SYNTHESIS OF NOVEL 1, 5-DIHYDROBENZOTHIAZEPINE DERIVATIVES BY CONVENTIONAL AND MICROWAVE IRRADIATION METHODS AND THEIR PHARMACOLOGICAL ACTIVITIES
HTML Full TextReceived on 11 September, 2013; received in revised form, 17 October, 2013; accepted, 09 January, 2014; published 01 February, 2014
SYNTHESIS OF NOVEL 1, 5-DIHYDROBENZOTHIAZEPINE DERIVATIVES BY CONVENTIONAL AND MICROWAVE IRRADIATION METHODS AND THEIR PHARMACOLOGICAL ACTIVITIES
Venkata Rao Vutla*1, Rajendra Prasad Yejella 2 andRamarao Nadendla 1
Department of Pharmaceutical Chemistry, Chalapathi Institute of Pharmaceutical Sciences 1, Lam, Guntur, Andhra Pradesh, India
Department of Pharmaceutical Chemistry, University College of Pharmaceutical Sciences , Andhra University 2, Visakhapatnam, Andhra Pradesh, India
ABSTRACT: 1, 5-Dihydrobenzothiazepines are synthesized by conventional and microwave assisted synthesis methods. By microwave assisted synthesis, a considerable increase in the reaction rate has been observed and that too, with better yields. The compounds have been screened for antimicrobial and cytotoxic activity. 1, 5-Dihydrobenzothiazepines are prepared by the reaction of 1, 3-diarylprop-2-enones with o-aminothiophenol. All the products were tested for purity by tlc and characterized by elemental analysis, IR, 1H-NMR, 13C-NMR and mass spectral studies.
Keywords: |
4-Fluoroacetophenone, 1, 5-DihydroBenzothiazepine, 2-Aminothiophenol, piperidine, microwave irradiation
INTRODUCTION:The 1, 5-benzothiazepines 1 (1and 2) are important nitrogen- and sulfur-containing seven-membered heterocyclic compounds in drug research since they possess diverse bioactivities 2-9.
1,5-Benzothiazepines are the most well-known representatives of benzologs of 1, 4-thiazepine (3) and one of the three possible benzo-condensed derivatives, viz. 1, 4-(4), 4,1- (5) and 1, 5-benzothiazepines 10-13.
GENERAL STRUCTURES OF 1, 5-BENZOTHIAZEPINE
The 1, 5-benzothiazepine derivatives are of particular interest for lead discovery because they have been found active against different families of targets 14-24. The first molecule of 1, 5-benzothiazepine used clinically was diltiazem (6), followed by clentiazem (7), for their cardiovascular action. Some of the 1, 5-benzothiazepine derivatives were also used clinically for CNS disorders which includes thiazesim (8), clothiapine (9) and quetiapine (10). Therefore, the 1,5-Dihydrobenzothiazepines are useful compounds in the drug research which has stimulated the invention of a wide range of synthetic methods for their preparation and chemical transformations 25-45.
Microwave-induced organic reaction enhancement (MORE) chemistry is gaining popularity as a non-conventional technique for rapid organic synthesis. Important features of this technique are easy access to very high temperature, good control over energy input in a reaction; higher yields and rapid synthesis of organic compounds. The synthesized compounds were purified by recrystallization and chromatography. The compounds were characterized by 1H NMR and IR analysis. The compounds were tested for their antimicrobial and cytotoxic activity by standard methods.
MATERIALS AND METHODS: All the chemicals used in the work were of analytical grade and procured from sigma Aldrich, Visakhapatnam.
a) General procedure for synthesis of 1, 5-benzothiazepines (BP-1-20): To a solution of chalcone derivative in dry acidic methanol acidified by adding few drops of glacial acetic acid to it, 2-aminothiophenol was added. The mixture was then refluxed until a crystalline solid separates out. After cooling, the solid product was collected and washed with diethyl ether and cold methanol. The crude solid was recrystallized from ethanol.
SCHEME-1: (BP-1-20)
b) General procedure for synthesis of 1, 5-benzothiazepines (BP-1-20) by Microwave irradiation method: Equimolar quantities (0.001 mol) of chalcone derivatives and 2-aminothiopheno (0.001 mol) were mixed and dissolved in minimum amount (3 ml) of glacial acetic acid l. To this, piperidine (0.003 mol) was added slowly and mixed. The entire reaction mixture was microwave irradiated for about 2–6 min at 180 watts.Physical characterization data and Elemental Analysis dataof 1, 5-benzothiazepines were represented in table1 and 2.
TABLE 1: PHYSICAL CHARACTERIZATION DATA OF 1, 5-BENZOTHIAZEPINES (BP1-BP20)
TABLE 2: ELEMENTAL ANALYSIS DATA OF 1,5-BENZOTHIAZEPINES (BP1-BP20)
Compound | %Calculated | %Found | ||||
C | H | N | C | H | N | |
BP1 | 76.05 | 5.22 | 4.03 | 76.07 | 5.17 | 4.09 |
BP2 | 71.77 | 4.30 | 3.99 | 71.72 | 4.32 | 3.91 |
BP3 | 68.56 | 4.11 | 3.81 | 68.46 | 4.09 | 3.77 |
BP4 | 68.56 | 4.11 | 3.81 | 68.51 | 4.10 | 3.77 |
BP5 | 68.28 | 3.82 | 3.79 | 68.29 | 3.77 | 3.69 |
BP6 | 62.69 | 3.51 | 3.48 | 62.72 | 3.49 | 3.38 |
BP7 | 62.69 | 3.51 | 3.48 | 62.74 | 3.46 | 3.41 |
BP8 | 66.65 | 4.00 | 7.40 | 66.62 | 4.04 | 7.43 |
BP9 | 66.65 | 4.00 | 7.40 | 66.67 | 4.01 | 7.42 |
BP10 | 72.18 | 4.62 | 4.01 | 72.11 | 4.61 | 4.07 |
BP11 | 67.33 | 4.37 | 7.14 | 67.37 | 4.31 | 7.16 |
BP12 | 68.07 | 5.24 | 3.31 | 68.11 | 5.21 | 3.39 |
BP13 | 70.01 | 4.27 | 3.71 | 70.09 | 4.29 | 3.69 |
BP14 | 56.73 | 3.26 | 3.48 | 56.77 | 3.20 | 3.42 |
BP15 | 73.37 | 5.62 | 7.44 | 73.33 | 5.67 | 7.49 |
BP16 | 69.64 | 4.78 | 3.69 | 69.65 | 4.77 | 3.61 |
BP17 | 71.83 | 4.52 | 8.38 | 71.86 | 4.54 | 8.33 |
BP18 | 71.83 | 4.52 | 8.38 | 71.81 | 4.56 | 8.35 |
BP19 | 71.83 | 4.52 | 8.38 | 71.85 | 4.59 | 8.33 |
BP20 | 67.23 | 4.16 | 4.13 | 67.25 | 4.12 | 4.11 |
Spectral Data for 1, 5-benzothiazepines (BP1-BP20) are given below:
BP-1:
2,3-Dihydro-2-(4-methylphenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP1): Mol.wt:, 347.45,yield: 89%,mp: 141-1430C ,IR (KBr) (cm-1) : 1585 (C=N), 1505 (C=C), 1395 (C-N), 923 (C-F) and 654 (C-S).1H-NMR (CDCl3) ppm : 4.94 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.25 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.9 Hz, 1H, C3-H-3a), 3.04 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 2.40 (3H, s, Ar-CH3), 7.22 (1H, s, Ar-H), 7.61 (3H, m, Ar-H), 7.20-8.10 (8H, Ar-H).
BP-2:
2,3-Dihydro-2-(4-fluorophenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP2): Mol. wt: 351.41, Yield: 89%, M.P: 152-1540C, IR (KBr) (cm-1): 1625 (C=N), 1509 (C=C),1399 C-N), 689(C-S), 931 (C-F) , 1H-NMR (CDCl3) ppm : 5.27 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H),3.50 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.6 Hz, 1H, C3-H-3a), 2.97 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.05 (1H, s,Ar-H), 7.19 (3H, m, Ar-H), 7.20-8.09 (8H, Ar-H).
BP-3:
2,3-Dihydro-2-(4-chlorophenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP3): Mol. wt: 367.87, Yield: 93%, M.P:144-1450C, IR (KBr) (cm-1): 1595 (C=N ), 1502 (C=C), 1384 ( C-N), 778 (C-Cl), 921 (C-F) and 667 (C-S) 1H-NMR (CDCl3) ppm : 5.0 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.53 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.9 Hz, 1H, C3-H-3a), 3.39 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.25 (1H, s, Ar-H), 7.65 (3H, m, Ar-H), 7.22-8.08 (8H, Ar-H).
BP-4:
2,3-Dihydro-2-(2-chlorophenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP4): Mol. wt: 367.87, Yield: 71%, M.P:121-1230C, IR (KBr) (cm-1): 1596 (C=N), 1510 (C=C), 1365 (C-N), 688 (C-S), 923 (C-F) and 805 (C-Cl) 1H-NMR (CDCl3) ppm: 4.89 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.43 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.6 Hz, 1H, C3-H-3a), 3.36 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.12 (1H, s, Ar-H), 7.72 (3H, m, Ar-H), 6.95-7.60 (8H, Ar-H).
BP-5:
2,3-Dihydro-2-(2,4-difluorophenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP5): Mol. wt: 369.40,yield:75%,mp:139-1410C.IR (KBr) (cm-1) : 1612 ( C=N), 1501 ( C=C),1382 (C-N), 689 (C-S), 913 (C-F) and 944 (C-F) 1H-NMR (CDCl3) ppm : 5.31 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.36 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.9 Hz, 1H, C3-H-3a), 2.87 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.08 (1H, s, Ar-H), 7.30 (3H, m, Ar-H), 6.98-8.12 (7H, Ar-H).
BP-6:
2,3-Dihydro-2-(2,4-dichlorophenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP6): Mol. wt: 402.31,yield:86%,mp:118-1200C. IR (KBr) (cm-1) : 1593 ( C=N), 1502 ( C=C), 1382 ( C-N), 687 (C-S), 925 (C-F) and 805 (C-Cl) 1H-NMR (CDCl3) ppm : 5.10 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.27 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.6 Hz, 1H, C3-H-3a), 2.66 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.15 (1H, s, Ar-H), 7.20 (3H, m, Ar-H), 7.05-7.95 (7H, Ar-H).
BP-7:
2,3-Dihydro-2-(2-chloro-5-nitrophenyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP7): Mol. wt: 412.86, Yield: 77%, M.p: 165-1670C,IR (KBr) (cm-1) : 1588 (C=N), 1520 (N=O, asymmetric), 1505 ( C=C), 1382 ( C-N), 1340 (N=O, symmetric), 656 ( C-S), 933 (C-F) and 781 (C-Cl), 1H-NMR (CDCl3) ppm : 4.32 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.74 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.9 Hz, 1H, C3-H-3a), 3.51 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.09 (1H, s, Ar-H), 7.12 (3H, m, Ar-H), 6.98-8.10 (7H, Ar-H).
BP-8:
2,3-Dihydro-2-(3-nitrophenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP8): Mol. wt: 378.42, Yield: 82%, M.p: 143-1450C,IR (KBr) (cm-1) : 1580 (C=N), 1522 (N=O, asymmetric),1501 ( C=C), 1385 ( C-N), 1345 (N=O, symmetric), 924 (C-F) and 689 ( C-S), 1H-NMR (CDCl3) ppm : 5.42 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.38 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.6 Hz, 1H, C3-H-3a), 2.86 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.30 (1H, s, Ar-H), 7.80 (3H, m, Ar-H), 7.48-8.60 (8H, Ar-H).
BP-9:
2,3-Dihydro-2-(4-nitrophenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP9): Mol. wt: 378.42, Yield: 89%, M.p: 129-1310C,IR (KBr) (cm-1) : 1586 (C=N), 1515 (N=O, asymmetric), 1506 ( C=C), 1380 ( C-N), 1338 (N=O, symmetric), 925 (C-F) and 713 ( C-S), 1H-NMR (CDCl3) ppm : 5.42 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.47 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.7 Hz, 1H, C3-H-3a), 3.10 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.18 (1H, s, Ar-H), 7.25 (3H, m, Ar-H), 7.25-8.20 (8H, Ar-H).
BP-10:
2,3-Dihydro-2-(3-hydroxyphenyl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP10): Mol.wt: 349.42, Yield: 84%, M.p: 227-2290C,IR (KBr) (cm-1) : 1653 ( C=N), 1528 ( C-N), 1502 (C=C), 925 (C-F) and 694 (C-S), 1H-NMR (CDCl3) ppm : 3.85 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.34 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.0 Hz, 1H, C3-H-3a), 2.41 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.25 (1H, s, Ar-H), 7.30 (3H, m, Ar-H), 7.15-7.80 (8H, Ar-H), 6.85 (1H, s, Ar-OH).
BP-11:
2,3-Dihydro-2-(3-nitro-4-methylphenyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP11): Mol. wt: 392.45, Yield: 94%, M.p: 177-17980C,IR (KBr) (cm-1) : 1642 ( C=N), 1548 (N=O, asymmetric), 1510 (C=C), 1380 (C-N), 1338 (N=O, symmetric), 927 (C-F) and 668 (C-S), 1H-NMR (CDCl3) ppm : 4.16 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.23 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.9 Hz, 1H, C3-H-3a), 2.53 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 2.50 (3H, s, Ar-CH3), 7.30 (1H, s,Ar-H), 6.70 (3H, m, Ar-H), 7.45-8.78 (7H, Ar-H)
BP-12:
2,3-Dihydro-2-(3,4,5-trimethoxyphenyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP12): Mol. wt:423.50, Yield:8 %, M.p: 149-1510C, IR (KBr) (cm-1) : 1648 ( C=N), 1505 ( C=C), 1365 (C-N), 1225 (-O-CH3), 923 (C-F) and 678 (C-S), 1H-NMR (CDCl3) ppm : 3.06 (dd, J2,3a = 5.3 Hz, J2,3b = 12 Hz, 1H, C2-H), 2.83 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.9 Hz, 1H, C3-H-3a), 2.0 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.22 (1H, s,Ar-H), 6.60 (3H, m, Ar-H), 7.30-7.50 (6H, Ar-H), 3.70 (3H, s, Ar-OCH3), 3.88 (6H, s, 2XAr-OCH3)
BP-13:
2,3-Dihydro-2-(3,4-methelenedioxyphenyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP13): Mol.wt:377.47, Yield: 74%, M.p: 155-1570C,IR (KBr) (cm-1) : 1592 (C=N), 1502 ( C=C), 1370 (C-N),1232 (-O-CH2-O-), 921 (C-F) and 689 (C-S), 1H-NMR (CDCl3) ppm : 4.94 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.25 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.1 Hz, 1H, C3-H-3a), 3.14 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.25 (1H, s,Ar-H), 7.40 (3H, m, Ar-H), 6.10 (2H, s, O-CH2-O), 7.21-7.85 (7H, Ar-H)
BP-14:
2,3-Dihydro-2-(5-bromofuran-2-yl)-4-(4-fluoro phenyl)-1,5-benzothiazepine (BP14): Mol. wt: 402.28, Yield: 79%, M.p: 133-1350C, IR (KBr) (cm-1): 1602 (C=N), 1505 (C=C), 1340 (C-N), 664 (C-S), 933 (C-F) and 790 (C-Br) , 1H-NMR (CDCl3) ppm : 5.07 (dd, J2,3a = 5.3 Hz, J2,3b = 12 Hz, 1H, C2-H), 4.10 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.2 Hz, 1H, C3-H-3a), 3.39 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.10 (1H, s,Ar-H), 6.80 (3H, m, Ar-H), 6.80-7.30 (6H, Ar-H)
BP-15:
2,3-Dihydro-2-(4-dimethylaminophenyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP15): Mol. wt: 376.49, Yield: 88%, M.p: 115-1170C, IR (KBr) (cm-1): 1608 (C=N), 1509 (C=C), 1390 (C-N), 1175 (-N-(CH3)2), 933 (C-F) and 679 (C-S),NMR (CDCl3) ppm : 4.96 (dd, J2,3a = 5.3 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.83 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.2 Hz, 1H, C3-H-3a), 3.26 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 3.20 (6H, s, N-(CH3)2, 7.20 (1H, s,Ar-H), 7.45 (3H, m, Ar-H), 6.70-8.20 (8H, Ar-H)
BP-16:2,3-Dihydro-2-(3-methoxy-4-hydroxy phenyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP16): Mol.wt:379.45, Yield: 86%, M.p: 152-1540C, , IR (KBr) (cm-1): 3540 (O-H), 1598 (C=N), 1502 (C=C), 1378 (C-N), 1234 (-O-CH3) 913 (C-F), and 688 (C-S) NMR (CDCl3) ppm : 3.43 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 2.50 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.4 Hz, 1H, C3-H-3a), 1.03 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.20 (1H, s,Ar-H), 6.85 (3H, m, Ar-H), 7.15-7.90 (7H, Ar-H), 6.95 (1H, s, Ar-OH), 3.80 (3H, s, Ar-O-CH3)
BP-17:
2,3-Dihydro-2-(2-pyridinyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP17): Mol.wt:334.41, Yield: 78%, M.p: 112-1140C,1602 (C=N), 1510 (C=C), 1390 (C-N), 924 (C-F) and 677 (C-S) ,NMR (CDCl3) ppm : 4.91 (dd, J2,3a = 5.3 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.44 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.4 Hz, 1H, C3-H-3a), 1.05 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.15 (1H, s,Ar-H), 7.20 (3H, m, Ar-H), 7.10-8.15 (8H, Ar-H)
BP-18:
2,3-Dihydro-2-(3-pyridinyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP18): Mol.wt:334.41, Yield: 82%, M.p: 119-1210C, IR (KBr) (cm-1):1599 (C=N), 1506 (C=C), 1382 (C-N), 927 (C-F) and 698 (C-S), NMR (CDCl3) ppm : 4.38 (dd, J2,3a = 5.3 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.37 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.8 Hz, 1H, C3-H-3a), 1.07 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.25 (1H, s,Ar-H), 7.30 (3H, m, Ar-H), 6.75-8.90 (8H, Ar-H)
BP-19:
2,3-Dihydro-2-(4-pyridinyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP19): Mol.wt:334.41, Yield: 92%, M.p: 109-1110C, IR (KBr) (cm-1):1606 (C=N), 1508 (C=C), 1388 (C-N), 933 (C-F) and 654 (C-S), NMR (CDCl3) ppm : 4.67 (dd, J2,3a = 5.1 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.42 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.8 Hz, 1H, C3-H-3a), 2.50 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.20 (1H, s,Ar-H), 7.50 (3H, m, Ar-H), 6.95-8.68 (8H, Ar-H)
BP-20:
2,3-Dihydro-2-(2-thienyl)-4-(4-fluorophenyl)-1,5-benzothiazepine (BP20): Mol.wt:339.45, Yield: 86%, M.p: 147-1490C, IR (KBr) (cm-1):1605 (C=N), 1503 (C=C), 1386 (C-N), 928 (C-F) and 644 (C-S), NMR (CDCl3) ppm : 5.50 (dd, J2,3a = 5.3 Hz, J2,3b = 12 Hz, 1H, C2-H), 3.53 (dd, J3a,3b = 14.4 Hz, J3a,2 = 9.9 Hz, 1H, C3-H-3a), 2.90 (t, J3b,3a = J3b,2 = 12.9 Hz, 1H, C3-H-3b), 7.20 (1H, s,Ar-H), 7.34 (3H, m, Ar-H), 6.60-7.80 (7H, Ar-H)
Antibacterial activity: The antibacterial activity was tested by determining the minimum inhibitory concentration (MIC) for each compound using Standard Serial Tube Dilution Technique. The organisms used are
Gram positive bacteria: Staphylococcus aureus (NCIM-2079), Bacillus subtilis (NCIM-2063)
Gram negative bacteria: Escherichia coli (NCIM-2068), Proteus vulgaris (NCIM-2027)
Antifungal activity: The antifungal activity was tested by the same procedure as described in the antibacterial activity, except using Potato-Dextrose-Agar medium.
The organisms used are: Aspergillus niger (ATCC-6275), Candida tropicalis (ATCC-1369)
The results are presented in Table 3.
TABLE 3: ANTIBACTERIAL ACTIVITY OF 1, 5-BENZOTHIAZEPINES (BP1 TO BP12): (Expressed as MIC in µg/mL)
Compound | R | B. subtilis | S. aureus | E. coli | P. vulgaris | |
BP1 | 4"-methylphenyl | 256 | 128 | 128 | 128 | |
BP2 | 4"-fluorophenyl | 128 | 128 | 256 | 128 | |
BP3 | 4"-chlorophenyl | 64 | 256 | 128 | 128 | |
BP4 | 2"-chlorophenyl | 128 | 64 | 128 | 128 | |
BP5 | 2",4"-difluorophenyl | 64 | 64 | 32 | 64 | |
BP6 | 2",4-dichlorophenyl | 64 | 128 | 64 | 128 | |
BP7 | 2"-chloro-5"-nitrophenyl | 128 | 64 | 128 | 256 | |
BP8 | 3"-nitrophenyl | 256 | 128 | 128 | 256 | |
BP9 | 4"-nitrophenyl | 128 | 128 | 64 | 128 | |
BP10 | 3"-hydroxyphenyl | 64 | 128 | 128 | 64 | |
BP11 | 3"-nitro-4"-methylphenyl | 128 | 128 | 256 | 128 | |
BP12 | 3",4",5"-trimethoxypheny | 128 | 128 | 64 | 128 | |
BP13 | 3",4"-methylendioxyphenyl | 256 | 512 | 128 | 256 | |
BP14 | 5"-bromofuran-2"-yl | 128 | 64 | 64 | 128 | |
BP15 | 4"-dimethylaminophenyl | 64 | 64 | 128 | 64 | |
BP16 | 3"-methoxy-4"-hydroxyphenyl | 128 | 256 | 256 | 128 | |
BP17 | 2"-pyridinyl | 256 | 256 | 512 | 256 | |
BP18 | 3"-pyridinyl | 256 | 128 | 256 | 128 | |
BP19 | 4"-pyridinyl | 128 | 64 | 64 | 128 | |
BP20 | 2"-thienyl | 256 | 128 | 128 | 64 | |
Standard (Ampicillin) | < 1 | < 1 | < 1 | < 1 |
DISCUSSION ON RESULTS:
Antibacterial activity: From the above results, it is evident that most of the 1,5-benzothiazepines synthesized showed antibacterial activity with different MIC values against the tested organisms, but not comparable with that of the standard. Among the compounds tested against B. subtilis, the compounds, BP3 having a chlorophenyl moiety, BP5 having a difluorophenyl moiety, BP6 having a dichlorophenyl moiety, BP10 having a hydroxyl-lphenyl and BP15 having a dimethylaminophenyl moiety proved to be more potent with a MIC value of 64 µg/mL in each case. Against S.aureus, BP4, BP5, BP7 (2-chloro-5-nitrophenyl moiety), BP14 (bromofuran moiety), BP15 and BP19 (4-pyridinyl moiety) showed maximum activity with a MIC value of 64 µg/mL in each case. Against E. coli BP5 proved to be the most potent with a MIC value of 32 µg/mL. This is followed by compounds, BP6, BP9 (nitrophenyl moiety), BP12 (trimethoxyphenyl moiety), BP14 and BP19 with a MIC value of 64 µg/mL in each case. Against P. vulgaris, BP5, BP10, BP15 and BP20 (thienyl moiety) showed maximum activity with a MIC value of 64 µg/mL in each case.
Procedure for Antifungal activity: The antifungal activity was tested by the same procedure as described in the antibacterial activity, except using Potato-Dextrose-Agar medium. The results are presented in Table 4.
TABLE 4: ANTIFUNGAL ACTIVITY OF 1,5-BENZOTHIAZEPINES (BP1 TO BP12)
Compound | R | Aspergillus niger | Candida tropicalis |
BP1 | 4"-methylphenyl | 64 | 32 |
BP2 | 4"-fluorophenyl | 32 | 64 |
BP3 | 4"-chlorophenyl | 32 | 34 |
BP4 | 2"-chlorophenyl | 32 | 64 |
BP5 | 2",4"-difluorophenyl | 16 | 16 |
BP6 | 2",4-dichlorophenyl | 16 | 32 |
BP7 | 2"-chloro-5"-nitrophenyl | 16 | 32 |
BP8 | 3"-nitrophenyl | 32 | 128 |
BP9 | 4"-nitrophenyl | 32 | 64 |
BP10 | 3"-hydroxyphenyl | 256 | 128 |
BP11 | 3"-nitro-4"-methylphenyl | 128 | 64 |
BP12 | 3",4",5"-trimethoxypheny | 128 | 64 |
BP13 | 3",4"-methylendioxyphenyl | 128 | 64 |
BP14 | 5"-bromofuran-2"-yl | 16 | 32 |
BP15 | 4"-dimethylaminophenyl | 128 | 64 |
BP16 | 3"-methoxy-4"-hydroxyphenyl | 128 | 64 |
BP17 | 2"-pyridinyl | 32 | 64 |
BP18 | 3"-pyridinyl | 128 | 64 |
BP19 | 4"-pyridinyl | 16 | 32 |
BP20 | 2"-thienyl | 32 | 16 |
Standard (Fluconazole) | < 2 | < 2 |
Antifungal activity: From the above results, It is noticed that the 1, 5-benzothiazepines tested showed more antifungal activity than the antibacterial activity. Among the compounds tested against A. niger, the compounds, BP5 having a difluorophenyl moiety, BP6 having a dichlorophenyl moiety, BP7 having a 2-chloro-5-nitrophenyl moiety, BP14 having a bromofuran moiety and BP19 having a 4-pyridinyl moiety proved to be the most potent compounds with a MIC value of 16 µg/mL in each case. This was followed by the compounds, BP2 (fluorophenyl moiety), BP3 and BP4 (chlorophenyl moieties), BP8 and BP9 (nitrophenyl moieties), BP17 (2-pyridinyl moiety) and BP20 (thienyl moiety) with a MIC value of 32 µg/mL in each case. Against C. tropicalis, the compounds, BP5 and BP20, showed maximum activity with a MIC value of 16 µg/mL in each case.
This was followed by compounds, BP1 (methylphenyl), BP6, BP7 (2-chloro-5-nitrophenyl moiety), BP14 and BP19 with a MIC value of 32 µg/mL in each case.
Cytotoxicity Studies: The in vitro cytotoxicity of the test compounds was evaluated by the MTT assay. HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer) cell lines were obtained from ACTREC, Mumbai, India.
Cytotoxicity evaluation: The cells were seeded in 96 well plates at a density of 1x104 (counted by Trypan blue exclusion dye method)per well and were incubated for 24 h to recover. After incubation the medium was replaced with fresh media containing different dilutions of the test compounds. Then the plated were incubated for additional 48 h at 370C in DMEM/MEM with 10% FBS medium. Following incubation, the medium was removed and replaced with 90 μl of fresh DMEM without FBS. To the above wells, 10 μl of MTT reagent (5 mg/mL of stock solution in DMEM without FBS) was added and incubated at 37oC for 3-4 h, there after the above media was replaced by adding 200 μl of DMSO to each well and incubated at 370C for 10 min. The absorbance at 570 nm was measured on a spectrophotometer. Methotrexate was used as reference drug for comparison. The results are presented in Table 5.
TABLE 5: CYTOTOXICITY OF THE NEW 1,5-BENZOTHIAZEPINES (BP1 TO BP11): (IC50 values in μg/mL)
Compound | R | Cell line | ||
HT-29 | MCF-7 | DU-145 | ||
BP1 | 4"-methyl phenyl | 55 ± 2 | 62 ± 2 | 52 ± 1 |
BP2 | 4"-fluorophenyl | 42 ± 2 | 48 ± 1 | 62 ± 2 |
BP3 | 4"-chlorophenyl | 92 ± 2 | 78 ± 2 | 65 ± 2 |
BP4 | 2"-chlorophenyl | 105 ± 2 | 168 ± 1 | 122 ± 2 |
BP5 | 2",4"-difluorophenyl | 28 ± 1 | 42 ± 2 | 33 ± 2 |
BP6 | 2",4"-dichlorophenyl | 42 ± 2 | 67 ± 1 | 56 ± 2 |
BP7 | 2"-chloro-5"-nitrophenyl | 115 ± 2 | NA | NA |
BP8 | 3"-nitrophenyl | 180 ± 2 | NA | NA |
BP9 | 4"-nitrophenyl | 155 ± 1 | NA | 105 ± 2 |
BP10 | 3"-hydroxyphenyl | 148 ± 2 | 129 ± 2 | 155 ± 1 |
BP11 | 3"-nitro-4"methylphenyl | 64 ± 2 | 58 ± 1 | 46 ± 2 |
BP12 | 3",4",5"-trimethoxyphenyl | 132 ± 2 | NA | 93 ± 2 |
BP13 | 3",4"-methelenedioxyphenyl | NA | NA | 75 ± 2 |
BP14 | 5"-bromofuran-2"-yl | 56 ± 2 | 27 ± 1 | 16 ± 1 |
BP15 | 4"-dimethylaminophenyl | 182 ± 1 | 106 ± 2 | 98 ± 2 |
BP16 | 3"-methoxy-4"-hydroxyphenyl | 123 ± 2 | 74 ± 1 | 68 ± 2 |
BP17 | 2"-pyridinyl | 195 ± 2 | 140 ± 1 | 92 ± 2 |
BP18 | 3"-pyridinyl | NA | 188 ± 2 | 110 ± 2 |
BP19 | 4"-pyridinyl | 128 ± 2 | NA | 148 ± 1 |
BP20 | 2"-thienyl | 36 ± 2 | 28 ± 1 | 16 ± 2 |
Methotrexate | 11 ± 1 | 9 ± 1 | 6 ± 1 |
Data presented as mean ± SD (n=3). All the compounds and the standard dissolved in DMSO, diluted with culture medium containing 0.1% DMSO. The control cells were treated with culture medium containing 0.1% DMSO. NA- No Activity (i.e IC50 > 200 μg/mL)
DISCUSSION ON RESULTS:
Cytotoxic studies: Of all the compounds tested against HT-29 cell lines, the compound BP5 having a difluorophenyl moiety in its structure showed maximum activity with a IC50 value of 28 µg/mL. This is followed by compounds, BP20 having a thienyl moiety (IC50 36 µg/mL), BP2 and BP6 having fluorophenyl and dichlorophenyl moieties respectively (IC50 42 µg/mL), BP1 having a methylphenyl moiety (IC50 55 µg/mL) and BP14 having a bromofuran moiety (IC50 56 µg/mL). The other compounds also showed activity but at a higher IC50 values.
Among the compounds tested for cytotoxicity on MCF-7 cell lines, the compound BP14 showed maximum activity (IC50 27 µg/mL). This was followed by compounds, BP20 (IC50 28 µg/mL), BP5 (IC50 42 µg/mL) and BP2 (IC50 48 µg/mL). All the other compounds showed cytotoxicity at higher values.
Among the compounds tested for cytotoxicity on DU-145 cell lines, the compounds, BP14 and BP20 showed maximum activity (IC50 16 µg/mL). This was followed by compounds, BP5 (IC50 33 µg/mL), BP11 having a 3-nitro-4-methylphenyl moiety (IC50 46 µg/mL), BP1 (IC50 52 µg/mL) and BP6 (IC50 56 µg/mL).
It was also observed that among all the compounds tested on these three cell lines, most of the compounds showed maximum activity on prostate cancer cell lines (DU-145).
ACKNOWLEDGMENTS: One of the authors (Venkata rao vutla) is thankful to the ACTREC Research center Mumbai for providing cytotoxic evaluation studies and to the Principal, Andhra University College of Pharmaceutical Sciences, Visakhapatnam for providing required help in carrying out the pharmacological studies
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How to cite this article:
Vutla VR, Yejella RP and Nadendla R: Synthesis of novel 1, 5-dihydrobenzothiazepine derivatives by conventional and microwave irradiation methods and their pharmacological activities. Int J Pharm Sci Res 2014; 5(2): 453-62.doi: 10.13040/IJPSR. 0975-8232.5(2).453-62
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Article Information
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453-462
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English
IJPSR
Venkata Rao Vutla*, Rajendra Prasad Yejella and Ramarao Nadendla
Associate Professor, Department of Pharmaceutical Chemistry, Chalapathi Institute of Pharmaceutical Sciences, Lam, Guntur, Andhra Pradesh, India
vvrao_pharma@yahoo.co.in
11 September, 2013
17 October, 2013
09 January, 2014
http://dx.doi.org/10.13040/IJPSR.0975-8232.5(2).453-62
01 February, 2014