Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers
Abstract
:1. Introduction
2. Results and Discussions
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Evaluation of Antihypertensive Activity
2.2.2. Evaluation of Calcium Channel Blocking Activity
2.3. Molecular Modeling and Binding Mode Prediction
2.4. Structure–Activity Relationships
3. Materials and Methods
3.1. Chemistry
Materials and Methods
- 4a: Ethyl 4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate: Yield: 76%; m.p.: 252–254 °C; IR ν (KBr cm−1): 3426 (NH), 3333 (NH), 3319 (NH), 3173 (CH, aromatic), 2978 (CH, aliphatic), 1749 (C=O ester), 1683 (C=O), 1277 (C=S), 1220 (C–O). 1HNMR (DMSO-d6, 400 MHz) δ: 1.19 (t, 3H, CH3), 2.1 (s, 3H, CH3), 3.76 (q, 2H, CH3CH2-O), 5.67 (s, 1H, CH), 7.28–8.05 (m, 5H, aromatic), 10.34, 10.51, 11.12 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 177.4 (1C, s), 161.6 (1C, s), 154.9, 146.0 (1C, s), 141.0, 139.67 (1C, s), 130.6 (1C, s), 128.1–128.3 (2C, 128.2 (s), 128.2 (s)), (1C, s), 113.4 (1C, s), 60.0 (1C, s), 52.1, (1C, s), 16.7 (1C, s), 14.9 (1C, s); MS (EI) m/z: 315.11 (M+, 12.5%); Calcd./Anal., for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32. Found: C, 60.68; H, 5.27; N, 13.66.
- 4b: Ethyl 4-(2-chloroquinolin-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate: Yield: 79%; m.p.: 218–220 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 1.18 (t, 3H, CH3), 2.39 (s, 3H, CH3), 3.67 (q, 2H, CH3CH2-O), 5.4 (s, 1H, CH), 7.36–8.09 (m, 5H, aromatic), 10.09, 11.33 (2 s, 2H, 2NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 178.1 (1C, s), 161.6 (1C, s), 154.7 (1C, s), 147.6 (1C, s), 146.0 (1C, s),134.7 (1C, s), 128.5 (1C, s), 128.3 (1C, s), 127.4 (1C, s), 126.0 (1C, s), 125.5 (1C, s), 121.7 (1C, s), 113.4 (1C, s), 60.0 (1C, s), 55.6 (1C, s), 15.0 (1C, s), 14.5 (1C, s); Calcd./Anal., for C17H16ClN3O2S: C, 56.43; H, 4.46; N, 11.61. Found: C, 56.68; H, 4.27; N, 11.66.
- 4c: Ethyl 4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate: Yield: 75%; m.p.: 218–220 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.23 (t, 3H, CH3), 2.50 (s, 3H, CH3), 3.92 (q, 2H, CH3CH2-O), 5.4 (s, 1H, CH), 7.16–8.11 (m, 11H, aromatic), 10.31, 11.49 (2 s, 2H, 2NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ ppm) 169.7 (1C, s), 162.0 (1C, s), 154.3 (1C, s), 146.1 (1C, s), 137.6 (1C, s), 130.6 (1C, s), 129.8 (2C, s), 128.2 (2C, s), 127.8-127.8 (2C, 127.8 (s), 127.8 (s)), 127.5 (1C, s), 127.3–127.8 (3C, 127.3 (s), 127.8 (s)), 121.8 (2C, s), 113.4 (1C, s), 60.2 (1C, s), 55.0 (1C, s), 15.1 (1C, s), 14.6 (1C, s), 14.2 (1C, s); Calcd./Anal., for C17H16ClN3O2S: C, 56.43; H, 4.46; N, 11.61. Found: C, 56.68; H, 4.27; N, 11.66.
- 5a: 4-(Indol-3yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid: Yield: 69%; m.p.: 233–235 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.23 (t, 3H, CH3), 5.53 (s, 1H, CH), 7.31–8.05 (m, 5H, aromatic), 10.32, 10.87, 11.19 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 177.5 (1C, s), 174.7 (1C, s), 154.9 (1C, s), 148.9 (1C, s), 128.1–128.3 (2C, 128.2 (s), 128.2 (s)), 128.4 (1C, s), 126.1 (1C, s), 125.8 (1C, s), 125.5 (1C, s), 121.7 (1C, s), 113.4 (1C, s), 51.9 (1C, s), 16.9 (1C, s); Calcd./Anal., for C14H13N3O3S: C, 55.43; H, 4.32; N, 13.85. Found: C, 55.66; H, 4.25; N, 13.55.
- 5b: 4-(2-Chloroquinolin-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid: Yield: 71%; m.p.: 244–246 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.44 (t, 3H, CH3), 5.47 (s, 1H, CH), 7.26–8.05 (m, 5H, aromatic), 10.35, 11.34 (2 s, 2H, 2NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 172.3 (1C, s), 165.3 (1C, s), 152.6 (1C, s), 146.0 (1C, s), 141.1 (1C, s), 130.6 (1C, s), 128.5 (1C, s), 128.3 (1C, s), 127.4 (1C, s), 126.0 (1C, s), 125.5 (1C, s), 121.8 (1C, s), 119.9 (1C, s), 55.8 (1C, s), 18.0 (1C, s); Calcd./Anal., for C15H12ClN3O3S: C, 51.51; H, 3.46; N, 12.01. Found: C, 51.60; H, 3.35; N, 12.25.
- 5c: 4-(1,3-Diphenyl-1H-pyrazol-4-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid: Yield: 68%; m.p.: 214–216 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.50 (t, 3H, CH3), 5.39 (s, 1H, CH), 7.1–7.91 (m, 11H, aromatic), 10.31, 11.39 (2 s, 2H, 2NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 169.2 (1C, s), 164.1 (1C, s), 154.3 (1C, s), 146.7 (1C, s), 138.1 (1C, s), 131.6 (1C, s), 130.0 (2C, s), 128.8 (2C, s), 126.0–127.5 (2C, 127.6 (s), 128.3 (s)), 125.5 (1C, s), 121.9 (2C, s), 114.6 (1C, s), 55.1 (1C, s), 16.8 (1C, s); Calcd./Anal., for C21H18N4O3S: C, 62.05; H, 4.46; N, 13.78. Found: C, 62.30; H, 4.45; N, 13.55.
- 6a: 4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl chloride: Yield: 68%; m.p.: 247–249 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.23 (t, 3H, CH3), 5.53 (s, 1H, CH), 7.41–8.07 (m, 5H, aromatic), 10.39, 10.67, 10.84 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 178.3 (1C, s), 173.4 (1C, s), 153.9, 149.0 (1C, s), 142.1(1C, s), 135.3 (1C, s), 129.3–128.3, (2C, 129.3 (s), 126.3 (s)) 127.4 (1C, s), 125.7 (1C, s), 122.0 (1C, s), 113.5 (1C, s), 110.9 (1C, s), 52.3 (1C, s), 17.8 (1C, s); Calcd./Anal., for C15H14ClN3OS: C, 56.33; H, 4.41; N, 13.14. Found: C, 56.28; H, 4.48; N, 13.22.
- 6b: 4-(2-Chloroquinolin-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl chloride: Yield: 73%; m.p.: 254–256 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.34 (t, 3H, CH3), 5.37 (s, 1H, CH), 7.26–8.05 (m, 5H, aromatic), 10.35, 10.94 (2 s, 2H, 2NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 178.1 (1C, s), 171.6 (1C, s), 152.7 (1C, s), 147.6 (1C, s), 146.1 (1C, s), 141.0 (1C, s), 130.6 (1C, s), 128.5 (1C, s), 128.2 (1C, s), 127.4 (1C, s), 126.0 (1C, s), 125.8 (1C, s), 121.8 (1C, s), 55.4 (1C, s), 16.8 (1C, s); Calcd./Anal., for C16H13Cl2N3OS: C, 52.47; H, 3.58; N, 11.47. Found: C, 52.29; H, 3.66; N, 11.25.
- 6c: 4-(Diphenyl-1H-pyrazol-4-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl chloride: Yield: 80%; m.p.: 235–237 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.34 (t, 3H, CH3), 5.32 (s, 1H, CH), 7.15–8.23 (m, 11H, aromatic), 10.41, 11.43 (2 s, 2H, 2NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 174.3 (1C, s), 167.0 (1C, s), 155.9 (1C, s), 148.0 (1C, s), 138.3 (1C, s), 130.6 (1C, s), 129.98 (2C, s), 128.8 (2C, s), 128.1–127.5 (1C, s), 127.5–121.8 (4C, 121.8 (s), 125.7 (s), 127.5 (s)), 112.8 (2C, s), 55.3 (1C, s), 17.9 (1C, s); Calcd./Anal., for C22H19ClN4OS: C, 62.48; H, 4.53; N, 13.25. Found: C, 62.21; H, 4.32; N, 13.25.
- 7a: 4-(1H-indoly-3-yl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 77%; m.p.: 266–268 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.36 (t, 3H, CH3), 5.19 (s, 1H, CH), 7.11–9.59 (m, 11H, aromatic), 10.65, 11.03, 11.37 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 167.6 (1C, s), 165.1 (1C, s), 153.9, 146.7 (1C, s), 139.1 (1C, s), 135.3 (1C, s), 130.5 (1C, s), 129.8-128.8 (4C, 128.8 (s), 129.0 (s), 129.8 (s)), 128.3 (1C, s), 127.5 (1C, s), 127.5 (1C, s), 125.4 (2C, s), 121.8 (1C, s), 113.4 (1C, s), 53.9 (1C, s), 17.3 (1C, s); Calcd./Anal., for C20H18N4OS: C, 66.28; H, 5.01; N, 15.46. Found: C, 66.45; H, 4.99; N, 15.35.
- 7b: 4-(2-Chloroquinolin-3-yl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 78%; m.p.: 260–262 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.24 (t, 3H, CH3), 5.3 (s, 1H, CH), 7.29–8.21 (m, 10H, aromatic), 9.89, 10.35, 11.39 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 177.9 (1C, s), 163.7 (1C, s), 155.9 (1C, s), 148.9 (1C, s), 145.1 (1C, s), 141.2 (1C, s), 139.7 (1C, s), 134.5 (1C, s), 130.6 (1C, s), 128.8 (2C, s), 128.6 (1C, s), 128.3–127.4 (2C, 128.3 (s), 127.4 (s)), 126.3 (1C, s), 125.8, 125.6 (1C, s), 121.7 (1C, s), 114.5 (2C, s), 57.1 (1C, s), 17.3 (1C, s); MS (EI) m/z: 408.11 (M+, 20.5%); Calcd./Anal., for C21H17ClN4OS: C, 61.68; H, 4.19; N, 13.70. Found: C, 61.69; H, 4.20; N, 13.46.
- 7c: 4-(1,3-Diphenyl-1H-pyrazol-4-yl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 73%; m.p.: 222–224 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.24 (t, 3H, CH3), 5.42 (s, 1H, CH), 7.25–8.18 (m, 10H, aromatic), 10.41, 10.73, 11.71 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 177.2 (1C, s), 161.62 (1C, s), 154.98 (1C, s), 148.93 (1C, s), 146.06 (1C, s), 141.07 (1C, s), 139.67 (1C, s), 134.53 (2C, s), 130.6–128.8 (4C, 130.61 (s), 128.8 (s)), 128.5–127.4 (3C, 128.5 (s), 128.3 (s), 127.4 (s)), 126.3 (1C, s), 126.0–125.5 (4C, 126.0 (s), 125.8 (s), 125.5 (s)), 121.75 (2C, s), 114.41(2C, s), 57.53 (1C, s), 17.38 (1C, s); Calcd./Anal., for C27H23N5OS: C, 69.65; H, 4.98; N, 15.04. Found: C, 69.59; H, 4.90; N, 14.98.
- 8a: 4-(1H-indol-3-yl)-6-methyl-thioxo-N-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 76%; m.p.: 262–264 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.14 (t, 3H, CH3), 2.29 (t, 3H, CH3), 5.51 (s, 1H, CH), 7.31–8.19 (m, 9H, aromatic), 9.68, 10.36, 10.83, 11.35 (4 s, 4H, 4NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 167.6 (1C, s), 163.8 (1C, s), 153.9 (1C, s), 146.7 (1C, s), 140.9 (1C, s), 135.3 (1C, s), 130.5 (2C, s), 129.8 (1C, s), 129–128.2 (4C, 129.2 (s), 128.2 (s)), 127.5 (1C, s), 127.5 (1C, s), 126.0 (1C, s), 125.4 (1C, s), 121.8 (2C, s), 113.4 (1C, s), 53.9 (1C, s), 20.5 (1C, s), 17.6 (1C, s); Calcd./Anal., for C21H20N4OS: C, 67.00; H, 5.35; N, 14.88. Found: C, 67.36; H, 5.01; N, 14.84.
- 8b: 4-(2-Chloroquinolin-3-yl)-6-methyl-thioxo-N-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 77%; m.p.: 282–284 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.13 (t, 3H, CH3), 2.25 (t, 3H, CH3), 5.47 (s, 1H, CH), 7.23–8.23 (m, 9H, aromatic), 10.15, 10.45, 11.5 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 172.3 (1C, s), 167.5 (1C, s), 152.6 (1C, s), 148.9 (1C, s), 144.2 (1C, s), 139.7 (1C, s), 130.6 (1C, s) (1C, s), 128.8 (2C, s), 128.6 (1C, s), 128.3 (1C, s), 127.4 (1C, s), 126.7 (1C, s), 126.3 (1C, s), 125.8 (1C, s), 121.7 (1C, s), 114.5 (2C, s), 57.4 (1C, s), 20.4 (1C, s), 17.3 (1C, s); Calcd./Anal., for C22H19ClN4OS: C, 62.48; H, 4.53; N, 13.25. Found: C, 62.55; H, 4.31; N, 13.36.
- 8c: 4-(1,3-Diphenyl-1H-pyrazol-4-yl)-6-methyl-2-thioxo-N-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 77%; m.p.: 275–277 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.12 (t, 3H, CH3), 2.34 (t, 3H, CH3), 5.42 (s, 1H, CH), 7.15–8.19 (m, 14H, aromatic), 9.82, 10.7, 11.3 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 178.7 (1C, s), 168.1 (1C, s), 155.1 (1C, s), 151.0 (1C, s), 143.7 (1C, s), 142.0 (1C, s), 141.2 (1C, s), 139.7 (1C, s), 134.5 (2C, s), 130.6 (2C, s), 128.8 (2C, s), 128.6–128.3 (4C, 128.6 (s), 128.5 (s), 128.3 (s)), 127.5 (1C, s), 126.2–125.5 (4C, 126.2 (s), 126.2 (s), 125.5 (s)), 121.8 (2C, s), 113.1 (2C, s), 57.9 (1C, s), 23.0 (1C, s), 17.4 (1C, s); Calcd./Anal., for C28H25N5OS: C, 70.12; H, 5.25; N, 14.60. Found: C, 70.35; H, 5.11; N, 14.50.
- 9a: 4-(1H-indol-3-yl)-6-methyl-N-(4-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 83%; m.p.: 263–265 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.29 (t, 3H, CH3), 5.5 (s, 1H, CH), 7.31–8.09 (m, 9H, aromatic), 9.89, 10.35, 10.8, 11.29 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 168.2 (1C, s), 164.0 (1C, s), 153.1 (1C, s), 148.5 (1C, s), 146.9 (1C, s), 139.3 (1C, s), 135.2 (1C, s), 129.2-128.3 (2C, 128.3 (s), 129.2 (s)), 128.4 (1C, s), 127.6 (1C, s), 127.5 (2C, s), 126.6 (1C, s), 125.4 (1C, s), 121.7 (2C, s), 114.0 (1C, s), 54.7 (1C, s), 17.6 (1C, s); Calcd./Anal., for C20H17N5O3S: C, 58.96; H, 4.21; N, 17.19. Found: C, 58.70; H, 4.06; N, 17.21.
- 9b: 4-(2-Chloroquinolin-3-yl)-6-methyl-N-(4-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 83%; m.p.: 276–278 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.13 (t, 3H, CH3), 5.45 (s, 1H, CH), 7.17–8.19 (m, 9H, aromatic), 9.95, 10.86, 11.3 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 174.4 (1C, s), 168.3 (1C, s), 156.1 (1C, s), 149.0 (1C, s), 146.5 (1C, s), 143.6 (1C, s), 135.2 (1C, s), 130.7 (1C, s), 128.8 (1C, s), 128.5 (1C, s), 128.2 (1C, s), 127.4 (1C, s), 126.6 (1C, s), 126.3 (1C, s), 125.6 (2C, s), 121.7 (1C, s), 115.0 (2C, s), 57.5 (1C, s), 17.4 (1C, s); Calcd./Anal., for C21H16ClN5O3S: C, 55.57; H, 3.55; N, 15.43. Found: C, 55.67; H, 3.88; N, 15.26.
- 9c: 4-(1,3-Diphenyl-1H-pyrazol-4-yl)-6-methyl-N-(4-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: Yield: 83%; m.p.: 261–263 °C; 1HNMR (DMSO-d6, 400 MHz) δ: 2.4 (t, 3H, CH3), 5.59 (s, 1H, CH), 7.25–8.19 (m, 14H, aromatic), 9.58, 10.5, 11.59 (3 s, 3H, 3NH (D2O exchangeable)). 13C NMR: (DMSO-d6, 400 MHz) δ (ppm) 178.7 (1C, s), 168.5 (1C, s), 158.9 (1C, s), 155.1 (1C, s), 151.6, (1C, s) 143.9 (1C, s), 142.0 (1C, s), 141.1 (1C, s), 130.7 (2C, s), 128.8 (2C, s), 128.6–128.3 (2C, 128.86 (s), 128.3 (s)), 127.4 (1C, s), 126.2, 125.6 (4C, 126.2 (s), 126.8 (s), 125.6 (s)), 125.5 (2C, s), 121.1 (2C, s), 114.2 (2C, s), 57.8 (1C, s), 17.5 (1C, s); Calcd./Anal., for C27H22N6O3S: C, 63.52; H, 4.34; N, 16.46. Found: C, 63.87; H, 4.35; N, 16.66.
3.2. Biological Evaluation
3.2.1. Evaluation of In Vivo Antihypertensive Activity
3.2.2. Evaluation of Calcium Channel Blocking Activity
3.3. Molecular Modeling and Binding Mode Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound Code | Dose (mL) | Control (mmHg) | Test (mmHg) | % Inhibition in Blood Pressure |
---|---|---|---|---|
Nifedipine | 0.3 | 29.07 | 20.02 | 31.32 |
0.3 | 28.35 | 20.78 | 26.54 | |
4a | 0.3 | 28.41 | 23.09 | 19.78 |
0.3 | 27.57 | 22.38 | 19.19 | |
4b | 0.3 | 28.34 | 23.5 | 18.53 |
0.3 | 28.38 | 24.18 | 18.79 | |
4c | 0.3 | 29.32 | 22.17 | 29.40 |
0.3 | 30.15 | 23.45 | 29.78 | |
5a | 0.3 | 29.27 | 25.07 | 15.82 |
0.3 | 29.13 | 25.63 | 15.12 | |
5b | 0.3 | 30.01 | 24.21 | 15.23 |
0.3 | 29.23 | 24.14 | 15.55 | |
5c | 0.3 | 28.19 | 23.43 | 16.32 |
0.3 | 28.32 | 23.54 | 16.09 | |
6a | 0.3 | 30.23 | 26.54 | 11.75 |
0.3 | 30.02 | 26.23 | 11.79 | |
6b | 0.3 | 28.90 | 26.85 | 11.09 |
0.3 | 28.38 | 26.92 | 11.07 | |
6c | 0.3 | 30.12 | 27.45 | 11.00 |
0.3 | 30.01 | 27.09 | 11.02 | |
7a | 0.3 | 29.34 | 20.19 | 31.42 |
0.3 | 30.18 | 21.42 | 27.58 | |
7b | 0.3 | 29.19 | 21.98 | 23.23 |
0.3 | 30.01 | 21.86 | 23.90 | |
7c | 0.3 | 29.33 | 22.50 | 27.32 |
0.3 | 28.45 | 22.21 | 28.41 | |
8a | 0.3 | 30.13 | 24.42 | 20.44 |
0.3 | 29.62 | 23.53 | 21.02 | |
8b | 0.3 | 30.51 | 25.61 | 18.21 |
0.3 | 30.00 | 25.03 | 19.81 | |
8c | 0.3 | 29.14 | 22.62 | 28.70 |
0.3 | 29.48 | 20.07 | 30.26 | |
9a | 0.3 | 29.15 | 23.15 | 24.30 |
0.3 | 30.17 | 22.54 | 26.86 | |
9b | 0.3 | 29.32 | 20.19 | 30.09 |
0.3 | 30.15 | 21.42 | 29.28 | |
9c | 0.3 | 29.71 | 21.42 | 27.44 |
0.3 | 30.43 | 20.53 | 31.02 |
Compound Code | Dose (mL) | Control (cm) | Test (cm) | % Inhibition | IC50 (μg/L) |
---|---|---|---|---|---|
Nifedipine | 0.1 | 3.4 | 3.0 | 11.74 | 21 ± 0.28 |
0.2 | 3.4 | 2.7 | 20.47 | ||
0.3 | 3.4 | 2.3 | 32.26 | ||
0.4 | 3.3 | 2.1 | 35.76 | ||
0.5 | 3.3 | 1.7 | 48.38 | ||
0.6 | 3.3 | 1.2 | 61.56 | ||
4a | 0.1 | 3.4 | 2.9 | 17.24 | 23.07 ± 0.32 |
0.3 | 3.4 | 2.3 | 20.56 | ||
0.5 | 3.3 | 1.8 | 30.80 | ||
4b | 0.1 | 3.4 | 2.8 | 16.78 | 24.69 ± 0.22 |
0.3 | 3.4 | 2.3 | 19.36 | ||
0.5 | 3.3 | 1.6 | 29.83 | ||
4c | 0.1 | 3.3 | 2.4 | 16.25 | 22.42 ± 0.13 |
0.3 | 3.4 | 2.5 | 25.69 | ||
0.5 | 3.4 | 1.3 | 37.27 | ||
5a | 0.1 | 3.4 | 2.6 | 14.88 | 24.37 ± 0.41 |
0.3 | 3.3 | 2.1 | 19.71 | ||
0.5 | 3.4 | 1.6 | 35.23 | ||
5b | 0.1 | 3.3 | 2.7 | 14.87 | 25.25 ± 0.38 |
0.3 | 3.4 | 2.3 | 19.98 | ||
0.5 | 3.4 | 1.8 | 34.89 | ||
5c | 0.1 | 3.4 | 2.7 | 13.67 | 24.81 ± 0.43 |
0.3 | 3.4 | 2.3 | 18.96 | ||
0.5 | 3.3 | 1.5 | 32.96 | ||
6a | 0.1 | 3.3 | 2.6 | 8.56 | 26.84 ± 0.26 |
0.3 | 3.4 | 2.3 | 17.87 | ||
0.5 | 3.4 | 1.8 | 30.84 | ||
6b | 0.1 | 3.4 | 2.7 | 7.98 | 30.78 ± 0.24 |
0.3 | 3.3 | 2.1 | 16.98 | ||
0.5 | 3.4 | 1.8 | 30.09 | ||
6c | 0.1 | 3.3 | 2.7 | 8.98 | 29.73 ± 0.19 |
0.3 | 3.4 | 2.1 | 17.43 | ||
0.5 | 3.4 | 1.5 | 30.53 | ||
7a | 0.1 | 3.4 | 2.8 | 16.64 | 21.57 ± 0.12 |
0.3 | 3.4 | 2.2 | 28.59 | ||
0.5 | 3.4 | 1.7 | 39.10 | ||
7b | 0.1 | 3.4 | 2.6 | 15.09 | 22.11 ± 0.20 |
0.3 | 3.4 | 2.2 | 30.93 | ||
0.5 | 3.3 | 1.8 | 36.89 | ||
7c | 0.1 | 3.4 | 2.7 | 17.96 | 20.05 ± 0.05 |
0.3 | 3.4 | 2.2 | 29.97 | ||
0.5 | 3.3 | 1.5 | 44.98 | ||
8a | 0.1 | 3.3 | 2.7 | 16.76 | 22.63 ± 0.36 |
0.3 | 3.4 | 2.1 | 28.98 | ||
0.5 | 3.4 | 1.5 | 45.83 | ||
8b | 0.1 | 3.3 | 2.7 | 16.76 | 22.91 ± 0.29 |
0.3 | 3.4 | 2.1 | 29.56 | ||
0.5 | 3.4 | 1.5 | 44.87 | ||
8c | 0.1 | 3.4 | 2.7 | 16.24 | 19.83 ± 0.36 |
0.3 | 3.4 | 2.1 | 35.23 | ||
0.5 | 3.4 | 1.5 | 50.13 | ||
9a | 0.1 | 3.4 | 2.8 | 15.81 | 21.33 ± 0.21 |
0.3 | 3.4 | 2.1 | 34.53 | ||
0.5 | 3.3 | 1.3 | 45.82 | ||
9b | 0.1 | 3.4 | 2.6 | 17.12 | 20.45 ± 1.07 |
0.3 | 3.4 | 2.01 | 37.45 | ||
0.5 | 3.3 | 1.4 | 49.75 | ||
9c | 0.1 | 3.3 | 2.5 | 17.76 | 19.57 ± 0.18 |
0.3 | 3.4 | 2.1 | 36.20 | ||
0.5 | 3.4 | 1.6 | 50.86 |
Ligands | Hydrogen Bonds between Atoms of Ligands and Amino Acids of Receptor | S-Score (Binding Energy) (kcal/mol) | |||||
---|---|---|---|---|---|---|---|
Ligands Atoms | Receptor | Type | Distance (Å) | Energy (kcal/mol) | |||
Atoms | Residues | ||||||
Ryanodine receptor | |||||||
KN93 | C11 | OE1 | GLU 11 | H-donor | 3.15 | −0.7 | −7.11 |
8c | O11 | SD | MET 72 | H-donor | 3.47 | −0.5 | −7.04 |
9c | C20 | 6-ring | PHE 92 | H-pi | 4.47 | −0.7 | −8.41 |
Nifedipine | N | O | GLU 11 | H-donor | 2.71 | −0.91 | −5.28 |
dihydropyridine receptor | |||||||
PX4 | O2 | NE1 | TRP 1076 | H-acceptor | 3.43 | −0.9 | −5.91 |
8c | 5-ring | NE1 | TRP 1076 | pi-H | 4.22 | −1.0 | −5.09 |
9c | S21 | CA | SER 1125 | H-acceptor | 4.13 | −0.8 | −6.89 |
Nifedipine | CO | N | GLU 1096 | H-acceptor | 2.50 | −0.9 | −5.74 |
CO | N | TYR 1193 | H-acceptor | 2.36 |
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Zohny, Y.M.; Awad, S.M.; Rabie, M.A.; Alsaidan, O.A. Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers. Molecules 2023, 28, 4869. https://doi.org/10.3390/molecules28124869
Zohny YM, Awad SM, Rabie MA, Alsaidan OA. Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers. Molecules. 2023; 28(12):4869. https://doi.org/10.3390/molecules28124869
Chicago/Turabian StyleZohny, Yasser M., Samir M. Awad, Maha A. Rabie, and Omar Awad Alsaidan. 2023. "Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers" Molecules 28, no. 12: 4869. https://doi.org/10.3390/molecules28124869