SUPPLEMENTARY MATERIAL
Pharmacophore combination as a useful strategy to discover new antitubercular agents
Dharmarajsinh N Rana,Mahesh T Chhabria, Nisha K Shah and Pathik S Brahmkshatriya
SPECTROSCOPIC DATA OF SYNTHESIZED COMPOUNDS
4-(1-acetyl-5-(3,4-dimethoxylphenyl)-4,5-dihydro-3-pyrazolyl)-2-nitrophenol (4a)
Yield: 75.5%; MP: 164-166oC; 1H NMR (400 MHz, DMSO-d6): δ 8.392(d, 1H, J= 2.35 Hz), 7.929(dd, 1H, J= 1.97 Hz, J= 8.41 Hz), 7.245-7.205(m, 2H), 7.152-7.137(m, 2H), 5.666-5.628(dd, 1H, JHH”= 3.92 Hz, JHH’= 12.19 Hz), 3.804(s, 3H), 3.748(s, 3H), 3.719-3.671(quartet, 1H, JH’H”= 18.11 Hz, JHH’= 12.15 Hz), 3.311-3.363(dd, 1H, JH’H”= 18.07 Hz, JHH”= 4.03 Hz), 1.874(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 22.08, 37.53, 56.03, 63.96, 110.72, 111.43, 119.4, 119.9, 122.77, 126.3, 127.47, 129.11, 136.85, 148.05, 149.35, 153.86, 155.78, 169.62; ESI-MS: 386.1 (M+1).
4-(1-acetyl-5-(4-methoxylphenyl)-4,5-dihydro-3-pyrazolyl)-2-nitrophenol (4b)
Yield: 68.0%; MP: 150-152oC; 1H NMR (400 MHz, DMSO-d6): δ 8.037(d, 1H, J= 1.82 Hz), 7.834-7.811(dd, 1H, J= 1.82 Hz, J= 7.98 Hz), 7.297-7.273(d, 2H, J= 8.32 Hz), 7.140-7.125(d, 1H, J= 8.02 Hz),6.884-6.854(d, 2H, J= 8.32 Hz),5.449-5.416(dd, 1H, JHH”= 4.00 Hz, JHH’= 12.38 Hz), 3.791(s, 3H), 3.787-3.634(quartet, 1H, JH’H”= 18.52 Hz, JHH’= 12.41 Hz), 3.372-3.325(dd, 1H, JH’H”= 18.52 Hz, JHH”= 3.97 Hz), 1.987(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 22.75, 37.84, 56.35, 64.11, 114.3, 119.62, 126.3, 127.47, 130.27, 132.91, 136.48, 147.07, 154.19, 158.23, 158.53, 170.33; ESI-MS: 356.2 (M+1).
4-(1-acetyl-5-(2-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-nitrophenol (4c)
Yield: 95.3%; MP: 141-143oC; 1H NMR (400 MHz, DMSO-d6): δ 8.452(d, 1H, J= 2.13 Hz), 7.863-7.849(dd, 1H, J= 1.99 Hz, J= 8.24 Hz), 7.517-7.498(d, 2H, J= 1.76 Hz, J= 7.83 Hz), 7.305-7.271(m, 1H), 7.207-7.117(m, 3H),6.250-6.228(dd, 1H, JHH”= 3.92 Hz, JHH’= 12.19 Hz), 3.734-3.685(quartet, 1H, JH’H”= 18.22 Hz, JHH’= 12.19 Hz), 3.382-3.337(dd, 1H, JH’H”= 18.29 Hz, JHH”= 3.90 Hz), 1.902(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.46, 37.51, 60.81, 120.01, 125.99, 126.59, 128.74, 128.22, 128.53, 130.11, 138.04, 137.94, 155.07, 156.16, 173.9; ESI-MS: 359.9 (M+1).
4-(1-acetyl-5-(3-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-nitrophenol (4d)
Yield: 77.0%; MP: 149-151oC; 1H NMR (400 MHz, DMSO-d6): δ 8.474(d, 1H, J= 1.81 Hz), 7.865-7.831(dd, 1H, J= 1.77 Hz, J= 8.17 Hz), 7.735-7.693(m, 1H), 7.528-7.468(m, 3H),7.213-7.191(d, 1H, J= 8.14 Hz),5.675-5.646(dd, 1H, JHH”= 3.77 Hz, JHH’= 11.90 Hz), 3.716-3.669(quartet, 1H, JH’H”= 17.94 Hz, JHH’= 11.86 Hz), 3.368-3.327(dd, 1H, JH’H”= 17.93Hz, JHH”= 3.83 Hz), 1.902(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.12, 37.53, 63.96, 121.39, 124.93, 125.6, 126.3, 127.44, 131.41, 129.3, 133.83, 136.42, 154.05, 156.12, 162.54, 172.14; ESI-MS: 360.4 (M+1).
4-(1-acetyl-5-(4-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-nitrophenol (4e)
Yield: 57.0%; MP: 157-160oC; 1H NMR (400 MHz, DMSO-d6): δ 8.469(d, 1H, J= 2.0 Hz), 7.868-7.836(dd, 1H, J= 2.04 Hz, J= 8.49 Hz), 7.504-7.488(d, 1H, J= 8.19 Hz), 7.415-7.393(d, 1H, J= 8.49 Hz), 7.216-7.199(d, 1H, J= 8.19 Hz), 5.636-5.601(dd, 1H, JHH”= 4.11 Hz, JHH’= 12.80 Hz), 3.622-3.581(quartet, 1H, JH’H”= 18.11 Hz, JHH’= 12.78 Hz), 2.994-2.959(dd, 1H, JH’H”= 18.26 Hz, JHH”= 4.08 Hz), 2.049(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.31, 39.16, 64.72, 121.56, 128.05, 127.47, 128.52, 130.29, 129.41, 132.71, 135.95, 136.92, 155.68, 157.82, 173.66; ESI-MS: 360.3 (M+1).
4-(1-acetyl-5-(3,4-dimethoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4f)
Yield: 78.4%; MP: 176-178oC;1H NMR (400 MHz, DMSO-d6): δ 7.576(s, 1H), 7.520(s, 1H), 7.028-6.984(m, 2H), 6.783(s, 1H), 5.539-5.507(dd, 1H, JHH”= 3.82 Hz, JHH’= 12.45 Hz), 3.812-3.810(d, 6H), 3.749(s, 3H), 3.767-3.620(quartet, 1H, JH’H”= 17.89 Hz, JHH’= 12.44 Hz), 3.357-3.310(dd, 1H, JH’H”= 17.90 Hz, JHH”= 3.82 Hz), 2.004(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 21.99, 35.78, 58.34, 64.66, 111.39, 112.43, 113.09, 119.9, 123.15, 123.87, 124.53, 134.71, 147.91, 148.05, 149.14, 149.35, 153.41, 168.45; ESI-MS: 416.2 (M+1).
4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4g)
Yield: 77.0%; MP: 162-164oC; 1H NMR (400 MHz, DMSO-d6): δ 7.818(s, 1H), 7.413(s, 1H), 7.309-7.293(d, 1H, J= 7.92 Hz), 6.879-6.860(d, 1H, J= 7.92 Hz), 5.561-5.529(dd, 1H, JHH”= 3.90 Hz, JHH’= 12.60 Hz), 3.848(s, 3H), 3.795(s, 3H), 3.695-3.647(quartet, 1H, JH’H”= 18.00 Hz, JHH’= 12.60 Hz), 3.358-3.304(dd, 1H, JH’H”= 18.02 Hz, JHH”= 3.90 Hz), 1.865(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 22.16, 36.94, 56.35, 56.89, 64.11, 112.88, 114.3, 124.13, 124.53, 127.38, 132.91, 136.12, 149.1, 152.37, 154.7, 158.53, 169.04; ESI-MS: 386.1 (M+1).
4-(1-acetyl-5-(2-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4h)
Yield: 80.5%; MP: 154-155oC; 1H NMR (400 MHz, DMSO-d6): δ 7.654-7.649(d, 1H), 7.492-7.402(m, 3H), 7.242-7.107(m, 2H), 5.356-5.316(dd, 1H, JHH”= 3.88 Hz, JHH’= 12.36 Hz), 3.818(s, 3H), 3.752-3.705(quartet, 1H, JH’H”= 17.98 Hz, JHH’= 12.41 Hz), 3.385-3.339(dd, 1H, JH’H”= 18.00 Hz, JHH”= 3.85 Hz), 1.977(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 19.67, 37.51, 55.89, 60.81, 114.12, 123.87, 125.6, 126.59, 128.22, 128.53, 128.78, 133.57, 133.81, 135.44, 146.82, 151.28, 155.32, 165.97; ESI-MS: 390.1 (M+1).
4-(1-acetyl-5-(3-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4i)
Yield: 84.1%; MP: 146-148oC;1H NMR (400 MHz, DMSO-d6):δ 7.704-7.686(m, 2H), 7.373-7.348(m, 4H), 5.659-5.627(dd, 1H, JHH”= 3.29 Hz, JHH’= 11.78 Hz), 3.821(s, 3H), 3.702-3.655(quartet, 1H, JH’H”= 17.49 Hz, JHH’= 11.85 Hz), 3.361-3.328(dd, 1H, JH’H”= 17.46 Hz, JHH”= 3.30 Hz), 1.863(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 20.33, 38.46, 56.89, 63.96, 114.71, 125.14, 127.18, 124.93, 125.6, 126.66, 127.43, 129.3, 133.83, 137.78, 149.21, 152.59, 158.16, 167.53; ESI-MS: 390.1 (M+1).
4-(1-acetyl-5-(4-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4j)
Yield: %; MP: 157-160oC; 1H NMR (400 MHz, DMSO-d6): δ 7.705(s, 1H), 7.426-7.387(t, 3H), 7.374-7.369(d, 2H), 5.633-5.601(dd, 1H, JHH”= 3.96 Hz, JHH’= 12.26 Hz), 3.827(s, 3H), 3.698-3.651(quartet, 1H, JH’H”= 17.88 Hz, JHH’= 12.26 Hz), 3.350-3.307(dd, 1H, JH’H”= 17.88 Hz, JHH”= 3.96 Hz), 1.878(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 24.58, 40.11, 58.82, 64.11, 116.19, 124.75, 126.46, 128.52, 129.21, 132.71, 134.79, 136.92, 149.3, 151.93, 156.62, 170.24; ESI-MS: 390.1 (M+1).
4-(1-acetyl-5-(3-bromophenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4k)
Yield: 79.8%; MP: 172-175oC; 1H NMR (400 MHz, DMSO-d6): δ 7.911(s, 1H), 7.769(s, 1H), 7.525-7.428(m, 3H), 7.251-7.193(m, 2H), 5.623-5.610(dd, 1H, JHH”=3.99 Hz, JHH’= 12.70 Hz), 3.788(s, 3H), 3.704-3.661(quartet, 1H, JH’H”= 17.91 Hz, JHH’= 12.68 Hz), 3.359-3.302(dd, 1H, JH’H”= 17.96 Hz, JHH”= 4.01 Hz), 1.87(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 24.47, 39.45, 59.22, 68.86, 116.35, 123.6, 123.65, 123.93, 125.43, 129.82, 130.38, 130.49, 139.5, 149.04, 150.86, 154.18, 169.96; ESI-MS: 435.4 (M+1).
4-(1-acetyl-5-(4-bromophenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4l)
Yield: 88.3%; MP: 128-130oC; 1H NMR (400 MHz, DMSO-d6): δ 7.898(s, 1H), 7.784 (s, 1H), 7.632-7.601(d, 2H, J= 7.70 Hz), 7.285-7.267(d, 2H, J= 7.72 Hz), 5.649-5.616(dd, 1H, JHH”= 4.12 Hz, JHH’= 12.88 Hz), 3.825(s, 3H), 3.796-3.643(quartet, 1H, JH’H”= 18.07 Hz, JHH’= 12.88 Hz), 3.355-3.299(dd, 1H, JH’H”= 18.05 Hz, JHH”= 4.16 Hz), 1.87(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 24.58, 38.98, 57.77, 68.35, 116.18, 122.13, 122.76, 125.56, 129.95, 131.12, 134.71, 135.96, 148.76, 151.15, 156.34, 170.1; ESI-MS: 435.2 (M+1).
4-(1-acetyl-5-(2,6-dimethoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-methoxy-6-nitrophenol (4m)
Yield: 50.6%; MP: 135-138oC; 1H NMR (400 MHz, DMSO-d6): δ 7.926(s, 1H), 7.747(s, 1H), 7.293-7.213(m, 3H), 6.059-6.025(dd, 1H, JHH”= 3.91 Hz, JHH’= 12.49 Hz), 3.781(s, 3H), 3.749(s, 6H), 3.722-3.674(quartet, 1H, JH’H”= 17.97 Hz, JHH’= 12.55 Hz), 3.437-3.385(dd, 1H, JH’H”= 17.92 Hz, JHH”= 3.88 Hz), 2.01(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 21.76, 37.77, 56.16, 63.112, 108.54, 114.27, 123.85, 124.53, 127.86, 135.58, 146.82, 149.14, 152.49, 159.62, 168.19; ESI-MS: 416.1 (M+1).
4-(1-acetyl-5-(3,4-dimethoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-aminophenol (5a)
Yield: 85.7%; MP: 155-159oC; 1H NMR (400 MHz, DMSO-d6): δ 7.112-7.106(d, 1H, J= 1.23 Hz), 6.986-6.954(m, 2H), 6.873-6.854(d, 1H, J= 7.60 Hz), 6.774-6.755(d, 1H, J= 7.91 Hz), 6.498-6.493(d, 1H, J= 1.67 Hz), 5.612-5.579(dd, 1H, JHH”= 3.82 Hz, JHH’= 12.09 Hz), 3.800(s, 3H), 3.742(s, 3H), 3.697-3.649(quartet, 1H, JH’H”= 17.97 Hz, JHH’= 12.11 Hz), 3.350-3.303(dd, 1H, JH’H”= 17.94 Hz, JHH”= 3.80 Hz), 1.861(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 22.68, 38.03, 56.33, 64.06, 110.92, 111.83, 115.48, 116.60, 120.91, 122.58, 124.18, 133.62, 136.36, 149.47, 150.47, 156.97, 159.58, 172.44; ESI-MS: 356.7 (M+1).
4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-aminophenol (5b)
Yield: 80.4%; MP: 143-145oC; 1H NMR (400 MHz, DMSO-d6): δ 7.320-7.300(d, 1H, J= 8.05 Hz), 7.066-7.042(d, 1H, J= 1.58 Hz, J= 7.83 Hz), 6.885-6.855(d, 1H, J= 8.05 Hz), 6.727-6.708(d, 1H, J= 7.82 Hz), 6.248-6.243(d, 1H, J= 1.56 Hz), 5.420-5.386(dd, 1H, JHH”= 3.92 Hz, JHH’= 12.39 Hz), 3.790(s, 3H), 3.685-3.633(quartet, 1H, JH’H”= 17.99 Hz, JHH’= 12.39 Hz), 3.372-3.325(dd, 1H, JH’H”= 18.00 Hz, JHH”= 3.96 Hz), 1.984(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 22.99, 38.24, 56.86, 65.64, 115.21, 115.59, 118.75, 124.12, 129.52, 133.94, 134.64, 136.08, 149.07, 156.61, 161.48, 172.78; ESI-MS: 326.2 (M+1).
4-(1-acetyl-5-(2-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-aminophenol (5c)
Yield: 90.0%; MP: 135-138oC; 1H NMR (400 MHz, DMSO-d6): δ 7.508-7.484(dd, 1H, J= 1.85 Hz, J= 7.96 Hz), 7.295-7.113(m, 3H), 6.775-6.756(d, 1H, J= 8.17 Hz), 6.543-6.538(d, 1H, J= 2.04 Hz), 6.228-6.194(dd, 1H, JHH”= 4.11 Hz, JHH’= 12.55 Hz), 3.721-3.674(quartet, 1H, JH’H”= 18.39 Hz, JHH’= 12.55 Hz), 3.364-3.317(dd, 1H, JH’H”= 18.42 Hz, JHH”= 4.09 Hz), 1.893(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 24.5, 39.73, 62.83, 116.7, 117.41, 122.78, 127.8, 129.03, 129.13, 129.83, 132.21, 133.97, 135.15, 138.74, 148.56, 157.24, 171.44; ESI-MS: 331.1 (M+1).
4-(1-acetyl-5-(3-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-aminophenol (5d)
Yield: 85.6%; MP: 141-145oC; 1H NMR (400 MHz, DMSO-d6): δ 7.789-7.787(m, 1H), 7.365-7.166(m, 3H), 6.937-6.913(dd, 1H, J= 1.78 Hz, J= 7.90 Hz), 6.705-6.686(d, 1H, J= 7.90 Hz), 6.360-6.355(d, 1H, J= 1.78 Hz), 5.535-5.503(dd, 1H, JHH”= 3.82 Hz, JHH’= 12.00 Hz), 3.689-3.638(quartet, 1H, JH’H”= 18.21 Hz, JHH’= 12.06 Hz), 3.343-3.296(dd, 1H, JH’H”= 18.21 Hz, JHH”= 3.80 Hz), 1.997(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 22.98, 37.94, 64.81, 115.03, 116.64, 122.27, 125.38, 126.5, 127.11, 128.33, 130.24, 132.46, 134.73, 135.0, 148.05, 158.31, 170.52; ESI-MS: 331.0 (M+1).
4-(1-acetyl-5-(4-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-aminophenol (5e)
Yield: 85.0%; MP: 152-154oC; 1H NMR (400 MHz, DMSO-d6): δ 7.521-7.487(d, 2H, J= 8.10 Hz), 7.435-7.409(d, 2H, J= 8.10 Hz), 7.015-6.991(dd, 1H, J= 1.85 Hz, J= 8.14 Hz), 6.780-6.761(d, 1H, J= 8.14 Hz), 6.552-6.547(d, 1H, J= 1.85 Hz), 5.606-5.573(dd, 1H, JHH”= 4.02 Hz, JHH’= 12.20 Hz), 3.694-3.646(quartet, 1H, JH’H”= 18.16 Hz, JHH’= 12.20 Hz), 3.350-3.303(dd, 1H, JH’H”= 18.16 Hz, JHH”= 4.00 Hz), 1.874(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 25.38, 46.53, 68.81, 116.38, 123.8, 128.77, 137.02, 129.41, 136.91, 135.41, 140.45, 143.82, 152.75, 161.66, 173.22; ESI-MS: 331.4 (M+1).
4-(1-acetyl-5-(3,4-dimethoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5f)
Yield: 95.0%; MP: 168-170oC;1H NMR (400 MHz, DMSO-d6): δ 7.187-7.82(d, 1H, J= 1.78 Hz), 7.066-7.021(m, 2H), 6.624(s, 1H), 6.615(s, 1H), 5.652-5.620(dd, 1H, JHH”= 3.56 Hz, JHH’= 11.72 Hz), 3.875(s, 3H), 3.849(s, 3H), 3.742(s, 3H), 3.701-3.654(quartet, 1H, JH’H”= 18.08 Hz, JHH’= 11.72 Hz), 3.445-3.308(dd, 1H, JH’H”= 18.08 Hz, JHH”= 3.56 Hz), 1.863(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.69, 39.35, 57.97, 58.71, 66.38, 111.55, 113.96, 114.89, 119.52, 122.93, 126.0, 133.18, 137.54, 138.36, 152.09, 152.73, 152.99, 159.68, 172.65; ESI-MS: 386.5 (M+1).
4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5g)
Yield: 80.8%; MP: 150-152oC;1H NMR (400 MHz, DMSO-d6): δ 7.314-7.293(d, 1H, J= 8.12 Hz), 6.885-6.860(d, 1H, J= 8.12 Hz), 6.563-6.558(d, 1H, J= 1.44 Hz), 6.615(d, 1H, J= 1.44 Hz), 5.545-5.513(dd, 1H, JHH”= 3.88 Hz, JHH’= 12.18 Hz), 3.875(s, 3H), 3.827(s, 3H), 3.684-3.637(quartet, 1H, JH’H”= 18.34 Hz, JHH’= 12.20 Hz), 3.351-3.298(dd, 1H, JH’H”= 18.34 Hz, JHH”= 3.9 Hz), 1.895(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.54, 38.64, 59.46, 66.77, 111.37, 115.55, 115.83, 128.74, 131.38, 135.11, 135.75, 136.13, 151.11, 155.85, 161.19, 172.5; ESI-MS: 356.3 (M+1).
4-(1-acetyl-5-(2-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5h)
Yield: 74.0%; MP: 137-140oC; 1H NMR (400 MHz, DMSO-d6): δ 7.476-7.438(m, 1H), 7.140-7.127(m, 3H), 6.591(s, 1H), 6.031(s, 1H), 5.962-5.930(dd, 1H, JHH”= 3.52 Hz, JHH’= 11.86 Hz), 3.849(s, 3H), 3.703-3.666(quartet, 1H, JH’H”= 18.20 Hz, JHH’= 11.86 Hz), 3.358-3.311(dd, 1H, JH’H”= 18.20 Hz, JHH”= 3.52 Hz), 2.019(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.74, 39.25, 58.15, 63.57, 111.68, 116.07, 129.12, 130.74, 130.81, 131.08, 132.28, 136.49, 136.74, 137.34, 140.97, 151.93, 161.36, 172.58; ESI-MS: 361.2 (M+1).
4-(1-acetyl-5-(3-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5i)
Yield: 92.7%; MP: 162-164oC; 1H NMR (400 MHz, DMSO-d6): δ 7.790(m, 1H), 7.342-7.251(m, 3H), 6.711(s, 1H), 6.228(s, 1H), 5.664-5.632(dd, 1H, JHH”= 2.93 Hz, JHH’= 11.37 Hz), 3.826(s, 3H), 3.709-3.652(quartet, 1H, JH’H”= 17.68 Hz, JHH’= 11.40 Hz), 3.364-3.317(dd, 1H, JH’H”= 17.65 Hz, JHH”= 2.96 Hz), 1.866(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 24.06, 41.26, 59.49, 67.24, 111.47, 116.08, 127.23, 127.86, 128.58, 130.99, 134.79, 135.59, 151.49, 160.73, 172.67; ESI-MS: 361.1 (M+1).
4-(1-acetyl-5-(4-chlorophenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5j)
Yield: 70.5%; MP: 158-160oC; 1H NMR (400 MHz, DMSO-d6): δ 7.541-7.526(d, 2H, J= 7.94 Hz), 7.496-7.477(d, 2H, J= 7.94 Hz), 6.544(s, 1H), 6.108(s, 1H), 5.623-5.591(dd, 1H, JHH”= 3.83 Hz, JHH’= 12.08 Hz), 3.837(s, 3H), 3.798-3.751(quartet, 1H, JH’H”= 18.17 Hz, JHH’= 12.10 Hz), 3.376-3.323(dd, 1H, JH’H”= 18.21 Hz, JHH”= 3.84 Hz), 1.868(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.17, 38.07, 57.49, 65.2, 109.47, 114.42, 129.06, 130.84, 133.8, 134.44, 135.61, 137.46, 149.98, 159.95, 170.71; ESI-MS: 361.1 (M+1).
4-(1-acetyl-5-(3-bromophenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5k)
Yield: 70.0%; MP: 172-175oC; 1H NMR (400 MHz, DMSO-d6): δ 7.598-7.595(m, 1H), 7.524-7.496(m, 1H), 7.272-7.250(m, 1H), 7.139-7.093(m, 1H), 6.556(s, 1H), 6.403(s, 1H), 5.515-5.483(dd, 1H, JHH”= 3.85 Hz, JHH’= 11.91 Hz), 3.676-3.629(quartet, 1H, JH’H”= 17.99 Hz, JHH’= 11.90 Hz), 3.334-3.287(dd, 1H, JH’H”= 18.00 Hz, JHH”= 3.85 Hz), 1.994(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.84, 39.21, 59.28, 66.74, 111.7, 115.89, 126.15, 127.73, 131.79, 131.96, 132.67, 136.63, 137.41, 151.67, 163.14, 172.24; ESI-MS: 406.0 (M+1).
4-(1-acetyl-5-(4-bromophenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5l)
Yield: 76.0%; MP: 140-142oC; 1H NMR (400 MHz, DMSO-d6): δ 7.621-7.602(d, 1H, J= 8.24 Hz), 7.285-7.283(d, 1H, J= 8.24 Hz), 6.498(s, 1H), 6.400(s, 1H), 5.608-5.575(dd, 1H, JHH”= 4.12 Hz, JHH’= 12.10 Hz), 3.688-3.641(quartet, 1H, JH’H”= 18.16 Hz, JHH’= 12.07 Hz), 3.341-3.293(dd, 1H, JH’H”= 18.16 Hz, JHH”= 4.12 Hz), 1.857(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 24.23, 40.21, 58.16, 66.0, 110.47, 114.12, 124.23, 133.58, 133.69, 135.84, 139.47, 153.05, 160.21, 172.58; ESI-MS: 406.3 (M+1).
4-(1-acetyl-5-(2,6-dimethoxyphenyl)-4,5-dihydro-3-pyrazolyl)-2-amino-6-methoxyphenol (5m)
Yield: 63.0%; MP: 128-130oC; 1H NMR (400 MHz, DMSO-d6): δ 7.279-7.242(m, 1H), 6.838-6.769(m, 3H), 6.467(s, 1H), 6.421(s, 1H), 6.005-5.969(dd, 1H, JHH”= 4.28 Hz, JHH’= 12.56 Hz), 3.740(s, 3H), 3.707-3.658(quartet, 1H, JH’H”= 18.44 Hz, JHH’= 12.56 Hz), 3.415-3.365(dd, 1H, JH’H”= 18.44 Hz, JHH”= 4.28 Hz), 1.998(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 23.05, 40.43, 59.47, 58.55, 65.45, 110.44, 114.40, 128.51, 133.06, 135.82, 138.14, 151.98, 158.57, 161.84, 173.2; ESI-MS: 385.8 (M+1).
a)b)
c)d)
Figure S1. A close-up view of the binding interactions of the docked ligand in Mycobacterium tuberculosis enoyl reductase (PDB code 2H7I). a) Binding interactions of compound 6l and crystal ligand with the neighboring residues; b) dispersion interactions of compound 6l fragments (in sticks) with neighboring residues (in surface, yellow for pyrazoline ring, blue for benzoxazole ring); c) and d) The fit of isoniazid and compound 6l (in spheres) in the active site, respectively. Color coding: Ligand carbon in yellow (docked geometry) or green (crystal geometry/benzoxazole core) or magenta (pyrazoline core) or red (phenyl ring), protein and co-factor carbon in cyan, nitrogen in blue, oxygen in red, bromine in brown, sulfur in light yellow, phosphorous in light brown, hydrogen in white. The figure was prepared using Pymol, ver. 0.99.
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