Lupine Publishers | Synthesis and Antitubercular Acitivity of New Imidazo [2,1-B] [1,3,4] Thiadiazole-Phenothiazine Derivatives

 

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Abstract

Keywords:Thiadiazole; Phenothiazine; Thiadiazole; Antitubercular Activity

Introduction

 

Materials and Methods

Synthesis of 5-Phenyl- [1,3,4] thiadiazol-2-ylamine

Equimolar mixture of thiosemicarbazide (0.004 mole) and benzoic acid (0.004mole) in presence of H₂SO₄ in dry ethanol (25ml) was refluxed on a water bath for about 2hrs TLC was used to check reaction progress, then mixture was removed and poured in crushed ice to get a white precipitate, compound 1. A solid product was obtained which was purified over a silica gel column using chloroform: methanol (8:2 v/v) mixture as eluant. The elute was concentrated to get a solid product which was recrystallized from ethanol to yielded compound 1: White crystalline solid. M.P. 223- 225 0C,Yield 70%, IR( ν max cm-1): 1430 (ν_C-C), 1070 (νC-N) 763 (ν_C-S), 1454 (ν_C=C), 1585 (ν_N=C), 3378 (ν_-NH2), 1H NMR: δ(ppm) 4.87 (2H, s, NH2) , 7.29 -7.73 (5H, m, Ar-H), 13C NMR : δ (ppm)126.9-131.01(C of aromatic ring), 169.4,163.8(C2,C5 of thiadiazole ring), Anal. Calcd. for C8H7N3S:C, 54.22, H, 3.98, N, 23.71% found C, 54.09, H, 3.70, N, 23.40%; MS 177.03 (M+).

The compounds 1a-1i were synthesized by the similar method as reported earlier.

a) 5-(2-chloro-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P.229-2300C, Yield 72%, IR( ν max cm-1): 1433(ν_C-C), 1072 (νCN ), 780 (ν_C-S),1541(ν_C=C), 1587 (ν_N=C), 745 (ν_C-Cl) 3380 (ν_-NH2), 1H NMR δ(ppm) 4.73(2H, s, NH2)7.27-8.18 (4H, m, Ar-H), 13C NMR: δ(ppm) 127.5-133.1(C of aromatic ring),163.3,169.4(C2C5 of thiadiazole ring), Anal. Calcd. for C8H6 ClN3S: C, 45.39, H, 2.86, N,19.85% found C,45.09, H, 2.70, N,19.40%; MS 211.01 (M+)

b) 5-(3-chloro-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P.228-2300C, Yield 69%, IR( ν max cm-1): 1429 (ν_C-C), 1069 (νC-N), 779 (ν_C-S), 1537(ν_C=C), 1587 (ν_N=C), 737 (ν_C-Cl) 3382 (ν_-NH2), 1HNMR: δ(ppm) 4.75 (2H, s, NH2), 7.35-7.68 (4H, m, Ar-H),13C NMR : δ (ppm) 126.91-31.01 (C of aromatic ring),169.2,162.9(C2C5 of thiadiazole ring), Anal. Calcd. for C8H6 ClN3S: C,45.39, H, 2.86, N, 19.85 % found C, 45.19, H, 2.65, N, 19.49%; MS 211.0 (M+)

c) 5-(4-chloro-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P.230-2320C,Yield73%, IR( ν max cm-1): 1427 (ν_C-C), 1050 (νCN ), 781 (ν_C-S), 1539 (ν_C=C), 1588 (ν_N=C), 749 (ν_C-Cl),3383 (ν_-NH2), 1HMNR: δ(ppm) 4.89 (2H, s, NH2), 7.73-7.85 (4H, m, Ar-H), 13C NMR: δ (ppm) 129.1-135.6 (C of aromatic ring), 163.4,168.8( C2C5 of thiadiazole ring), Anal. Calcd. for C8H6 ClN3S: C,45.39, H, 2.86, N, 19.85% found C, 45.19, H,2.61, N, 19.38%; MS 211.02 (M+)

d) 5-(2-bromo-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P.228-2300C,Yield 68%, IR ( ν max cm-1): 1426 (ν_C-C),1055 (νC-N), 768 (ν_C-S), 1545 (ν_C=C), 1640 (ν_N=C), 545 (νC-Br) 3386 (ν- NH2), 1HNMR: δ(ppm) 4.80 (2H, s, NH2) 7.25-7.89 (4H, m, Ar- H), 13C NMR : δ (ppm) 163.1,169.5( C2 C5 of thiadiazole ring), 120.7- 132.1(C of aromatic ring), Anal. Calcd. for C8H6BrN3S: C, 37.52, H, 2.36, N, 16.41% found C, 37.18, H, 2.21, N, 16.35%; MS 254.94 (M+).

e) 5-(3-bromo-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P. 229-2300C, Yield 67%, IR ( ν max cm-1): 1431 (ν_C-C), 1052 (νC-N), 767 (ν_C-S), 1540 (ν_C=C), 1646 (ν_N=C), 536 (νC-Br), 3388 (ν_-NH2), 1H NMR: δ(ppm) 4.84 (2H, s, NH2), 7.31-7.64 (4H, m, Hz, Ar-H), 13C NMR: δ (ppm): 118.1-132.9(C of aromatic ring),164.08,168.9(C2 C5 of thiadiazole ring), Anal. Calcd. for C8H6BrN3S: C, 37.52, H, 2.36, N, 16.41% found C, 37.28, H, 2.24, N, 16.25%; MS 254.82 (M+).

f) 5-(4-bromo-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P. 231-233 0C, Yield 69%, IR (ν max cm-1): 1429 (ν_C-C), 1041 (νC-N), 766 (ν_C-S), 1543 (ν_C=C), 1642 (ν_N=C), 541(νC-Br), 3390 (ν- NH2), 1H NMR: δ(ppm) 4.79(2H, s, NH2) ,7.68-7.79(4H, m, Ar-H), 13C NMR :δ (ppm) 124.0-131.0 (C of aromatic ring), 164.1- 169.5(C2 C5 of thiadiazole ring), Anal. Calcd. for C8H6BrN3S: C, 37.52, H, 2.36, N, 16.41% found C, 37.24, H, 2.20, N, 16.35%; MS 254 .86(M+).

g) 5-(2-nitro-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P. 257-2590C, Yield 78%, IR (ν max cm-1): 1428 (ν_C-C), 1053 (νC-N), 778 (ν_C-S), 1515 (ν_C=C), 1651 (ν_N=C), 1341(ν_C-NO2), 3391 (-νNH2), 1H NMR: δ(ppm) 4.90 (2H, s, NH2), 7.59-8.27 (4H, m, Ar- H), 13C NMR : δ (ppm) 127.5-148.3(C of aromatic ring), 164.01, 169.6(C2C5 of thiadiazole ring), Anal. Calcd. for C₈H₆N₄O_{2S: C, 43.24, H, 2.72, N, 25.21% found C,43.14, H, 2.52, N, 25.8%; MS 222.02 (M+).}

h) 5-(3-nitro-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P. 259-2610C, Yield 80%, IR: (ν max cm-1): 1426 (ν_C-C), 1048 (νC-N), 776 (ν_C-S), 1527 (ν_C=C), 1656 (ν_N=C), 1343 (ν_C-NO2), 3393 (-νNH2),1H NMR: δ(ppm) 4.78 (2H, s, NH2), 7.59-7.91 (4H, m, Ar- H),13CNMR: δ (ppm) 116.3-140.4 (C of aromatic ring), 164.2 169.3 (C2 C5 of thiadiazole ring), Anal. Calcd. for C₈H₆N₄O_{2S: C, 43.24, H, 2.72, N, 25.21% found C, 43.16, H, 2.62, N, 25.10%; MS 222.22 (M+).}

i) 5-(4-nitro-phenyl)-[1,3,4]thiadiazole-2-ylamine: M.P. 258-2600C, Yield 79%, IR(ν max cm-1): 1432 (ν_C-C), 1055(νCN ), 771 (ν_C-S), 1522 (ν_C=C), 1655 (ν_N=C), 1340 (ν_C-NO2), 3395 (ν_-NH2), 1H NMR: δ(ppm) 4.81(2H, s, NH2) , 7.71-8.27 (4H, m, Ar-H), 13C NMR: δ (ppm)117.2-140.4( C of aromatic ring), 164.2-168.8 (C2C5 of thiadiazole ring), Anal. Calcd. for C₈H₆N₄O_{2S: C, 43.24, H, 2.72, N, 25.21% found C, 43.26, H, 2.60, N, 25.12%; MS 222.19 (M+).}

Synthesis of 2-Chloro-1-phenothiazin-10-yl-ethanone

Chloroacetyl chloride (0.06 mol) was added drop wise at 0.5 0C to phenothiazine (0.06 mol) in dry benzene (100 ml) and the mixture was stirred for 2 hrs. Reaction progress was checked by TLC during the reaction. After the completion of the reaction, the benzene was distilled off to get a solid product washed with petroleum ether which was purified over a silica gel column using chloroform: methanol (8:2 v/v) mixture as eluant. The elute was concentrated to give a product which was recrystallized from ethanol to yielded compound 2. M.P.190-1920C, Yield 94%, IR: (ν max cm-1) 1470 (ν_C-C), 2936 (ν C-H), 1333(ν_N-C),1552 (ν_C=C), 2836 (ν-CH2),1671(νC=O), 685 (ν C-S-C),735(ν C-Cl). 1H NMR: δ(ppm) 4.35(2H, s acyclic CH2), 7.14-7.40 (8H, m, Ar-H),13C NMR δ (ppm) 123.1-138.8 (C of phenothiazine ring), 165.5(C=O acyclic), 42.2 (CH2 acyclic), Anal. Calcd. for C14H10ClNOS: C, 60.98; H, 3.66, N, 5.08, found C, 60.76, H, 3.50, N, 5.01, MS 275.02 (M+).

10-(2-Phenyl-imidazo[2,1-b] [1,3,4] thiadiazol-6-yl)- 10H-phenothiazine

Equimolar amount of 5-Phenyl- [1,3,4] thiadiazol-2-ylamine, compound 1 (0.004 Mole) and Chloro-1-phenothiazin-10-ylethanone, compound 2 (0.004mol) in ethanol (20ml) was refluxed on a water bath for about 18 hr. After the completion of the reaction, the methanol was distilled off to get a solid product which was purified over a silica gel column using chloroform: methanol (8:2 v/v) mixture as eluant. The elute was concentrated to give a product which was recrystallized from ethanol to yielded compound 3. Light green shinny crystalline solid. Light green crystalline solid, M.P. 210- 2120C, Yield 70%, IR: (ν max cm-1) 1481 (ν_C-C), 3171(ν_C-H),1638(νC=N thiadiazole),1589(νC=N imidazole),1286(ν_N-C),772(ν_C-S),1495 (ν_C=C), 681 (ν_C-S-C phenothiazine). 1H NMR:δ(ppm) 6.77(1H, s, imidazole),7.1-7.4 (8H, m, Ar-H phenothiazine),7.45-7.46 (3H, m Ar-H thiadiazole),8.00(2H, d, J = 8.0, Hz, Ar-H), 13C NMR: δ(ppm) 125.9-130.4(C of aromatic ring), 124.2, 144.0 and 116.6-128.1(C of phenothiazine), 175.2,164.4 (C2,C5 thiadiazole), 100.9 and 150.6(C of imidazole), Anal. Calcd. for C22 H14 N4 S2: C, 61.03, H, 3.03, N, 12.94 %, found C, 61.00, H,3.01, N, 12.74%; MS 398.06 (M+).

The compounds 3a-3i were synthesized by the similar method as reported earlier

a. 10-[2-(2-Chloro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol- 6-yl]-10H-phenothiazine: M.P. 209-211 0C,Yield 71%, IR: (νmax cm-1)1479 (ν_C-C), 3172(ν_C-H), 1640 (νC=N thiadiazole), 1597(νC=N imidazole),1280(ν_N-C), 772(ν_C-S), 741(ν_C-Cl), 1493(ν_C=C),682(ν_C-S-C phenothiazine). 1H NMR: δ(ppm)6.71(1H, s, imidazole), 7.11-7.45 (8H, m, Ar-H phenothiazine), 7.40- 7.76 (4H, m, Ar-H aromatic ring),13C NMR:δ (ppm) 127.6- 133.2 (C of aromatic ring), 124.4,144.2 and 116.7-129.3 (C of phenothiazine),164.7,156.3 (C2,C5 thiadiazole), 100.8 and 150.4 (C of imidazole), Anal. Calcd. for C22H13Cl N4 S2, C, 61.03, H, 3.03, N,12.94%, found C, 61.00, H, 3.01, N, 12.74%; MS 432.03(M+).

b. 10-[2-(3-Chloro-phenyl)-imidazo[2,1-b][1,3,4] thiadiazol-6-yl]-10H-phenothiazine: M.P. 210-2110C, Yield 72%, IR:(ν max cm-1)1482 (ν_C-C), 3169 (ν_C-H), 1639 (νC=N thiadiazole), 1598 (νC=N imidazole), 1284(ν N-C),77(ν_C-S),737(νCCl ),1491(ν_C=C),679 (ν_C-S-C phenothiazine). 1H NMR: δ(ppm) 6.76(1H, s, imidazole), 7.42-7.71 (3H, m, Ar-H aromatic ring), 7.11-7.44 (8H, m Ar-H penothiazine), 7.95 (1H, t, J = 1.5, 0.4 Hz, Ar-H), 13C NMR: δ (ppm)126.9-131(C of aromatic ring), 124.1,145.1 and 116.6-128.0(C of phenothiazine), 157.7,164.3 (C2,C5 thiadiazole), 100.7 and 150.7 (C of imidazole), Anal. Calcd. for C22H13 ClN4S2: C, 61.03, H, 3.03, N, 12.94%, found C, 61.01, H, 3.00, N, 12.84%; MS 432.02 (M+).

c. 10-[2-(4-Chloro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-6- yl]-10H-phenothiazine: M.P. 212-2140C, Yield 70%, IR:(νmax cm-1) 1480 (ν_C-C), 3176 (ν_C-H), 1638 (νC=N thiadiazole), 1589 (νC=N imidazole), 1285 (ν N-C), 770 (ν C-S), 742 (ν C-Cl), 1488 (ν_C=C), 682 (ν C-S-C phenothiazine).1H NMR: δ(ppm) 6.79(1H, s, imidazole),7.68-7.70 (4H, m, Ar-H aromatic ring), 7.12- 7.46 (8H, m Ar-H phenothiazine), 13C NMR : δ (ppm) 127.2- 135.7 (C of aromatic ring), 124.4,145.3 and 116.1-128.3(C of phenothiazine),157.7,156.3 (C2,C5 thiadiazole), 100.6 and 150.3 (C of imidazole), Anal. Calcd. for C22 H13 Cl N4S2:C, 61.03, H ,3.03, N, 12.94%, found C, 61.00, H, 3.02, N, 12.72%; MS 432.05 (M+).

d. 10-[2-(2-Bromo-phenyl)-imidazo[2,1-b][1,3,4] thiadiazol-6-yl]-10H-phenothiazine: M.P. 211-2120C Yield 70%, IR: (νmax cm-1) 1478 (ν_C-C),3175 (ν_C-H),1637(νC=N thiadiazole), 1588(νC=N imidazole), 1279(ν N-C) ,768 (ν_C-S), 542 (νC-Br), 1490 (ν_C=C), 685 (ν C-S-C phenothiazine). 1H NMR: δ(ppm) 6.73(1H, s, imidazole), 7.37-7.77 (4H, m, Ar-H aromatic ring),7.11-7.48 (8H, m Ar-H phenothiazine), 13C NMR: δ (ppm) 120.7-132.1 (C of aromatic ring),124.5,145.5 and 116.5- 128.3(C of phenothiazine),156.2,164.5(C2, C5 thiadiazole), 100.4 and 150.1 (C of imidazole), Anal. Calcd. for C22 H13 Br N4 S2: C, 55.35, H, 2.74, N,11.74%, found C, 55.20, H, 2.52, N, 11.62%, MS 475.96 (M+).

e. 10-[2-(3-Bromo-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol- 6-yl]-10H-phenothiazine: M.P. 213-2140C, Yield 69%, IR:(ν max cm-1)1480(ν_C-C), 3174 (ν_C-H), 1638 (νC=N thiadiazole), 1590(νC=N imidazole),1281(ν_N-C)766 (ν_C-S), 540 (νC-Br) 1491 (ν_C=C), 683(ν_{CS- C} phenothiazine). 1H NMR: δ(ppm) 6.76 (1H, s, imidazole), 7.41-7.61 (3H, m, Ar-H aromatic ring), 7.10-7.49 (8H, m, Ar-H phenothiazine), 7.76 (1H, td, J = 1.5, Hz, Ar-H aromatic ring),13C NMR: δ(ppm)118.7-133.0 (C of aromatic ring), 124.6,145.7 and 116.7-128.4 (C of phenothiazine) , 175.1,164.4 (C2,C5 thiadiazole), 100.1 and 150.2(C of imidazole), Anal. Calcd. for C22 H13 Br N4 S2: C, 55.35%, H, 2.74, N,11.74 found C, 55.20, H, 2.52, N, 11.62%; MS 475.98(M+).

f. 10-[2-(4-Bromo-phenyl)-imidazo[2,1-b][1,3,4] thiadiazol-6-yl]-10H-phenothiazine: M.P. 215-2160C, Yield 68 %, IR:(ν max cm-1)1482 (ν_C-C), 3171 (ν_C-H), 1636 (νC=N thiadiazole), 1594 (νC=N imidazole), 1286 (ν_N-C) 769 (ν_C-S), 538 (νC-Br) 1489 (ν_C=C), 688 (ν_C-S-C phenothiazine), 1H NMR: δ(ppm) 6.72 (1H, s, imidazole), 7.69-7.78 (4H, m, Ar-H aromatic ring), 7.10-7.49 (8H, m Ar-H penothiazine), 13C NMR: δ(ppm)- 124- 131(C of aromatic ring), 124.2,145.8 and 116.8-128.7 (C of phenothiazine), 175.5,164.6 (C2,C5 thiadiazole), 100.3 and 150.7 (C of imidazole), Anal. Calcd. for C22H13BrN4S2: C, 55.35, H, 2.74, N, 11.74% found C, 55.19, H, 2.42, N, 11.72%; MS 475.99 (M+).

g. 10-[2-(2-Nitro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol- 6-yl]-10H-phenothiazine: M.P. 215-2170C, Yield 74%, IR :(ν max cm-1) 1487 (ν_C-C), 3170 (ν_C-H),1642(νC=N thiadiazole), 1598 (νC=N imidazole), 1287 (ν_N-C), 770 (νC-C), 1343 (ν_C-NO2) 1494 (ν_C=C), 689 (ν_C-S-C phenothiazine), 1H NMR: δ (ppm) 6.73 (1H, s, imidazole), 7.49-8.35 (4H, m, Ar-H aromatic ring), 7.11-7.48 (8H, m Ar-H phenothiazine), 13C NMR : δ (ppm) 127.6-148.4 (C of aromatic ring), 124.7,144.9 and 115.9-127.8( C of phenothiazine), 156.5,164.4 (C2,C5 thiadiazole), 100.2 and 150.6 (C of imidazole), Anal. Calcd. for C₂₂H₁₃N₅O₂S₂: C, 59.58, H, 2.95, N, 15.79%, found C, 59.38, H, 2.85, N,15.59 %; MS 443.05 (M+).

h. 10-[2-(3-Nitro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol- 6-yl]-10H-phenothiazine (3h): M.P. 216-2180C, Yield 75 %,IR: (νmax cm-1)(ν_C-C) 1483, (ν_C-H) 3172, 1641 (νC=N thiadiazole), 1596 (νC=N imidazole), 1286 (ν_N-C), 773 (ν_C-S), 1340 (ν_C-NO2) ,1492 (ν_C=C), 685 (ν_C-S-C phenothiazine), 1H NMR: δ (ppm) 6.68 (1H, s, imidazole), 7.58-8.84 (4H, m, Ar-H aromatic ring), 7.10- 7.49 (8H, m Ar-H phenothiazine), 13C NMR : δ (ppm) 116.4- 140.5(C of aromatic ring), 124.8, 145.9 and 115.8-128.5(C of phenothiazine), 175.7,164.6 (C2,C5 thiadiazole), 100.1 and 150.9 C of imidazole, Anal. Calcd. for C₂₂H₁₃N₅O₂S₂: C, 59.58, H, 2.95, N, 15.79 found C, 59.40, H, 2.81, N, 15.55; MS 443.04 (M+).

i. 10-[2-(4-Nitro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol- 6-yl]-10H-phenothiazine: M.P.220-2220C,Yield 76%, IR: (νmax cm-1) 1480 (ν_C-C), 3170 (ν_C-H), 1638 (νC=N thiadiazole), 1592 (νC=N imidazole), 1285 (ν_N-C), 770 (ν_C-S),1338 (ν_C-NO2), 1491 (ν_C=C), 685 (ν_C-S-C phenothiazine), 1H NMR: δ (ppm) 6.72 (1H, s, imidazole), 7.80-8.33 (4H, m, Ar-H aromatic ring), 7.11- 7.49 (8H, m Ar-H phenothiazine), 13C NMR : δ(ppm) 117.3- 140.5( C of aromatic ring), 124.9,145.6 and 116.8-128 (C of phenothiazine),175.1,163.4 (C2,C5 thiadiazole),100.5 and 150.8 (C of imidazole), Anal. Calcd. for C₂₂H₁₃N₅O₂S₂: C, 59.58, H, 2.95, N,15.79%, found C, 59.37, H, 2.81, N, 15.59%; MS 443.02 (M+).

Antitubercular activity

The above synthesized compounds were screened against M. tuberculosis (H37Rv strain) using Lowenstein-Jensen (L.J.) Agar method at 50 and 100 μg/mL concentrations. The results were showing in Table 1. The standard antitubercular drugs isoniazid was taken as standards, showed 100% activity at both the above concentrations. The minimum inhibitory concentration (MIC) values of the synthesized compounds were determined.

Conclusion

In the conclusion we were successful in the initial hypothesis of synthesizing broad-spectrum antibiotics through experimentation. We report a successful effort to combine pharmacophoric groups; 5-Phenyl- [1,3,4] thiadiazol-2-ylamine and Chloro-1-phenothiazin- 10-yl-ethanone and the compounds were synthesised in good yield. The structures of compounds were established by FT-IR, 1H NMR, 13CNMR and Mass spectrometry techniques. The synthesized compounds posses antitubercular activity against Mycobacterium tuberculosis H37Rv strain.

 

 

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