Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Antibacterial Activity
2.2.2. Antifungal Activity
2.3. In Silico Studies—Molecular Docking
2.3.1. In Silico Studies to Antibacterial Targets
2.3.2. In Silico Studies to Antifungal Targets
2.4. Drug Likeness
3. Materials and Methods
3.1. Chemistry-General Information
3.1.1. General Procedure for the Synthesis of Compounds 2a–o and 3a,b
- 2-{[(1-Methyl-1H-benzo[d]imidazol-2-yl)methyl]thio}benzo[d]thiazole (2a). Yield 2.99 g (96%), colorless crystals, m.p. 90–92 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.93 (s, 3H, Me), 4.98 (s, 2H, CH2), 7.14–7.25 (m, 2H, H-5′, H-6′), 7.29–7.48 (m, 3H, H-5, H-6, H-4′), 7.58 (d, J 7.6, 1H, H-7′), 7.85–7.88 (m, 2H, H-4, H-7). 13C NMR (100 MHz, DMSO-d6) δ 165.85 (S-C-S), 152.89 (C-12), 150.16 (C-4), 142.28 (C-15), 136.36 (C-14), 135.32 (C-5), 126.89 (C-8), 125.10 (C-7), 122.80 (C-18), 122.38 (C-19), 122.18 (C-6), 121.68 (C-9), 119.21 (C-17), 110.65 (C-20), 30.56 (CH3), 29.46. Found (%): C, 61.45; H, 4.00; N, 13.16; S, 20.72. Calc. for C16H13N3S2 (%): C, 61.71; H, 4.21; N, 13.49; S, 20.59.
- 2-(4-Methylphthalazin-1-yl)benzo[d]thiazole (2b). Yield 2.47 g (89%), colorless crystals, m.p. 163–165 °C (EtOH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.99 (s, 3H, Me), 7.35–7.56 (m, 2H, H-5, H-6), 8.22–8.38 (m, 2H, H-6′), 8.02–8.15 (m, 3H, H-5′, H-7′, H-8′), 8.22–8.38 (m, 2H, H-4, H-7). 13C NMR (100 MHz, DMSO-d6) δ 161.14, 159.82, 155.43, 152.07 (C-4), 139.85 (C-10), 136.05 (C-5), 134.74 (C-16), 134.33 (C-17), 132.81 (C-14), 129.65 (C-15), 127.51 (C-8), 126.19 (C-19), 125.24 (C-7), 124.48 (C-18), 122.39 (2C, C-6, C-9), 30.24 (CH3). Found (%): C, 68.98; H, 3.68; N, 15.00; S, 11.72. Calc. for C16H11N3S (%): C, 69.29; H, 4.00; N, 15.15; S, 11.56.
- 2-(4-Phenylphthalazin-1-yl)benzo[d]thiazole (2c). Yield 3.12 g (92%), colorless crystals, m.p. 214–216 °C (methycellosolve). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 7.39–7.59 (m, 2H, H-5, H-6), 7.60–7.85 (m, 5H, H″–H-6″), 7.88–8.20, (m, 2H, 8.22–8.38 (m, 5H, H-7, H-5′–H-8′), 8.35–8.46 (m, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 161.10 (N=C-S), 159.83 (C-13), 155.32 (C-4), 152.01 (C-10), 139.82 (C-20), 136.03 (C-5), 134.72 (C-14), 134.33 (C-16), 132.81 (C-21), 129.60 (2C, C-25, C-6), 127.52 (C-23), 126.21 (2C, C-22, C-24), 125.23 (C-17), 331 124.29 (2C, C-7, C-8), 122.38 (2C, C-9, C-19), 121.79 (2C, C-15, C-18). Found (%): C, 74.10; H, 3.61; N, 12.11; S, 9.72. Calc. for C21H13N3S (%): C, 74.31; H, 3.86; N, 12.38; S, 9.45.
- 2-(4-(p-Tolyl)phthalazin-1-yl)benzo[d]thiazole (2d). Yield 3.11 g (88%), colorless crystals, m.p. 202–205 °C (DMF:EtOAc). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.91 (s, 6H, Me, H2O), 7.36–7.51 (m, 4H, H-2″, H-3″, H-5″, H-6″), 7.65 (d, 2H, H-5, H-6), 7.91–8.16 (m, 5H, H-5′–H-8′, H-7), 8.31–8.42 (m, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 167.82 (N-C-S), 159.10 (S-C=N), 158.86 (C-14), 148.14 (C-5), 144.38 (2C, C-13, C-21), 134.09 (2C, C-4, C-24), 132.54 (C-19), 130.07 (2C, C-22, C-26), 127.22 (3C, C-1, C-2, C-3), 126.57 (3C, C-12, C-23, C-25), 124.80 (2C, C-17, C-18), 123.10 (C-6), 116.08 (C-20), 18.87 (CH3). Found (%):C, 74.49; H, 4.00; N, 11.48; S, 9.29.Calc. for C22H15N3S (%): C, 74.76; H, 4.28; N, 11.89; S, 9.07.
- 2-[4-(4-Chlorophenyl)phthalazin-1-yl]benzo[d]thiazole (2e). Yield 3.14 g (84%), colorless crystals, m.p. 195–196 °C (methycellosolve). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 7.42 (td, J 7.5, 1.4, 1H, H-6), 7.50 (td, J 7.5, 1.4, 1H, H-5), 7.63–7.68 (m, 2H, H-3″, H-5″), 7.79 (d, J 7.5, 2H, H-5′, H-8′), 7.92–7.97 (m, 1H, H-7′), 8.02 (d, J 7.9, 1H, H-6), 8.03–8.17 (m, 3H, H-2″, H-6″, H-7), 8.40 (d, 1H, J 7.8, H-4). 13C NMR (100 MHz, DMSO-d6) δ 160.75 (N=C-S), 158.84 (C-13), 155.95 (C-4), 152.01 (C-10), 136.09 (C-20), 135.15 (C-5), 134.51 (C-Cl), 132.32 (3C, C-14, C-21, C-25), 129.21(3C, C-16, C-22, C-24), 127.30 (C-17), 127.02 (C-19), 126.01 (C-8), 125.81 (C-7), 125.08 (C-18), 124.45 (C-15), 122.47 (C-6), 122.39 (C-9). Found (%):C, 67.22; H, 3.01; Cl, 9.72; N, 11.00; S, 8.74. Calc. for C21H12ClN3S (%): C, 67.47; H, 3.24; Cl, 9.48; N, 11.24; S, 8.58.
- 4-[4-(Benzo[d]thiazol-2-yl)phthalazin-1-yl]-N,N-diethylbenzamide (2f). Yield 2.81 g (64%), colorless crystals, m.p. 180–181 °C (DMF). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.24 (t, J 7.0, 6H, 2CH3), 3.45 (s, 4H, 2CH2), 7.36–7.43 (m, 1H, H-6), 7.44–7.51 (m, 1H, H-5), 7.59 (d, J 7.8, 2H, H-5′, H-8′), 7.83 (d, J 7.9, 2H, H-2″, H-6″), 7.95 (t, J 8.7, 2H, H-6′, H-7′), 8.02–8.19 (m, 3H, H-3″, H-5″, H-7), 8.35–8.42 (m, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 166.63 (C=O), 165.61 (S-C=N), 152.83 (C-14), 142.40 (C-27), 141.68 (C-2), 139.63 (C-17), 136.58 (C-28), 135.21 (C-5), 133.47 (C-23), 132.26 (2C, C-4, C-6), 130.31 (2C, C-3, C-7), 129.58 (C-21), 128.68 (C-18), 127.98 (C-20), 126.84 (C-31), 125.35 (C-19), 124.97 (C-22), 124.20 (C-30), 124.14 (C-29), 122.36 (C-32), 21.35 (2C, CH3). Found (%): C, 71.00; H, 4.82; N, 12.49; S, 7.56. Calc. for C26H22N4OS (%): C, 71.21; H, 5.06; N, 12.78; S, 7.31.
- 5-(4-(Benzo[d]thiazol-2-yl)phthalazin-1-yl)-N,N,2-trimethylbenzenesulfonamide (2g). Yield 3.41 g (74%), colorless crystals, m.p. 163–165 °C (PrOH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.74 (s, 3H, CH3), 2.83 (s, 6H, N(CH3)2), 7.44 (td, J 7.6, 1.3, 1H, H-6), 7.52 (td, J 7.6, 1.5, 1H, H-5), 7.69 (d, J 7.9, 1H, H-3″), 7.93–7.96 (m, 2H, H-6′, H-7′), 8.02–8.06 (m, 1H, H-4″), 8.09–8.18 (m, 4H, H-4, H-7, H-5′, H-8′), 8.38–8.43 (m, 1H, H-6″. 13C NMR (100 MHz, DMSO-d6) δ 167.20 (N-C-S), 159.42 (S-C=N), 152.60 (C-5), 146.22 (C-14), 137.35 (C-24), 137.12 (C-23), 134.93 (C-4), 133.42 (C-13), 132.63 (C-21), 132.05 (C-25), 130.50 (C-26), 128.92 (C-22), 128.43 (C-12), 128.31 (C-19), 127.66 (C-17), 126.82 (C-18), 126.58 (C-20), 126.42 (C-1), 124.74 (C-2), 121.95 (C-3), 121.02 (C-6), 36.80 (2C, N-(CH3)2), 19.88 (C-CH3). Found (%): C, 62.32; H, 4.12; N, 12.00; S, 14.26. Calc. for C24H20N4O2S2 (%): C, 62.59; H, 4.38; N, 12.16; S, 13.92.
- 3-{4-[4-(Benzo[d]thiazol-2-ylthio)phthalazin-1-yl]benzoyl}-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2h). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.01–2.14 (m, 2H, H-5), 2.50–2.57 (m, 1H, H-6, DMSO), 3.00 (s, 2H, H-7), 3.15–3.41 (m, 3H, H-4, H-1), 3.68–3.75 (m, 1H, H-2), 4.05–4.11 (m, 1H, H-2), 6.05 (d, 1H, H-11), 6.33 (dd, J 9.1, 1.3, 1H, H-9), 7.03–7.37 (m, 3H, H-5′, H-6′, H-10), 7.40–7.54 (m, 2H, H-6″, H-7″), 7.72 (d, J 7.8, 2H, H-5″, H-8″), 7.95 (d, J 8.0, 1H, H-5‴), 8.03 (d, J 7.9, 1H, H-3‴), 8.07–8.16 (m, 3H, H-4′, H-2‴, H-6‴), 8.40–8.42 (m, 1H, H-10). 13C NMR (100 MHz, DMSO-d6) δ 175.96 (2C, C=O, C-2), 156.54 (C=O), 153.10 (C-7), 147.82 (2C, C-14, C-19), 144.93 (C-4), 140.62 (C-27), 136.71 (C-24), 134.79 (C-21), 134.54 (C-26), 130.06 (3C, C-15, C-33, C-34), 129.18 (3C, C-31, C-32, C-39), 127.77 (2C, C-35, C-40), 126.52 (2C, C-17, C-36), 125.29 (2C, C-41, C-42), 122.75 (2C, C-28, C-38), 122.61 (C-37), 109.99 (C-25), 56.70 (C-22), 53.17 (2C, C-16, C-20), 40.65 (C-8), 32.37 (C-18), 21.58 (C-23). Found (%): C, 67.12; H, 4.20; N, 11.69; S, 11.22. Calc. for C33H25N5O2S2 (%): C, 67.44; H, 4.29; N, 11.92; S, 10.91.
- 4-[3-(Benzo[d]thiazol-2-ylthio)-4-methylphenyl]-2-methylphthalazin-1(2H)-one (2i). Yield 3.82 g (89%), colorless crystals, m.p. 111–112 °C (DMF). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.57 (s, 3H, CH3), 3.79 (s, 3H, NCH3), 4.74 (s, 1H, CH2), 7.30–7.44 (m, 4H, H-5′, H-5″, H-6″, H-8), 7.50–7.61 (m, 2H, H-6′, H-7), 7.67 (d, J 7.9, 1H, H-2′), 7.71–7.82 (m, 2H, H-6, H-7′), 7.83–7.88 (m, 1H, H-9), 8.36 (d, J 7.9, 1H, H-7″). 13C NMR (100 MHz, DMSO-d6) δ 166.13 (C-1), 158.62 (C=O), 153.01 (C-5), 145.86 (C-18), 138.40 (C-13), 135.19 (C-6), 134.94 (C-16), 133.56 (C-12), 132.91 (C-14), 132.18 (C-28), 131.14 (C-17), 131.10 (C-27), 129.29 (C-20), 128.90 (C-29), 127.75 (C-19), 126.86 (C-26), 126.73 (C-9), 126.71 (C-15), 125.08 (C-10), 122.31 (C-8), 121.69 (C-7), 39.50 (C-25), 35.33 (C-11), 19.23 (CH3). Found (%): C, 66.72; H, 4.18; N, 9.53; S, 15.27. Calc. for C24H19N3OS2 (%): C, 67.11; H, 4.46; N, 9.78; S, 14.93.
- 2-(Benzo[d]thiazol-2-ylthio)-N-[2-methyl-5-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl]acetamide (2j). Yield 4.09 g (84%), colorless crystals, m.p. 201–202 °C (DMF). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.41 (s, 3H, CH3), 3.77 (s, 3H, NCH3), 4.10 (s, 2H, SCH2), 4.43 (d, J 5.7, 2H, NCH2) 7.21–7.32 (m, 4H, H-5, H-6, H-3′, H-6″), 7.46 (d, J 1.7, H-7‴), 7.59–7.69 (m, 2H, H-7, H-6′), 7.72–7.77 (m, 3H, H-4, H-4, H-8″), 8.27–8.37 (m, 1H, H-5″), 8.56 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 167.17 (S-C-N), 166.46 (C=O), 158.55 (C=O), 152.66 (C-23), 146.23 (C-25), 137.36 (C-5), 137.00 (C-11), 134.95 (C-4), 133.42 (C-24), 132.65 (C-16), 132.07 (C-18), 130.51 (C-19), 128.95 (C-17), 128.42(C-3), 128.29 (C-2), 127.64 (C-30), 126.85 (C-6), 126.56 (C-31), 126.40 (C-33), 124.73 (C-32), 121.98 (C-20), 121.04 (C-21), 41.24 (CH2-NH), 36.81 (2C, N-CH3), 18.98 (C-CH3). Found (%): C, 64.00; H, 4.22; N, 11.18; S, 13.54. Calc. for C26H22N4O2S2 (%): C, 64.18; H, 4.56; N, 11.51; S, 13.18.
- 2-(Benzo[d]thiazol-2-ylthio)-1-[4-(4-phenylphthalazin-1-yl)piperazin-1-yl]ethan-1-one (2k). Yield 3.68 g (74%), colorless crystals, m.p. 162–163 °C (EtOH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.53 (s, 2H, 2H-2′), 3.65 (s, 2H, 2H-6′), 3.88 (s, 2H, H-3′), 3.97 (s, 2H, H-5′), 4.57 (s, 2H, SCH2), 7.31 (t, J 7.6, H-4‴), 7.42 (t, J 7.6, H-6), 7.51–7.60 (m, 3H, H-5, H-3‴, H-5‴), 7.62–7.69 (m, 2H, H-6″, H-7″), 7.59–7.69 (m, 2H, H-7, H-6′), 7.99–7.80 (m, 5H, H-7, H-2‴, H-6‴,H-8″), 8.22 (d, J 8.2, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 161.14(S-C=N), 159.82 (C=O), 155.43 (C-20), 152.07 (2C, C-5, C-23), 139.85 (C-30), 136.05 (C-4), 134.74 (C-22), 134.33 (C-33), 132.81 (2C, C-11, C-28), 129.65 (4C, C-16, C-18, C-25, C-31), 127.51 (2C, C-27, C-2), 126.19 (C26), 125.24 (2C, C-1, C-29), 124.48 (2C, C-32, C-34), 122.39 (2C, C-19, C-15), 121.56 (3C, C-3, C-6, C-21). Found (%): C, 65.00; H, 4.39; N, 13.86; S, 12.99. Calc. for C27H23N5OS2 (%): C, 65.17; H, 4.66; N, 14.07; S, 12.88.
- 2-(Benzo[d]thiazol-2-ylthio)-1-(4-(4-(p-tolyl)phthalazin-1-yl)piperazin-1-yl)ethan-1-one (2l). Yield 3.53 g (69%), colorless crystals, m.p. 155–156 °C (CH3CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.02 (s, 3H, CH3), 3.51 (s, 2H, 2H-2′), 3.63 (s, 2H, 2H-6′), 3.87 (s, 2H, H-3′), 3.97 (s, 2H, H-5′), 4.57 (s, 2H, SCH2), 7.27–7.47 (m, 4H, H-3‴, H-4‴, H-5‴, H-6‴), 7.52–7.58 (m, 2H, H-5, H-6), 7.78–8.01 (m, 5H, H-7, H-5″–H-8″), 8.21 (d, J 8.1, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 166.50 (S-C-S), 165.94 (C=O), 155.37 (C-10), 152.95 (C-13), 147.79 (C-31), 139.59 (C-22), 135.21 (C-20), 134.37 (C-32), 131.49 (C-14), 129.79 (C-16), 127.77 (2C, C-24, C-25), 126.85 (C-17), 124.98 (C-18), 123.32 (C-15), 122.96 (C-35), 122.32 (3C, C-21, C-23, C-19), 121.51 (2C, C-33, C-34), 118.48 (C-36), 38.24 (4C, C-4, C-6, C-8, C-9), 20.20 (2C, C-2, CH3). Found (%): C, 65.48; H, 4.69; N, 13.46; S, 12.74. Calc. for C28H25N5OS2 (%): C, 65.73; H, 4.93; N, 13.69; S, 12.53.
- 2-(Benzo[d]thiazol-2-ylthio)-N-(3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)phenyl)acetamide (2m). Yield 3.74 g (72%), colorless crystals, m.p. 235–237 °(DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.91 (s, 3H, Me), 4.38 (s, 2H, CH2), 7.27–7.36 (m, 1H, H-4″), 7.37–7.51 (m, 2H, H-5, H-6), 7.80–7.92 (m, 4H, H-7′–H-10′), 8.00 (t, J 7.6, 1H, H-5″), 8.17 (d, J 7.9, 2H, H-4, H-7), 8.61 (d, J 7.9, 1H, H-6″), 8.67 (d, J 2.0, 1H, H-2″), 10.48 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 166.50 (S-C=N), 165.95 (C=O), 155.37 (C-27), 152.95 (C-11), 147.79 (C-CH3), 143.79 (N-C-N), 139.58 (C-18), 135.21 (C-28), 134.37 (C-2), 131.49 (C-1), 129.79 (C-4), 127.77 (C-16), 127.43 (C-14), 126.85 (C-3), 124.98 (C-31), 123.32 (2C, C-6, C-15), 122.97 (C-17), 122.90 (C-5), 122.33 (C-32), 121.51 (C-33), 121.02 (C-30), 118.48 (C-19), 38.23 (CH2-C=O), 20.21 (CH3). Found (%): C, 62.00; H, 3.41; N, 17.21; S, 13.04. Calc. for C25H18N6OS2 (%): C, 62.22; H, 3.76; N, 17.41; S, 13.29.
- 2-(Benzo[d]thiazol-2-ylthio)-N-(2-methyl-5-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)phenyl)acetamide (2n). Yield 3.87 g (78%), colorless crystals, m.p. 251–253 °C (DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.36 (s, 3H, Me), 2.87 (s, 6H, Me, DMSO), 4.39 (s, 2H, CH2), 7.32–7.42 (m, 3H, H-5, H-6, H-5″), 7.84–7.89 (m, 3H, H-7, H-8′, H-9′), 7.96–8.03 (m, 1H, H-7), 8.13–8.18 (m, 2H, H-7′, H-10′), 8.61 (d, J 8.0, 1H, H-4″), 8.69 (s, 1H, H-2″), 9.67 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 166.53 (S-C=N), 165.92 (C=O), 155.35 (C-27), 152.92 (C-11), 147.80 (C-7), 143.77 (C-10), 139.56 (C-18), 135.18 (C-28), 134.35 (C-16), 131.46 (C-17), 129.80 (C-2), 127.76 (C-1), 127.32 (C-4), 126.91 (C-14), 124.95 (C-3), 123.30 (C-31), 122.99 (2C, C-6, C-32), 122.91 (C-15), 122.34 (C-5), 121.50 (C-33), 121.07 (C-30), 118.46 (C-19), 38.24 (C-23), 24.51 (CH3), 20.19 (CH3). Found (%): C, 62.56; H, 4.40; N, 17.11; S, 13.15. Calc. for C26H20N6OS2 (%): C, 62.88; H, 4.06; N, 16.92; S, 12.91.
- 2-(Benzo[d]thiazol-2-ylthio)-N-(5-(p-tolyl)benzo[4,5]imidazo[2,1-a]phthalazin-9-yl)acetamide (2o). Yield 4.68 g (88%), colorless crystals, m.p. 248–250 °C (DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.52 (s, 3H, Me), 4.40 (s, 2H, CH2), 7.33–7.44 (m, 3H, H-3″, H-5″, H-10′), 7.57–7.69 (m, 3H, H-2″, H-6″, H-11′), 7.76–8.03 (m, 6H, H-5, H-6, H-1′–H-4′), 8.26 (d, J 1.8, 1H, H-8′), 8.74–8.78 (m, 2H, H-4, H-7), 10.47 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 166.59 (S-C=N), 165.60 (2C, N=C-N, C=O), 152.98 (C-33), 142.42 (C-8), 141.68 (C-16), 139.63 (C-24), 136.57 (C-17), 135.21 (C-19), 133.47 (C-34), 132.25 (C-22), 130.20 (2C, C-23, C-25), 129.61 (2C, C-26, C-27), 128.68 (C-11), 127.97 (C-12), 126.86 (C-9), 125.35 (C-10), 124.97 (C-13), 124.21 (C-36), 124.12 (C-37), 122.35 (C-20), 121.51 (C-35), 116.21 (C-38), 111.51 (C-14), 109.66 (2C, C-18, C-21), 38.34(CH2-C=O), 21.44 (CH3). Found (%): C, 67.42; H, 4.21; N, 13.54; S, 12.36. Calc. for C30H21N5OS2 (%): C, 67.77; H, 3.98; N, 13.17; S, 12.06.
- 2,2′-{[(2,5-Dimethyl-1,4-phenylene)bis(methylene)]bis(sulfanediyl)}bis(benzo[d]thiazole) (3a). Yield 90%, colorless crystals, m.p. 170–171 °C (methylcellosolve), 1H NMR (200 MHz, DMSO-d6, δ, ppm): 2.32 (s, 6H, 2Me), 4.54 (s, 4H, 2CH2), 7.26 (s, 2H, H-3″, H-5″), 7.34–7.37 (m, 2H, H-5, H-5′), 7.43–7.47 (m, 2H, H-6, H-6′), 7.86 (d, J 1.1, H-7), 7.88 (d, J 1.1, H-7′), 7.92 (d, J 1.3, H-4), 7.93 (d, J 1.3, H-4′). 13C NMR (100 MHz, DMSO-d6) δ 166.60 (S-C=N), 165.72 (S-C-S), 152.92 (C-5), 142.40 (C-23), 141.62 (C-14), 136.56 (C-17), 135.23 (C-4), 133.24 (C-22), 130.20 (2C, C-13, C-16), 129.63 (2C, C-12, C-15), 127.97 (C-1), 126.86 (C-2), 125.35 (C-27), 124.97 (C-26), 124.23 (2C, C-3, C-25), 124.11 (2C, C-6, C-28), 37.15 (2C, C-11, C-18), 21.42 (2C, CH3). Found (%): C, 62.36; H, 4.56; N, 6.34; S, 27.81. Calc. for C24H20N2S4 (%): C, 62.03; H, 4.34; N, 6.03; S, 27.60.
- 2,2′-{[(2,5-Dimethoxy-1,4-phenylene)bis(methylene)]bis(sulfanediyl)}bis(benzo[d]thiazole) (3b). Yield 95%, colorless crystals, m.p. 184–186 °C (DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.79 (s, 6H, 2OMe), 4.56 (s, 4H, 2CH2), 7.18 (s, 2H, H-3″, H-6″), 7.30–7.36 (m, 2H, H-5, H-5′), 7.41–7.47 (m, 2H, H-6, H-6′), 7.84–7.92 (m, 4H, H-4, H-4′, H-7, H-7′). 13C NMR (100 MHz, DMSO-d6) δ 166.59 (S-C=N), 166.45 (S-C-S), 159.14 (2C, C-OCH3), 152.66 (C-5), 148.82 (C-23), 137.53 (C-4), 136.67 (C-22), 133.48 (C-15), 132.65 (C-12), 132.05 (2C, C-1, C-17), 128.44 (2C, C-2, C-26), 127.65 (2C, C-3, C-25), 124.78 (2C, C-6, C-28), 121.05 (2C, C-13, C-16), 53.28 (2C, O-CH3), 36.84 (2C, C-11, C-18). Found (%): C, 58.40; H, 4.29; N, 5.26; S, 25.49. Calc. for C24H20N2O2S4 (%): C, 58.04; H, 4.06; N, 5.64; S, 25.82.
3.1.2. Synthesis of 9-((4-(Benzo[d]thiazol-2-yl)piperidin-1-yl)sulfonyl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (5)
3.1.3. Synthesis of 2-{1-[(2-Tosylpyridin-3-yl)methyl]piperidin-4-yl}benzo[d]thiazole (6)
3.1.4. Synthesis of N-[6-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl]benzo[d]thiazole-6-carboxamide (8)
3.1.5. Synthesis of N-(6-Bromobenzo[d]thiazol-2-yl)-2-(4-methyl-1-oxophthalazin-2(1H)-yl) acetamide (10)
3.2. Biological Evaluation
3.2.1. Antibacterial Activity
3.2.2. Antifungal Activity
3.3. Docking Studies
3.4. Drug Likeness
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No. | S.a. | B.c. | L.m. | E.c. | S.t. | En.cl. | |
---|---|---|---|---|---|---|---|
2a | MIC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.35 ± 0.08 | 0.70 ± 0.19 | 0.70 ± 0.19 |
MBC | 3.75 ± 0.00 | 1.88 ± 0.00 | 1.88 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
2b | MIC | 1.41 ± 0.38 | 0.47 ± 0.00 | 0.47 ± 0.00 | >3.75 | 0.23 ± 0.00 | 0.47 ± 0.00 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | >3.75 | 0.47 ± 0.00 | 0.94 ± 0.00 | |
2c | MIC | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 |
MBC | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
2d | MIC | 1.41 ± 0.38 | 0.35 ± 0.08 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 |
MBC | 1.88 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
2e | MIC | 1.41 ± 0.38 | 0.94 ± 0.00 | 0.70 ± 0.19 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 |
MBC | 1.88 ± 0.00 | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | |
2f | MIC | 2.50 ± 0.88 | 1.41 ± 0.38 | 0.94 ± 0.00 | 0.70 ± 0.19 | 1.41 ± 0.38 | 2.50 ± 0.88 |
MBC | 3.75 ± 0.00 | 1.88 ± 0.00 | 1.88 ± 0.00 | 0.94 ± 0.00 | 1.88 ± 0.00 | 3.75 ± 0.00 | |
2g | MIC | 1.41 ± 0.38 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.23 ± 0.00 | 0.70 ± 0.19 | 0.70 ± 0.19 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
2h | MIC | 0.94 ± 0.00 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.47 ± 0.00 | 0.70 ± 0.19 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
2i | MIC | 1.41 ± 0.38 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.35 ± 0.08 | 0.70 ± 0.19 | 0.94 ± 0.00 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | 1.88 ± 0.00 | |
2j | MIC | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.47 ± 0.00 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | |
2k | MIC | 0.94 ± 0.00 | 0.23 ± 0.00 | 0.35 ± 0.08 | >3.75 | >3.75 | 0.23 ± 0.00 |
MBC | 1.88 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | >3.75 | >3.75 | 0.47 ± 0.00 | |
2l | MIC | 1.41 ± 0.38 | 0.94 ± 0.00 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.94 ± 0.00 |
MBC | 1.88 ± 0.00 | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 1.88 ± 0.00 | |
2m | MIC | 1.41 ± 0.38 | >3.75 | 0.70 ± 0.19 | 0.47 ± 0.00 | 0.35 ± 0.08 | 0.70 ± 0.19 |
MBC | 1.88 ± 0.00 | >3.75 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | |
2n | MIC | 1.41 ± 0.38 | 0.70 ± 0.19 | 0.70 ± 0.19 | >3.75 | 0.47 ± 0.00 | 0.70 ± 0.19 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | >3.75 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
2o | MIC | 1.41 ± 0.38 | 0.70 ± 0.19 | 0.70 ± 0.19 | >3.75 | 0.47 ± 0.00 | 0.47 ± 0.00 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | >3.75 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
3a | MIC | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.47 ± 0.00 | 0.70 ± 0.19 |
MBC | 3.75 ± 0.00 | 1.88 ± 0.00 | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 1.88 ± 0.00 | |
3b | MIC | 1.41 ± 0.38 | 0.70 ± 0.19 | 0.70 ± 0.19 | >3.75 | 0.70 ± 0.19 | 0.70 ± 0.19 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | >3.75 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
5 | MIC | 1.41 ± 0.38 | 0.47 ± 0.00 | 0.70 ± 0.19 | 0.35 ± 0.08 | 0.70 ± 0.19 | 1.41 ± 0.38 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | 1.88 ± 0.00 | |
6 | MIC | 0.94 ± 0.00 | 0.70 ± 0.19 | 0.70 ± 0.19 | >3.75 | 0.70 ± 0.19 | 0.47 ± 0.00 |
MBC | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | >3.75 | 0.94 ± 0.00 | 0.94 ± 0.00 | |
8 | MIC | 2.50 ± 0.88 | 1.41 ± 0.38 | 1.41 ± 0.00 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.94 ± 0.00 |
MBC | 3.75 ± 0.00 | 1.88 ± 0.00 | 1.88 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 1.88 ± 0.00 | |
10 | MIC | 1.41 ± 0.38 | 0.23 ± 0.00 | 0.70 ± 0.19 | 0.70 ± 0.19 | 0.23 ± 0.00 | 0.70 ± 0.19 |
MBC | 1.88 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | |
Streptomycin | MIC | 0.10 ± 0.00 | 0.02 ± 0.00 | 0.15 ± 0.00 | 0.10 ± 0.00 | 0.10 ± 0.00 | 0.02 ± 0.00 |
MBC | 0.20 ± 0.01 | 0.05 ± 0.00 | 0.30 ± 0.01 | 0.20 ± 0.00 | 0.20 ± 0.01 | 0.05 ± 0.00 | |
Ampicillin | MIC | 0.10 ± 0.00 | 0.10 ± 0.00 | 0.15 ± 0.00 | 0.15 ± 0.00 | 0.10 ± 0.00 | 0.10 ± 0.00 |
MBC | 0.15 ± 0.00 | 0.15 ± 0.00 | 0.30 ± 0.02 | 0.20 ± 0.01 | 0.20 ± 0.00 | 0.15 ± 0.01 |
No. | A.f. | A.n. | A.v. | P.f. | T.v. | P.v.c. | |
---|---|---|---|---|---|---|---|
2a | MIC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.35 ± 0.08 | 0.11 ± 0.00 | 0.11 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | |
2b | MIC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
2c | MIC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.23 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | |
2d | MIC | 0.17 ± 0.05 | 0.11 ± 0.00 | 0.17 ± 0.05 | 0.17 ± 0.05 | 0.08 ± 0.00 | 0.17 ± 0.05 |
MFC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 | |
2e | MIC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.35 ± 0.08 | 0.17 ± 0.05 | 0.35 ± 0.08 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
2f | MIC | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.17 ± 0.05 | 0.23 ± 0.00 |
MFC | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
2g | MIC | 0.47 ± 0.00 | 0.17 ± 0.05 | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.17 ± 0.05 | 0.35 ± 0.08 |
MFC | 0.94 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
2h | MIC | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.35 ± 0.08 | 0.11 ± 0.00 | 0.70 ± 0.19 |
MFC | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.94 ± 0.00 | |
2i | MIC | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.06 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.11 ± 0.00 | 0.47 ± 0.00 | |
2j | MIC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
2k | MIC | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.94 ± 0.00 | |
2l | MIC | 0.23 ± 0.00 | 0.17 ± 0.05 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
2m | MIC | 0.17 ± 0.05 | 0.11 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 | 0.17 ± 0.05 | 0.35 ± 0.08 |
MFC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
2n | MIC | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.23 ± 0.00 | 0.35 ± 0.08 |
MFC | 0.94 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | |
2o | MIC | 0.17 ± 0.05 | 0.17 ± 0.05 | 0.11 ± 0.00 | 0.23 ± 0.00 | 0.17 ± 0.05 | 0.23 ± 0.00 |
MFC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
3a | MIC | 0.17 ± 0.05 | 0.11 ± 0.00 | 0.23 ± 0.00 | 0.17 ± 0.05 | 0.11 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
3b | MIC | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.17 ± 0.05 | 0.17 ± 0.05 | 0.06 ± 0.00 | 0.17 ± 0.05 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 | |
5 | MIC | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.11 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.23 ± 0.00 | 0.47 ± 0.00 | |
6 | MIC | 0.23 ± 0.00 | 0.35 ± 0.08 | 0.23 ± 0.00 | 0.23 ± 0.00 | 0.06 ± 0.00 | 0.23 ± 0.00 |
MFC | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.47 ± 0.00 | 0.11 ± 0.00 | 0.47 ± 0.00 | |
8 | MIC | 3.75 ± 0.00 | 3.75 ± 0.00 | 3.75 ± 0.00 | 3.75 ± 0.00 | 3.75 ± 0.00 | 3.75 ± 0.00 |
MFC | >3.75 | >3.75 | >3.75 | >3.75 | >3.75 | >3.75 | |
10 | MIC | 1.88 ± 0.00 | 0.47 ± 0.00 | 0.70 ± 0.019 | 1.41 ± 0.38 | 0.70 ± 0.19 | 2.50 ± 0.88 |
MFC | 3.75 ± 0.00 | 0.94 ± 0.00 | 0.94 ± 0.00 | 1.88 ± 0.00 | 0.94 ± 0.00 | 3.75 ± 0.00 | |
Bifonazole | MIC | 0.15 ± 0.00 | 0.15 ± 0.00 | 0.10 ± 0.00 | 0.20 ± 0.00 | 0.15 ± 0.00 | 0.10 ± 0.00 |
MFC | 0.20 ± 0.00 | 0.20 ± 0.00 | 0.20 ± 0.00 | 0.25 ± 0.00 | 0.20 ± 0.00 | 0.20 ± 0.00 | |
Ketoconazole | MIC | 0.20 ± 0.00 | 0.20 ± 0.00 | 0.20 ± 0.00 | 0.20 ± 0.00 | 1.00 ± 0.01 | 0.20 ± 0.00 |
MFC | 0.50 ± 0.00 | 0.50 ± 0.00 | 0.50 ± 0.00 | 0.50 ± 0.00 | 1.50 ± 0.00 | 0.30 ± 0.010 |
Comp. | Est. Binding Energy (kcal/mol) | I-H E. coli MurB | Residues E. coli MurB | ||||
---|---|---|---|---|---|---|---|
E. coli Gyrase 1KZN | Thymidylate Kinase 4QGG | E. coli Primase 1DDE | E. coli MurA JV4T | E. coli MurB 2Q85 | |||
2a | −4.52 | - | - | −3.62 | −8.03 | 1 | Ser229 |
2b | −5.28 | - | −1.23 | −4.27 | −7.86 | 1 | Arg158 |
2c | −4.39 | −2.55 | - | −5.19 | −10.13 | 2 | Ser50, Ser229 |
2d | −5.19 | −1.03 | −2.26 | −6.52 | −9.64 | 2 | Arg158, Arg213 |
2e | −4.55 | - | −1.39 | −5.24 | −9.61 | 2 | Arg213, Ser229 |
2f | −4.37 | - | - | −5.37 | −6.53 | 1 | Arg213 |
2g | −5.37 | −1.54 | −2.33 | −6.72 | −10.02 | 2 | Arg158, Arg213 |
2h | −4.19 | - | - | −5.68 | −9.71 | 2 | Arg213, Ser229 |
2i | −5.63 | −1.28 | −1.30 | −5.22 | −9.34 | 2 | Ser50, Ser229 |
2j | −5.27 | - | - | −6.34 | −10.75 | 3 | Ser50, Ser116, Ile173 |
2k | −4.23 | - | - | −4.53 | −8.76 | 1 | Ser229 |
2l | −4.96 | - | −2.38 | −6.59 | −9.11 | 2 | Ser50, Ser229 |
2m | −5.23 | - | - | −4.56 | −7.80 | 1 | Arg158 |
2n | −4.31 | −1.85 | - | −3.11 | −7.30 | 1 | Arg213 |
2o | −3.62 | - | - | −2.54 | −7.35 | 1 | Arg213 |
3a | −4.35 | - | - | −3.64 | −8.45 | 1 | Ser229 |
3b | −2.32 | −1.68 | - | −4.52 | −7.18 | 1 | Arg158 |
5 | −5.12 | - | −1.30 | −5.57 | −9.53 | 2 | Arg213, Ser229 |
6 | −3.66 | - | - | −2.50 | −7.42 | 1 | Arg213 |
8 | −5.10 | −1.52 | −2.46 | −6.22 | −9.90 | 2 | Arg158, Arg213 |
10 | −4.28 | - | - | −3.55 | −6.92 | 1 | Arg213 |
Naphthyl Tetronic Acid inhibitor | - | - | - | - | −8.82 | - | Asn233 |
Est. Binding Energy(kcal/mol) | Residues Involved in H-Bond Formation | Residues Involved in Hydrophobic Interactions | Residues Involved in Aromatic Interactions | Interactions with HEM601 | ||
---|---|---|---|---|---|---|
N/N | DNA TopoIV 1S16 | CYP51 of C. albicans 5V5Z | ||||
2a | −1.38 | −9.85 | Tyr132 | Tyr118, Leu121, Thr311, Phe380, Met508, Hem601 | Hem601 | Hydrophobic, aromatic |
2b | −3.59 | −8.82 | Tyr132 | Tyr118, Tyr122, Ile304, Thr311, Hem601 | Tyr118 | Hydrophobic |
2c | −2.64 | −8.03 | - | Tyr118, Thr311, Leu376, Met508, Hem601 | Hem601 | Hydrophobic, aromatic |
2d | −3.57 | −11.32 | - | Tyr118, Leu121, Tyr122, Thr311, Leu376, Phe380, Met508, Hem601 | Tyr118, Hem601 | Hydrophobic, aromatic |
2e | −3.15 | −8.50 | Tyr118 | Tyr118, Leu376, Met508, Hem601 | Tyr118 | Hydrophobic |
2f | −1.29 | −7.46 | - | Met508, Hem601 | Hem601 | Hydrophobic, aromatic |
2g | - | −7.93 | - | Ile304, Thr311, Met508, Hem601 | - | Hydrophobic |
2h | −2.44 | −7.21 | - | Tyr118, Leu376, Met508, Hem601 | Tyr118 | Hydrophobic |
2i | - | −9.82 | Tyr132 | Tyr118, Phe380, Met508, Hem601 | - | Hydrophobic |
2j | −3.83 | −9.56 | - | Tyr118, Tyr122, Thr311, Leu376, Met508, Hem601 | Tyr118, Hem601 | Hydrophobic, aromatic |
2k | - | −7.39 | - | Tyr118, Met508, Hem601 | - | Hydrophobic |
2l | −1.27 | 9.52 | - | Tyr118, Tyr122, Leu376, Met508, Hem601 | Tyr122, Hem601 | Hydrophobic, aromatic |
2m | −3.21 | −10.02 | Tyr64 | Tyr118, Tyr122, Thr311, Leu376, Phe380, Hem601 | Tyr118 | Hydrophobic |
2n | - | −7.25 | - | Tyr118, Leu376, Met508, Hem601 | - | Hydrophobic |
2o | −2.50 | −10.25 | - | Tyr118, Leu121, Tyr122, Thr311, Hem601 | Hem601 | Hydrophobic, aromatic |
3a | −2.75 | −10.31 | - | Tyr118, Leu121, Leu376, Phe380, Met508, Hem601 | Hem601 | Hydrophobic, aromatic |
3b | −3.23 | −10.87 | - | Tyr118, Tyr122, Thr311, Leu376, Met508, Hem601 | Tyr118, Hem601 | Hydrophobic, aromatic |
5 | - | −8.62 | - | Tyr118, Tyr122, Thr311, Met508, Hem601 | Hem601 | Hydrophobic, aromatic |
6 | −2.45 | −9.10 | - | Tyr118, Tyr122, Ile304, Thr311, Leu376, Hem601 | Ile131, Hem601 | Hydrophobic, aromatic |
8 | −2.06 | −8.21 | - | Tyr118, Tyr122, Ile131, Leu376, Met508, Hem601 | - | Hydrophobic |
10 | −2.41 | −7.20 | - | Tyr118, Leu376, Met508, Hem601 | Tyr118 | Hydrophobic |
ketoconazole | - | −8.23 | Tyr64 | Tyr118, Ile131, Tyr132, Leu300, Ile304, Leu376, Met508, Hem601 | Hem601 | Hydrophobic, aromatic |
No. | MW | Number of HBA a | Number of HBD b | Log Po/w (iLOGP) c | Log S d | TPSA e | BBB Permeant f | Lipinski, Ghose, Veber, Egan, and Muegge Violations | Bioavailability Score | Drug-Likeness Model Score |
---|---|---|---|---|---|---|---|---|---|---|
2a | 311.42 | 2 | 0 | 2.81 | Poorly soluble | 84.25 | No | 0 | 0.55 | −0.08 |
2b | 309.41 | 3 | 0 | 3.19 | Poorly soluble | 92.21 | No | 0 | 0.55 | −0.19 |
2c | 371.48 | 3 | 0 | 3.69 | Poorly soluble | 92.21 | No | 0 | 0.55 | −0.35 |
2d | 385.50 | 3 | 0 | 3.86 | Poorly soluble | 92.21 | No | 0 | 0.55 | −0.12 |
2e | 405.92 | 3 | 0 | 4.03 | Poorly soluble | 92.21 | No | 0 | 0.55 | 0.20 |
2f | 470.61 | 4 | 0 | 4.30 | Poorly soluble | 112.52 | No | 2 * | 0.55 | 0.65 |
2g | 492.64 | 6 | 0 | 4.13 | Poorly soluble | 137.97 | No | 3 ** | 0.55 | −0.22 |
2h | 587.71 | 5 | 0 | 4.65 | Insoluble | 134.52 | No | 2 *** | 0.17 | 0.37 |
2i | 429.56 | 3 | 0 | 3.65 | Poorly soluble | 101.32 | No | 0 | 0.55 | 0.06 |
2j | 486.61 | 4 | 1 | 3.73 | Poorly soluble | 130.42 | No | 0 | 0.55 | 0.43 |
2k | 497.63 | 4 | 0 | 4.36 | Poorly soluble | 115.76 | No | 0 | 0.55 | 0.21 |
2l | 511.66 | 4 | 0 | 4.31 | Poorly soluble | 115.76 | No | 0 | 0.55 | 0.42 |
2m | 482.58 | 5 | 1 | 3.61 | Poorly soluble | 138.61 | No | 0 | 0.55 | 0.32 |
2n | 496.61 | 5 | 1 | 4.14 | Poorly soluble | 138.61 | No | 0 | 0.55 | 0.34 |
2o | 531.65 | 4 | 1 | 4.38 | Poorly soluble | 125.72 | No | 2 *** | 0.17 | −0.03 |
3a | 464.69 | 2 | 0 | 4.75 | Poorly soluble | 132.86 | No | 0 | 0.55 | −0.05 |
3b | 496.69 | 4 | 0 | 4.87 | Poorly soluble | 151.32 | No | 0 | 0.55 | 0.43 |
5 | 501.62 | 8 | 0 | 3.85 | Poorly soluble | 117.82 | No | 0 | 0.55 | 0.79 |
6 | 463.61 | 5 | 0 | 3.56 | Poorly soluble | 99.78 | No | 0 | 0.55 | 0.49 |
8 | 400.25 | 4 | 1 | 2.93 | Poorly soluble | 100.94 | No | 0 | 0.55 | −0.60 |
10 | 429.29 | 4 | 1 | 2.65 | Poorly soluble | 105.12 | No | 0 | 0.55 | 0.44 |
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Zubenko, A.; Kartsev, V.; Petrou, A.; Geronikaki, A.; Ivanov, M.; Glamočlija, J.; Soković, M.; Divaeva, L.; Morkovnik, A.; Klimenko, A. Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents. Antibiotics 2022, 11, 1654. https://doi.org/10.3390/antibiotics11111654
Zubenko A, Kartsev V, Petrou A, Geronikaki A, Ivanov M, Glamočlija J, Soković M, Divaeva L, Morkovnik A, Klimenko A. Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents. Antibiotics. 2022; 11(11):1654. https://doi.org/10.3390/antibiotics11111654
Chicago/Turabian StyleZubenko, Alexander, Victor Kartsev, Anthi Petrou, Athina Geronikaki, Marija Ivanov, Jasmina Glamočlija, Marina Soković, Lyudmila Divaeva, Anatolii Morkovnik, and Alexander Klimenko. 2022. "Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents" Antibiotics 11, no. 11: 1654. https://doi.org/10.3390/antibiotics11111654