3H)-one (VIII4): Yield: 74%; MP: 171-173°C; IR (KBr, ν, cm-1): 3010 (CH-aromatic), 1680 (C=O quinazoline ring), 1550 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.50 (s, 1H, CH), 8.25-7.20 (m, 12H, aromatic protons), 4.71 (s, 1H, NH, D2O exchangeable), 4.00 (s, 2H, CH2). MS (m/z): 512.2 (M+2, 21.6%), 510(M+, 22.3%). Anal. Calcd. for C22H16Br2N4O: C, 51.59; H, 3.15; N, 10.94. Found: C, 51.68; H, 3.34; N, 11.12.

2-(benzylamino)-6,8-dibromo-3-(2-chlorobenzylid eneamino) quinazolin-4(3H)-one (VIII5): Yield: 77%; MP: 192-194°C; IR (KBr, ν, cm-1): 3012 (CH-aromatic), 1692 (C=O quinazoline ring), 1555 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 9.10 (s, 1H, CH), 7.90- 6.80 (m, 11H, aromatic protons), 4.65 (s, 1H, NH, D2O exchangeable), 3.90 (s, 2H, CH2). 13C NMR (300 MHz, [D6] DMSO): δ = 45, 113.2, 122, 125.4, 126.7, 126.7, 126.9, 127.2, 128.5, 128.5, 130.5, 131.4, 132.4, 133.5, 134.5, 137.5, 137.9, 139.5, 143.5, 150.3, 153.5, 162.3. MS (m/z):583 (M+4, 11.2%), 548(M+2, 22.7%), 5546 (M+, 72.44%). Anal. Calcd. for C22H15Br2ClN4O: C, 48.34; H, 2.77; N, 10.25. Found: C, 48.41; H, 2.86; N, 10.35.

2-(benzylamino)-6, 8-dibromo-3-(2, 4-dimethoxybenzylid eneamino)-quinazolin-4(3H)-one (VIII6): Yield: 86%; MP: 231- 233°C; IR (KBr, ν, cm-1): 3009 (CH-aromatic), 1690 (C=O quinazoline ring), 1550 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.85 (s, 1H, CH), 8.20-7.20 (m, 10H, aromatic protons), 4.65 (s, 1H, NH, D2O exchangeable), 3.95 (s, 2H, CH2), 3.66 (s, 6H, OCH3). MS (m/z): 572 (M+2, 51.01%), 570(M+, 52.5%). Anal. Calcd. for C24H20Br2N4O3: C, 50.37; H, 3.52; N, 9.79. Found: C, 50.52; H, 3.58; N, 9.83.

2-(benzylamino)-3-(benzylideneamino)-6-chloroquin azolin- 4(3H)-one (VIII7): Yield: 80%; MP: 159-161°C; IR (KBr, ν, cm-1): 3010 (CH-aromatic), 1690 (C=O quinazoline ring), 1550 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.90 (s, 1H, CH), 8.30-7.16 (m, 12H, aromatic protons), 4.65 (s, 1H, NH, D2O exchangeable), 3.90 (s, 2H, CH2). MS (m/z): 425 (M+2, 11.39%), 423(M+, 34.3%). Anal. Calcd. for C22H16Cl2N4O: C, 62.42; H, 3.81; N, 13.24. Found: C, 62.56; H, 3.92; N, 13.36.

2-(benzylamino)-6-chloro-3-(2-chlorobenzylidene amino) quinazolin-4(3H)-one (VIII8): Yield: 71%; mp 172-174°C; IR (KBr, ν, cm-1): 3018 (CH-aromatic), 1690 (C=O quinazoline ring), 1557 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.97 (s, 1H, CH), 8.33-7.25 (m, 11H, aromatic protons), 4.68 (s, 1H, NH, D2O exchangeable), 3.95 (s, 2H, CH2). MS (m/z): 458 (M+2, 19.3%), 456(M+, 58.3%). Anal. Calcd. for C22H15Cl3N4O: C, 57.73; H, 3.30; N, 12.24. Found: C, 57.87; H, 3.42; N, 12.27.

2-(benzylamino)-6-chloro-3-(2,4-dimethoxybenzylide neamino)-quinazolin-4(3H)-one (VIII9): Yield: 80%; MP: 212- 214°C; IR (KBr, ν, cm-1): 3010 (CH-aromatic), 1688 (C=O quinazoline ring), 1550 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.96 (s, 1H, CH), 8.20-7.00 (m, 11H, aromatic protons), 4.65 (s, 1H, NH, D2O exchangeable), 3.87 (s, 2H, CH2), 3.62(s, 6H, OCH3). MS (m/z): 450 (M+2, 3.19%), 448(M+, 10.1%). Anal. Calcd. for C24H21ClN4O3: C, 64.21; H, 4.68; N, 12.48. Found: C, 64.35; H, 4.81; N, 12.60.

2-(benzylamino)-3-(benzylideneamino)-6,8-dichloro quinazolin-4(3H)-one (VIII10): Yield: 87%; MP: 201-203°C; IR (KBr, ν, cm-1): 3010 (CH-aromatic), 1680 (C=O quinazoline ring), 1550 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.65 (s, 1H, CH), 8.30-7.20 (m, 12H, aromatic protons), 4.73 (s, 1H, NH, D2O exchangeable), 3.80 (s, 2H, CH2). MS (m/z): 427(M+4, 5.9%), 425 (M+2, 12.1%), 423(M+, 42.1%). Anal. Calcd. for C22H16Cl2N4O: C, 62.42; H, 3.81; N, 13.24. Found: C, 62.55; H, 3.61; N, 13.39.

2-(benzylamino)-6,8-dichloro-3-(2-chlorobenzylidene amino) quinazolin-4(3H)-one (VIII11): Yield: 79%; MP: 207-209°C; IR (KBr, ν, cm-1): 3020 (CH-aromatic), 1688 (C=O quinazoline ring), 1557 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.96 (s, 1H, CH), 8.35-7.25 (m, 11H, aromatic protons), 4.73 (s, 1H, NH, D2O exchangeable), 4.01 (s, 2H, CH2). MS (m/z): 461 (M+4, 14.2%), 459(M+2, 17.2%), 457(M+, 14.7%). Anal. Calcd. for C22H15Cl3N4O: C, 57.73; H, 3.30; N, 12.24. Found: C, 57.82; H, 3.49; N, 12.39.

2 - ( b enzylam i n o ) - 6 , 8 - d ichloro - 3 - ( 2 , 4 - d i m ethoxy benzylideneamino)-quinazolin-4(3H)-one (VIII12): Yield: 78%; MP: 231-233°C; IR (KBr, ν, cm-1): 3009 (CH-aromatic), 1688 (C=O quinazoline ring), 1542 (C=N). 1HNMR (300 MHz, [D6] DMSO): δ = 8.76 (s, 1H, CH), 8.13-7.02 (m, 10H, aromatic protons), 4.35 (s, 1H, NH, D2O exchangeable), 3.93 (s, 2H, CH2), 3.46 (s, 6H, OCH3). 13C NMR (300 MHz, [D6] DMSO): δ = 49, 56, 56, 101.6, 106.8, 109.2, 123.7, 126, 126.8, 127, 127, 128.7, 128.7, 129.4, 133.1, 134.3, 135.2, 137.8, 143.4,153.5, 159.3, 159.6, 162.4, 164. MS (m/z): 487 (M+4, 1.1%), 485(M+2, 5.7%), 483 (M+, 7.7%). Anal. Calcd. for C24H20Cl2N4O3: C, 59.64; H, 4.17; N, 11.59. Found: C, 59.80; H, 4.27; N, 11.70.

Pharmacology

All the newly synthesized compounds VIII1-12 were preliminarily evaluated for their analgesic and Anti-inflammatory activities (using writhing test) using paracetamol as writhing protective stander. The analgesic activity of the newly synthesized compounds VIII1-12 compared to paracetamol (Sigma Chemical Co., St. Louis, MO, USA) as a reference was measured after and 30, 60, 90, 120, 150, and 180 after p-benzoquinone (Aldrich) subcutaneous injection. All the tested compounds significantly showed highly percentage of protection against writhing compared with the control untreated group.

Analgesic screening

Adult albino mice of either sex weighing 20-25 gm which was obtained from animal house of Department of Pharmacology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt. Mice’s were divided into twelve groups; each group consists of six mice’s per cage. The mice’s were kept under constant temperature 30°C and 12 hours light/dark cycle. All animals were acclimatized in the animal facility for at least two weeks prior the experiments. The animals were kept fastened for 24 hours prior to the experiment, but they were allowed free access to water [20,21]. The animal experiments described below comply with the ethical principles and guidelines for the care and use of laboratory animals adopted by the National Egyptian Community. The equipment used was Dial micrometer model (120 - 1206 Baty, Sussex, England). The test compounds as well Paracetamol were suspended in water by the aid of few drops of Tween-80 (Sigma) to produce 2% suspension. And p-benzoquinone (Aldrich) was dissolved in water for injection containing a few drops of Tween-80 to produce 0.02% solution and was used as writhing inducer.

Analgesic activity

The analgesic action of some newly synthesized compound was determined using the writhing method on mice [22]. The mice were randomly arranged in groups each of 10 animal's one group was kept as control. The animals of another group were given paracetamol subcutaneously in a dose of 30 mg/kg body weight. Mice of the other groups were blindly injected subcutaneously with test compounds in a dose of 150 mg/kg body weight. After 30 minutes, each animal of each group was injected with 0.25 ml of 0.02% aqueous solution of p-benzoquinone and was observed for writhing after 30, 60, 90, 120, 150 and 180 minutes. Animals protected from writhing were recorded in each group and the analgesic potency of the test compounds was determined as percentage of protection against writhing. The results are presented in Table 1.

Comp. No. VIII Dose mg/kg   % of mice showing abolished writhing Comp. No. VIII Dose mg/kg   % of mice showing abolished writhing
Time (minutes) Time (minutes)
30 60 90 120 150 180 30 60 90 120 150 180
Paracetamol (control) 20 100 100 100 100 100 100 Paracetamol (control) 20 100 100 100 100 100 100
VIII1 150 100 100 100 100 100 100 VIII7 150 100 100 100 100 100 100
VIII2 150 100 100 100 100 100 100 VIII8 150 100 100 100 100 100 100
VIII3 150 100 100 100 100 100 100 VIII9 150 100 100 100 100 100 100
VIII4 150 100 100 100 100 100 100 VIII10 150 100 100 100 100 100 100
VIII5 150 100 100 100 100 100 100 VIII11 150 100 100 100 100 100 100
VIII6 150 100 100 100 100 100 100 VIII12 150 100 100 100 100 100 100

Table 1: The analgesic effect of paracetamol and tested compounds VIII1-12 in mice.

Molecular Modeling

Docking studies were carried out to examine the analgesic effect of compounds VIII1-12 which subjected to docking using Molecular Operating Environment (MOE) program [23] on the 3D structure of the cyclooxygenase-2 enzyme (COX-2) in a trial to predict their analgesic action drugs and the aim of the flexible docking calculations is prediction of correct binding geometry for each binder.

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 ChemBio Draw Ultra 14.0 and saved in MDL-SDfile format. SD file 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 present work, involves the synthesis of new derivatives of substituted- 2-Benzylamino-3-(substituted benzylidene amino) quinazolin-4(3H)-one VIII1-12 via starting with key intermediates through bromination and chlorination of methylanthranilate using reported method [17-19] to get compound I1-4. Compound I1-4 underwent reaction with carbon disulfide and sodium hydroxide to afford II1-4 that suspected to dimethylsulfate resulting the compound III1-4 that when reacted with hydrazine hydrate it yielded compound V1-4. The structures of such new compounds were confirmed by both elemental and spectral analyses. The IR spectra of V1-4 in KBr showed carbonyl stretching around 1700 cm-1 in addition, to NH2 stretching around 3300 cm-1. The 1H NMR spectra of V1-4 in DMSO-d6, showed singlet of one proton, at 3.20-3.29 ppm due to SH group and NH2 group appeared as abroad singlet at 5.21-5.69 ppm which is D2O exchangeable moreover, In the 13C-NMR spectra of these compounds showed C=O peak at about 160 ppm corresponded to carbonyl groups of quinazoline ring that confirm the cyclization of intermediate IV into V. Consequently compound VI was obtained from V upon treatment with dimethyl sulfate in sodium hydroxide and the structure of the resulting compounds clearly confirmed from 1HNMR spectra that showed disappearance of SH signal and appearance of singlet signal around 2.5 ppm belong SCH3. Frequently, replacement of alkylthio group at 2-position with benzyl amine in simple electrophilic substitution reaction it produce new quinazoline compounds VII1-4 where the elemental analysis and spectral data confirm the existence of this substitution reaction where the 1HNMR of new compound contain two signals one at 4.40-4.80 ppm and another one at 5.40-5.80 ppm that exchangeable with D2O which belong to NH and NH2 respectively, also the structure of some the compounds were established from the spectral data of the resulting compounds. The title compounds substituted- 2-Benzylamino-3-(substituted benzylidene amino) quinazolin-4(3H)-one VIII1-12 were obtained by the condensation of amino group of 3-amino-2-substituted-benzylamino Quinazolin-4(3H)-one VII1-4 with a different aromatic aldehydes that afford new Schiff 's bases. The assignment of the produced Schiff ’s bases were based on spectral and elemental analysis where 1H-NMR spectrum of all the compounds VIII1–12 showed disappearance of signal due to NH2 group in addition, the 1H-NMR spectrum of all the compounds VIII1–12 exhibit singlet of one proton around 8.50-8.97 ppm which belong the (N=CH) proton. The IR spectrum of titled compounds VIII1–12 showed the presence of peak carbonyl (C=O), NH and Aryl groups. Because titled compounds contain halogen atom(s) its mass spectrum showed molecular ion peaks corresponding to their molecular formula in addition, to its isotopic peak moreover, in some compounds containing two halogen the mass spectrum showed peaks of M+, M+2, and M+4 that clearly observed and consequently, proven the resulting product. Finally, the structure of the newly synthesized product compounds VIII1–12 was proven on the basis of their elemental and spectral data. From the previous mentioned discussion it was observed that our synthetic strategies adopted to obtain the newly synthesized quinazolin-4(3H)-one depending using whether simple synthetic procedure or simple reagent(s). The results of analgesic testing indicate that the test compounds exhibited excellent significant analgesic activity and docking study revealed that the synthesized compounds have potential analgesic activity and can be further optimized and developed as a lead compound. The rationalized steps depend on ligand based drug design particularly a molecular hybridization approach that involves the coupling of two or more groups with relevant biological properties.

Docking Discussion

The obtained results indicated that all studied ligand have similar position and orientation inside the putative binding site of the COX -2 enzyme. The selected compounds VIII12, VIII9, VIII3, and VIII11 showed good binding energies ranging from -37.18 to -39.12 kcal/mol (Table 2).

Compound ΔG Compound ΔG Compound ΔG Compound ΔG
VIII1 -40.42 VIII4 -42.08 VIII7 -40.99 VIII10 -40.86
VIII2 -43.80 VIII5 -43.80 VIII8 -39.84 VIII11 -39.12
VIII3 -39.09 VIII6 -39.96 VIII9 -37.33 VIII12 -37.18
Paracetamol ΔG=49.12

Table 2: ΔG for ligand VIII1-12.

The proposed binding mode of compound VIII2 (affinity value of -43.80 kcal/mol and 2 H-bonds) is shown in Figure 1. One carbonyl group formed a hydrogen bond with a distance of 2-12 A° with Ser530. The chloride atom formed a further hydrogen bond with a distance of 2.30 A° with the acidic proton of Arg120. Furthermore, the compound formed Pi-sigma interaction with Phe518 and with ser353. The proposed binding mode of compound VIII4 (affinity value of -42.08 kcal/mol and 2 H-bonds) is shown in Figure 2. One carbonyl group formed a hydrogen bond with a distance of 1.80 A° with ser530. One bromide atom of the ring formed a further hydrogen bond with a distance of 2.37 A° with the acidic proton of Arg120. Furthermore, the compound formed Pi-sigma interaction with Phe518, Trp387 and with Ser353. The proposed binding mode of compound VIII8 (affinity value of -39.12 kcal/mol and 2 H-bonds) is shown in Figure 3. One carbonyl group formed a hydrogen bond with a distance of 2.09 A° with Ser530. The chloride atom of the side chain formed a further hydrogen bond with a distance of 2.32 A° with the acidic proton of Arg120. Furthermore, the compound formed Pi-sigma interaction with Phe518 and with Trp387 (Figure 4).

medicinal-chemistry-Binding-mode-comp

Figure 1: Binding mode of comp. VIII2.

medicinal-chemistry-Binding-mode-comp

Figure 2: Binding mode of comp. VIII4.

medicinal-chemistry-Binding-mode-comp

Figure 3: Binding mode of comp. VIII.

medicinal-chemistry-Binding-mode-paracetamol

Figure 4: Binding mode of paracetamol.

Conclusions

We have synthesized newly derivatives of disubstituted quinazolin- 4(3H)-ones that showed analgesic activity. From the data obtained in Table 1 it was found that all derivative VIII1-12 have excellent significant analgesic activity. In addition to, the molecular docking for all compounds was performed on the active site of COX-2 enzyme in a trial to predict their mode of action as analgesic drugs, in which the compounds showed several interactions leading to the conclusion that they might exert their action through inhibition of COX-2 enzyme. The biological analgesic screening was performed in Pharmacology Department, Faculty of Pharmacy Al-Azher University, Cairo, Egypt.

Acknowledgements

The authors would like to express their sincere thanks to Dr. Ahmad Mansour, Pharmacology Department, Faculty of Pharmacy Al-Azher University, Cairo, Egypt, for carrying out the analgesic activity for testing compounds. And I would like to thanks all members of Pharmacology Department, Faculty of Pharmacy Al-Azher University, Cairo, Egypt.

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Review summary

  1. Judzea
    Posted on Sep 29 2016 at 9:40 pm
    Authors have good hypothesis to synthesize novel compounds and screen against the analgesic activity, and the design derivatives would demonstrate well than existing clinically used NSAIDs that they have ability to inhibit the cyclooxygenase (COX), again as a result in safety when taking paracetamol because it used in medication to treat pain and fever through acting by inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2. The synthetic process of all those compounds and their structure elucidation with various spectroscopic studies was well tabulated.

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