Design, Synthesis and Evaluation of Some Novel1, 4-Naphthoquinone Derivatives to TreatCancer (original) (raw)

Abstract

Objective: In the present study, a series of nineteen compound of 1-phenyl-3-(5-phenyl-1H-imidazol-1-yl) thiourea derivatives (5a-9b) were designed, synthesized, characterized by physicochemical and spectral data (IR, 1H NMR, and mass spectroscopy) and evaluated for their Anti-HIV activity with the aim to develop novel substituted imidazole derivatives with broad-spectrum chemotherapeutic properties. Methods: Compounds (5a-9b) were designed by using Glide 5.0 to carry out binding mode analysis of N-substituted imidazoles against reverse transcriptase enzyme of wild type as well as resistant strains of HIV-1 virus with PDB ID: 1RT2, synthesized by reacting various substituted anilines and substituted phenacyl bromides in four steps and evaluated their anti HIV activity as well as cytotoxicity assay through MTT colorimetric measure. Results: Compounds 6a, 6b, 6c, 6d, 7c, 9a and 9b being the most active exhibited therapeutic index that were >22.4, 31.1, 30.5, 51.5, 34.6, 30.5 and 85.6 compared to Zidovudine (AZT) having therapeutic index (TI) 514342.6. Compound 9b showed the highest docking score-12.47 in the active site of the HIV protein of 1RT2 as well better in vitro anti-HIV activity.

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References (61)

  1. MHz): 2.29 (s; 3H; CH 3 ) 3.95 (s; 1H; SH), 6.29 (s; 1H; NH-Ar), 7.38-7.55 (m; 8H; Ar-H), 8.01 (s;1H;=CH), 4.70 (s;1H; NH-imidazole), EI MS: 374.04 [M + 1], Analysis calculated for C 17 H 15 ClN 4 S 2 : C, 54.46;
  2. H, 4.03; N, 14.94, Cl, 9.46, S, 17.11
  3. -(5-(4-bromophenyl)-2-mercapto-1H-imidazol- 1-yl)-3-o-tolylthiourea (5b) Yield: 68%, M.P. 80-82 o C, IR (KBr, cm -1 ): 3012 (N-H stretching),2123 (C-H stretch CH 3 group) 1602 (C=S stretching), 1321 (C-N stretching) cm -1 , NMR (DMSO, 400
  4. NH-Ar), 7.84-6.89 (m; 8H; Ar-H), 6.30 (s;1H;=CH),
  5. 32 (s;1H; NH-imidazole), 419.99 [M + 1], Analysis calculated for C 17 H 15 ClN 4 S 2 : C, 48.69; H, 3.61; N, 13.36, Br, 19.05, S, 15.29.
  6. -(2-mercapto-5-p-tolyl-1H-imidazol-1-yl)-3-o-tol- ylthiourea (5c) Yield: 72%, M.P. 60-62 o C, IR (KBr, cm -1 ): 3076 (N-H stretching),2024 (C-H stretch CH 3 group) 1564 (C=S stretching), 1330 (C-N stretching) cm -1 , NMR (DMSO, 400
  7. MHz): 2.35 (s; 3H; CH 3 ) 2.61 (s; 1H; SH), 6.30 (s; 1H; NH-Ar), 7.49-7.15 (m; 8H; Ar-H), 6.88 (s;1H;=CH), 5.96 (s;1H; NH-imidazole), 354.10 [M + 1], Analysis calculated for C 18 H 18 N 4 S 2 : C, 60.99; H, 5.12; N, 15.80, S, 18.09.
  8. -(2-mercapto-5-(4-methoxyphenyl)-1H-imidazol- 1-yl)-3-o-tolylthiourea (5d) Yield: 64%, M.P. 72-74 o C, IR (KBr, cm -1 ): 3082 (N-H stretching),2042 (C-H stretch CH 3 group) 1620 (C=S stretching), 1280 (C-N stretching) cm -1 , NMR (DMSO, 400
  9. MHz): 2.19 (s; 3H; CH 3 ) 1.25 (s; 1H; SH), 6.23 (s; 1H; NH-Ar), 7.83-6.82 (m; 8H; Ar-H), 5.96 (s;1H;=CH), 3.82 (s;1H; NH-imidazole), 370.09 [M + 1], Analysis calculated for C 18 H 18 N 4 OS 2 : C, 58.35; H, 4.90;
  10. -(5-(4-methoxyl phenyl) -2-mercapto-1H-imid- azol-1-yl)-3-o-tolylthiourea (5e) Yield: 82%, M.P. 102-104 o C, IR (KBr, cm -1 ): 3078 (N-H stretching),2152 (C-H stretch CH 3 group) 1608 (C=S stretching), 1192 (C-N stretching) cm -1 , NMR (DMSO, 400
  11. MHz): 2.33 (s; 3H; CH 3 ) 1.42 (s; 1H; SH), 8.02 (s; 1H; NH-Ar), 7.99-7.15 (m; 8H; Ar-H), 7.13 (s;1H;=CH), 4.61 (s;1H; NH-imidazole), 416.11 [M + 1], Analysis calculated for C 23 H 20 N 4 S 2 : C, 66.32; H, 4.84; N, 13.45, S, 15.40.
  12. -(4-chlorophenyl)-3-(5-(4-chlorophenyl)-2-mer- capto-1H-imidazol-1-yl) thiourea (6a) Yield: 68%, M.P. 72-74 o C, IR (KBr, cm -1 ): 3028 (N-H stretching),2012 (C-H stretch CH 3 group) 1564 (C=S stretching), 1290 (C-N stretching) cm -1 , NMR (DMSO, 400
  13. MHz): 2.62 (s; 1H; SH), 5.32 (s; 1H; NH-Ar), 7.93-7.02 (m; 8H; Ar-H), 6.24 (s;1H;=CH), 3.97 (s;1H;
  14. NH-imidazole), 393.11[M + 1], Analysis calculated for C 16 H 12 Cl 2 N 4 S 2 : C, 48.61; H, 3.06; N, 14.17, S, 16.22; Cl, 17.94. 1-(5-(4-bromophenyl)-2-mercapto-1H-imidazol-1- yl)-3-(4-chloro phenyl) thiourea (6b) Yield: 54%, M.P. 70-72 o C, IR (KBr, cm -1 ): 3078 (N-H stretching),2024 (C-H stretch CH 3 group) 1582 (C=S stretching), 1264 (C-N stretching) cm -1 , NMR (DMSO, 400 MHz): 2.20 (s; 1H; SH), 6.27 (s; 1H; NH-Ar), 7.64-7.21 (m; 8H; Ar-H), 6.24 (s;1H;=CH), 2.29 (s;1H;
  15. NH-imidazole), 437.94 [M + 1], Analysis calculated for C 16 H 12 BrClN 4 S 2 : C, 43.70; H, 2.75; N, 12.74, S, 14.58, Cl, 8.06; Br, 18.17.
  16. -(4-chlorophenyl)-3-(2-mercapto-5-p-tolyl-1H-im- idazol-1-yl) thiourea (6c) Yield: 62%, M.P. 78-80 o C, IR (KBr, cm -1 ): 3012 (N-H stretching), 2028 (C-H stretch CH 3 group), 1602 (C=S stretching), 1282 (C-N stretching) cm -1 , NMR (DMSO, 400 MHz): 2.20 (s; 1H; SH), 6.27 (s; 1H; NH-Ar), 7.64-7.21 (m; 8H; Ar-H), 6.24 (s;1H;=CH), 2.29 (s;1H;
  17. NH-imidazole), 437.94 [M + 1], Analysis calculated for C 17 H 15 ClN 4 S 2 : C, 54.46; H, 4.03; N, 14.94, S, 54.46, Cl, 9.46. 1-(4-chlorophenyl)-3-(2-mercapto-5-(4-methoxy phenyl)-1H-imidazol-1-yl)thiourea (6d) Yield: 68%, M.P. 68-70 o C, IR (KBr, cm -1 ): 3042 (N-H stretching), 2112 (C-H stretch CH 3 group), 1546 (C=S stretching), 1260 (C-N stretching) cm -1 , NMR (DMSO, 400 MHz): 2.32 (s; 1H; SH), 6.20 (s; 1H; NH-Ar), 8.01-7.08 (m; 8H; Ar-H), 6.96 (s;1H;=CH), 3.87 (s;1H;
  18. NH-imidazole), 374.04 [M + 1], Analysis calculated for C 17 H 15 ClN 4 OS 2 : C, 52.23; H, 3.87; N, 14.33, O, 4.09; S, 16.41, Cl, 9.07.
  19. -(4-bromophenyl)-3-(5-(4-chlorophenyl)-2-mer- capto-1H-imidazol-1-yl) thiourea (7a) Yield: 72%, M.P. 98-100 o C, IR (KBr, cm -1 ): 3086 (N-H stretching),2048 (C-H stretch CH 3 group) 1580 (C=S stretching), 1256 (C-N stretching) cm -1 , NMR (DMSO, 400 MHz): 1.44 (s; 1H; SH), 6.25 (s; 1H; NH-Ar), 7.74-7.01 (m; 8H; Ar-H), 7.92 (s;1H;=CH), 4.55 (s;1H;
  20. NH-imidazole), 439.06 [M + 1], Analysis calculated for C 16 H 12 BrClN 4 S 2 : C, 43.70; H, 2.75; N, 12.74; S, 16.41; Cl, 9.07; Br, 18.17.
  21. -(4-bromophenyl)-3-(5-(4-bromophenyl)-2-mer- capto-1H-imidazol-1-yl) thiourea (7b) Yield: 58%, M.P. 80-82 o C, IR (KBr, cm -1 ): 3054 (N-H stretching),2066 (C-H stretch CH 3 group) 1542 (C=S stretching), 1260 (C-N stretching) cm -1 , NMR (DMSO, 400 MHz): 1.22 (s; 1H; SH), 3.49 (s; 1H; NH-Ar), 7.84-6.91 (m; 8H; Ar-H), 4.69 (s;1H;=CH), 2.68 (s;1H;
  22. NH-imidazole), 483.88 [M + 1], Analysis calculated for C 16 H 12 Br 2 N 4 S 2 : C, 39.69; H, 2.50; N, 11.57; S, 13.24; Br, 33.00.
  23. -(4-bromophenyl)-3-(2-mercapto-5-p-tolyl-1H- imidazol-1-yl) thiourea (7c) Yield: 66%, M.P. 76-78 o C, IR (KBr, cm -1 ): 3072 (N-H stretching),2084 (C-H stretch CH 3 group) 1560 (C=S stretching), 1248 (C-N stretching) cm -1 , NMR (DMSO, 400
  24. MHz): 2.43 (s,3H, CH 3 ), 2.08 (s; 1H; SH), 4.81 (s; 1H; NH-Ar), 7.93-7.04 (m; 8H; Ar-H), 7.99 (s;1H;=CH), 2.28 (s;1H; NH-imidazole), 419.99 [M + 1], Analysis calculated for C 17 H 15 BrN 4 S 2 : C, 48.69; H, 3.61;
  25. N, 13.36; S, 15.29; Br, 19.05.
  26. -( 4 -b r o m o p h e n y l ) -3 -( 2 -m e r c a p t o -5 -( 4 - methoxyphenyl)-1H-imidazol-1-yl) thiourea (7d) Yield: 52%, M.P. 60-62 o C, IR (KBr, cm -1 ): 3084 (N-H stretching),2052 (C-H stretch CH 3 group) 1522 (C=S stretching), 1208 (C-N stretching) cm -1 , NMR (DMSO, 400
  27. MHz): 3.83 (s,3H, CH 3 ),1.28 (s; 1H; SH), 4.69 (s; 1H; NH-Ar), 7.93-6.87 (m; 8H; Ar-H), 6.88 (s;1H;=CH), 2.32 (s;1H; NH-imidazole), 433.99 [M + 1], Analysis calculated for C 17 H 15 BrN 4 OS 2 : C, 46.90; H, 3.47; N, 12.87; S, 14.73; O, 3.67; Br, 18.35.
  28. -(5-(4-chlorophenyl)-2-mercapto-1H-imidazol- 1-yl)-3-(2, 4-dimethyl phenyl)thiourea (8a) Yield: 58%, M.P. 71-73 o C, IR (KBr, cm -1 ): 3064 (N-H stretching),2042 (C-H stretch CH 3 group) 1558 (C=S stretching), 1224 (C-N stretching) cm -1 , NMR (DMSO, 400
  29. MHz): 2.32 (s; 6H; CH 3 ) ,3.99 (s; 1H; SH), 9.87 (s; 1H; NH-Ar), 7.93-7.10 (m; 8H; Ar-H), 388.06 [M + 1], Analysis calculated for C 18 H 17 ClN 4 S 2 : C, 55.59; H, 4.41;
  30. N, 14.41; S, 16.49; Cl, 9.12.
  31. -(5-(4-bromophenyl)-2-mercapto-1H-imidazol- 1-yl)-3-(2, 4-dimethylphenyl) thiourea (8b) Yield: 66%, M.P. 68-70 o C, IR (KBr, cm -1 ): 3042 (N-H stretching),2012 (C-H stretch CH 3 group) 1612 (C=S stretching), 1204 (C-N stretching) cm -1 , NMR (DMSO, 400
  32. 70 (s; 1H; NH-Ar), 7.84-7.06 (m; 8H; Ar-H), 7.02 (s;1H;=CH), 2.61 (s;1H; NH-imidazole), 432.01 [M + 1], Analysis calculated for C 18 H 17 BrN 4 S 2 : C, 49.88; H, 3.95; N, 12.93; S, 14.80; Br, 18.44.
  33. -(2-mercapto-5-p-tolyl-1H-imidazol-1-yl)-3-(2, 4-dimethylphenyl) thiourea (8c) Yield: 72%, M.P. 55-58 o C, IR (KBr, cm -1 ): 3072 (N-H stretching),2052 (C-H stretch CH 3 group) 1562 (C=S stretching), 1236 (C-N stretching) cm -1 , NMR (DMSO, 400
  34. 75 (s; 1H; NH-Ar), 7.22-6.97 (m; 8H; Ar-H), 7.42 (s;1H;=CH), 2.39 (s;1H; NH-imidazole), 388.06 [M + 1], Analysis calculated for C 19 H 20 N 4 S 2 : C, 61.92; H, 5.47; N, 15.20; S, 17.40.
  35. -(2-mercapto-5-(4-methoxyphenyl)-1H-imidazol- 1-yl)-3-(2,4-dimethylphenyl)thiourea (8d) Yield: 72%, M.P. 70-72 o C, IR (KBr, cm -1 ): 3066 (N-H stretching),2028 (C-H stretch CH 3 group) 1586 (C=S stretching), 1202 (C-N stretching) cm -1 , NMR (DMSO, 400 MHz): 3.85 (d;3H, OCH 3 ), 2.34-2.04 (s; 6H; CH 3 ), 2.59 (s; 1H; SH), 6.58 (s; 1H; NH-Ar), 7.55-6.88 (m; 8H;
  36. Ar-H), 7.97 (s;1H;=CH), 3.90 (s;1H; NH-imidazole), 384.06 [M + 1], Analysis calculated for C 19 H 20 N 4 OS 2 : C, 59.35; H, 5.24; N, 14.57; S, 16.68; O, 4.16.
  37. -(5-(4-chlorophenyl)-2-mercapto-1H-imidazol-1- yl)-3-(naphthalen-5-yl) thiourea (9a) Yield: 58%, M.P. 63-65 o C, IR (KBr, cm -1 ): 2984.78 (NH stretching), 2846.63 cm -1 (symmetrical C-H stretching of methyl group), 2368.83 (S-H stretching), 1637.74 (C=S stretching), 1584.24 cm -1 (N-H aromatic bending vibration), 1474.10 cm -1 (C-N stretching of aromatic amine),872.74 cm -1 (C=S group attached to N atom), NMR (DMSO, 400 MHz): 2.32 (s; 1H; SH), 6.30 (s; 1H;
  38. NH-Ar), 8.01-6.77 (m; 8H; Ar-H), 7.25 (s;1H;=CH), 4.73 (s;1H; NH-imidazole), 410.04 [M + 1], Analysis calculated for C 20 H 15 ClN 4 S 2 : C, 58.45; H, 3.68; N, 13.63;
  39. -(5-(4-bromophenyl)-2-mercapto-1H-imidazol-1- yl)-3-(naphthalen-5-yl) thiourea (9b) Yield: 51%, M.P. 67-69
  40. C, IR (KBr, cm-1): 2959.39 (NH stretching), 2712.62 cm-1 (symmetrical C-H stretching of methyl group), 2348.72 (S-H stretching), 1653.47 (C=S stretching), 1526.83 cm-1 (N-H aromatic bending vibration), 1439.14 cm-1 (C-N stretching of aromatic amine),874.39 cm-1 (C=S group attached to N atom), NMR (DMSO, 400 MHz): 2.14 (s; 1H; SH), 6.29 (s; 1H;
  41. NH-Ar), 7.91-7.38 (m; 8H; Ar-H), 6.94 (s;1H;=CH), 4.71 (s;1H; NH-imidazole), 455.9 [M + 1], Analysis calculated for C 20 H 15 BrN 4 S 2 : C, 52.75; H, 3.32; N, 12.30;
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