Synthesis, Biological Evaluation, Molecular Docking and ADMET studies of some Isoxazole based Amides

SushamaKauthale1, Sunil Tekale1, Manoj Damale2, Jaiprakash Sangshetti3, Rajendra Pawar1*

1Department of Chemistry, Deogiri College, Station Road, Aurangabad (MS) 431 005 India.

2Department of Pharmaceutical Chemistry, Shri. Bhagwan College of Pharmacy, Aurangabad (MS) 431003 India.

3Y.B. Chavan College of Pharmacy, Dr. RafiqZakaria Campus, Aurangabad (MS) 431001 India.

[Corresponding author Email:

Supporting information

Procedure for the synthesis of isoxazole amides:

  • Procedure for the synthesis of A1: A solution of thiosemicarbazide (5 mmol) in acetone (5 mL) was reacted with 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (5 mmol) in the presence of sodium bicarbonate (7.5 mmol) with continuous stirring under ice cold condition. After completion of reaction (monitored by TLC); acetone was evaporated under reduced pressure, the resulting solid precipitated was filtered, washed (3 x 5 mL) with water and then recrystallized from ethanol.
  • General procedure for the synthesis of amides A2-A13: Triethyl amine (6 mmol) was added to an ice cold solution of amine (5 mmol) in dichloromethane (5 mL) followed by portion wise addition of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (5 mmol). Contents were then slowly warmed to room temperature and stirred for 1 h. After completion of the reaction as monitored by TLC, DCM was evaporated under vacuum on rotary evaporator; the reaction mixture was basified with an ice cold aqueous saturated sodium bicarbonate and extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated to get the crude product which was further recrystallized by triturating with DCM and n-hexane.
  • Procedure for the synthesis of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamide (A14): A mixture of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (5 mmol) in concentrated ammonia (10 mL) was refluxed at 100 oC for 1 h in a sealed tube. After completion of reaction as monitored by TLC, the contents were cooled to room temperature and the precipitated product was filtered off under vacuum. The product was washed with ice-cold water (3 x 5 mL) and dried which was further recrystallized from ethanol.

The synthesized compounds were characterized by analysis of spectroscopic data -1H NMR, 13C NMR, IR and mass.

Spectral Data of isoxazole based amides (A1-A14)

Amide A1- White solid, M. P. 175-177 oC; IR (KBr) cm-1 3386 (-NH2), 3210 (-NH), 2976 (-CH3), 1630 (-C=O amide), 1462 (C=N), 1251 (C-O), 829 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm 7.46 (m, 4H),6.07 (s, 2H),3.28 (s, 1H),2.55 (s, 1H),1.13 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm168.71, 159.96,157.67,150.06,132.02,131.12,130.36,129.11,128.54,126.48,

114.72,12.30; Mass: 351.1 (M+41)+.

Amide A2- White solid, M. P. 171-173 oC; IR (KBr) cm-1 3226 (NH –amide), 2950 (-CH3), 1660 (C=O), 1494 (C=N), 1296 (C-O), 825 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm10.21 (brs, 1H, -NH), 7.59 (d, 3H),7.47 (d, 3H),7.32 (d, 2H), 2.72 (s, 3H).13C NMR (100.6 MHz, CDCl3) δ ppm 174.73; 169.60,162.21,160.48,159.85,137.53,133.04,130.96,129.50,128.43,126.68,121.28,114.39,78.4,12.78; Mass: 347 (M+1)+.

Amide A3- Off white solid, M. P. 158-160 oC; IR (KBr) cm-1 3230 (-NH), 2980 (CH3), 1662 (C=O), 1450 (C=N), 1220 (C-O), 820 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm 7.57 (d, 3H), 7.47 (m, 3H),7.06 (d, 2H),2.67 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm169.45, 159.37,157.24,134.96,132.52,131.64,131.16,129.48,127.51,126.99,121.70,115.15,114.43,78.75,12.25; Mass : 331.0 (M+1)+.

Amide A4- White solid, M. P. 151-153 oC; IR (KBr) cm-1 3197 (N-H), 2960 (-CH3), 1606 (C=O), 1467 (C=N), 1215 (C-O), 820 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm7.63 (m, 2H), 7.52 (m, 1H),7.44 (m, 1H),7.0 (d, 1H), 6.93 (s, 1H), 6.82 (m, 1H),2.81 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm175.41,159.13,157.79,156.15,153.70,133.77,132.45,131.89,130.54,127.91,127.33,122.13,121.31,119.46,116.73,111.72,13.20; Mass: 365 (M+1)+.

AmideA5- White solid, M. P. 148-150 oC; IR (KBr) cm-1 3210 (-NH), 2949 (CH3), 1650 (C=O),1465 (C=N), 1160 (C-O), 825 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm 10.22 (s, 1H), 7.66 (d, 2H),7.57 (d, 1H),7.48 (m, 3H),7.22 (d, 2H),2.52 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm169.52, 159.77,144.69,137.63, 132.49,131.10,129.44,127.41,126.92,123.84,121.30,118.76,116.21,114.30,12.26; Mass: 397.1 (M+1)+.

AmideA6- White solid, M. P. 111-113 oC; IR (KBr) cm-1 3230 (-NH), 2966 (-CH3), 1680 (C=O), 1427 (C=N), 1259 (C-O), 822 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm7.42 (m, 3H), 7.27 (s, 1H),7.0 (m, 2H),6.89 (m, 2H), 5.45 (brs, 1H),4.32 (s, 2H),2.75 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm174.22,163.36, 160.95,158.16,133.99,133.10,131.78,130.22,129.28,127.65,127.47,115.54,115.33, 111.76,42.83,12.95; Mass: 345.1 (M+1)+

AmideA7- Off white solid, M. P. 172-174 oC; IR (KBr) cm-1 3260 (-NH), 2920 (-CH3), 1660 (C=O), 1473 (C=N), 1661 (C-O), 875 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm11.89 (brs, 1H, -NH),7.44 (m, 3H),7.30 (d, 1H),6.94-6.97 (dd, 2H),2.62 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm172.73, 159.41,159.35,135.96,133.50,131.64,130.05,127.25,126.82,114.05,112.34,12.79; Mass: 320 (M+1)+.

AmideA8-Faint brown solid, M. P. 161-163 oC; IR (KBr) cm-1 3230 (NH), 2920 (-CH3), 1680 (C=O), 1429 (C=N), 1150 (C-O), 819 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm12.55 (s, 1H),7.25-7.81 (m, 8H),2.74 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm171.29, 161.21,159.83,158.95,146.84,132.63,131.65,131.11,130.95,129.46,127.39,126.85,125.91,123.47,121.28,119.55,112.84,12.59; Mass: 370 (M+1) +.

AmideA9- Faint brown solid, M. P. 124-126 oC; IR (KBr) cm-1 3250 (-NH), 2930 (-CH3), 1660 (C=O), 1400 (C=N), 1190 (C-O), 840 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm7.35-7.51 (m, 4H), 3.56 (s, 4H),3.15 (s, 4H), 2.56 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm170.24,162.25,159.23, 133.27,131.42,130.18,127.85,127.27,112.26,66.27,47.59,42.46,12.13, Mass: 307.1 (M+1)+.

AmideA10- Off white solid, M. P. 116-118 oC; IR (KBr) cm-1 3269 (-NH), 2941 (-CH3), 1640 (C=O), 1450 (C=N), 1180 (C-O), 825 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm7.27-7.51 (m, 4H), 3.54 (s, 2H), 3.12 (s, 2H), 2.58 (s, 3H),1.49 (s, 4H), 1.05 (s, 2H); 13C NMR (100.6 MHz, CDCl3) δ ppm169.38, 161.99, 159.37,133.32,131.63,131.11,130.08,128.05,127.08,113.17,48.23,42.90,25.26,12.10; Mass: 305.1 (M+1)+.

AmideA11-Faint pink solid, M. P. 179-181 oC; IR (KBr) cm-1 3370 (-NH), 2950 (-CH3), 1620 (C=O), 1420 (C=N), 1236 (C-O), 825 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm8.12 (brs, 1H, -NH), 7.76-7.78 (d, 1H),7.51-7.55 (d, 2H),7.37-7.43 (m, 3H),7.18-7.23 (m, 3H),6.62 (s, 1H), 6.61-6.62 (dd, 1H),2.85 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm175.66, 159.63,157.82,134.64,133.90,132.27,131.96,131.83,130.88,128.81,127.91,127.75,126.16,126.08,125.88,125.79,125.60,119.65,119.38, 112.35,13.38; Mass : 363.54 (M+1)+.

AmideA12- White solid, M. P. 119-121 oCIR (KBr) cm-1 3260 (-NH), 2920 (-CH3), 1690 (C=O), 1450 (C=N), 1257 (C-O), 820 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm7.25-7.58 (m, 5H), 6.97-7.63 (d, 4H),2.78 (s, 3H),2.25 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm174.83,159.07,158.00,134.65,132.22,131.85,131.11,130.47,129.50,129.19,127.74,126.41,119.93,112.25,45.44, 20.85,13.10; Mass: 327.56 (M+1)+.

AmideA13- Off white solid, M. P. 122-124 oC; IR (KBr) cm-1 3270 (-NH), 2931 (-CH3), 1680 (C=O), 1436 (C=N), 1242 (C-O), 860 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm 8.09 (s, 1H),7.89 (s, 1H), 7.61 (s, 3H),7.42 (s, 2H),7.25 (s, 1H),2.82 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm175.54,159.41,157.87,148.51,138.32,134.13,132.55,131.71,130.57,129.84,127.99,

127.19,125.30,119.17,114.54,111.72,13.40, Mass: 358.54 (M+1)+.

AmideA14- White solid, M. P. 138-140 oC;IR (KBr) cm-1 3390 (-NH), 2933 (-CH3), 1675 (C=O), 1448 (C=N), 1251 (C-O), 898 (C-Cl);1H NMR (400 MHz, CDCl3) δ ppm7.44-7.54 (m, 4H), 6.95-7.35 (2H, -NH2),2.65 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ ppm170.11,162.61,

159.56,132.81,131.44,131.11,129.44,127.85,126.95,113.55,12.26; Mass: 237.54 (M+1)+.