Synthesis and Antibacterial Activity of Novel Benzimidazole Linked 1,3,4-Oxadiazole Derivatives

With an intention to develop potent antimicrobial agents from the source of benzimidazole1,3,4-oxadiazole combined heterocyclic derivatives, novel 6-Chloro-2-(2-(5-(substituted phenyl)-1,3,4-oxadiazol-2-yl)ethyl)1H-benzo[d]imidazole derivatives were synthesized using condensation reaction of 3-(6-chloro-1H-benzo[d] imidazol-2-yl)propane hydrazide and benzoic acids as key step in presence of POCl3. All newly synthesized target compounds (4a-4n) were characterized by 1H NMR, Mass and IR spectral studies and were screened for their antibacterial activity with two bacterial pathogens (Gram positive: Bacillus subtilis, Gram negative: Escherichia coli) which confirmed that compounds 4a, 4b, 4d, 4g, 4h and 4n have potent activity against B. subtilis as compare with gentamicin at concentration 500 μg/mL. We hope that this study may helpful for further optimization in finding of lead antimicrobials from the origin of benzimidazole linked oxadiazole derivatives. Citation: Mothukuri BG, Settypalli T, Begari N, Dalavai VK, Chunduri VR (2019) Synthesis and Antibacterial Activity of Novel Benzimidazole Linked 1,3,4-Oxadiazole Derivatives. Med Chem (Los Angeles) 9: 014-019. doi: 10.4172/2161-0444.1000529 Med Chem (Los Angeles), an open access journal ISSN: 2161-0444 Volume 9(2): 014-019 (2019) 15 our ongoing synthesis and biological evaluation of novel heterocycles [21-29], in this study, we designed (Figure 2) and synthesized some benzimidazole linked 1,3,4-oxadiazole derivatives and examined their preliminary antibacterial activity. Materials and Methods Chemistry All the chemicals were obtained from Sigma Aldrich in synthetic grade. Reaction progress was monitored from time to time by analytical thin layer chromatography (TLC) using E-Merck 0.25 mm silica gel plates. UV light (256 nm) sodium chamber was used for spots visualisation. Before reaction, all solvents were dried by appropriate drying agents based on Vogel’s protocol. Purification was achieved with column chromatography using hexane and ethyl acetate as eluents. ACME grade silica gel (60-120 mesh) was used for column chromatography unless otherwise mentioned. The reagents were purified employing standard laboratory techniques. All the 1H-NMR spectra have been recorded with Bruker 300 MHz instrument in CDCl3 and DMSO-d6 solvents. Chemical shifts reported were relative to TMS on the delta scale. The electron ionization mass spectra were recorded on Agilent 1100 series mass spectrometer. Melting points were determined in one ended capillaries on a Mel-temp apparatus and were uncorrected. IR spectra were recorded on a Thermo Nicolet IR 200 FT-IR in KBr pellets. General procedure for the synthesis of (6-chlo-1-phenyl)-1Hbenzimidazol-2-yl) Propanoic acid (1): A mixture of compound 4-chlorobenzene-1,2-diamine (A, 10 g, 0.070 mol) and succinic acid (25 g, 0.211 mol) in dil HCl (100 mL) was stirred for 4 h at reflux condition and cooled to 0-5°C, filtered the solid and washed with 50 mL of water to get a solid (8.0 g, 50%); m.p. 176-178°C; IR (KBr ν cm-1): 892, 961, 991, 1109 (C−O str), 1599, 1690 (C=O), 2995, 3203 (NH); 1HNMR (DMSO-d6) δ (ppm): 2.78 (t, 2H, -CH2CH2-), 3.01 (t, 2H, -CH2CH2-), 7.12 (dd, 1H, J=8.7 and 1.8 Hz, Ar-H), 7.47 (d, 1H, J=8.4 Hz, Ar-H), 7.51 (d, 1H, J=1.8 Hz); MS (m/z): 223.04 (M-1) Anal. calcd. General procedure for the synthesis of Ethyl 3-(6-chloro-1Hbenzo[d]imidazol-2-yl)propanoate (2): Compound 1 (8.0 g, 0.0357 mol) was dissolved in 50 mL ethanol and placed in a cooling condition (0-5°C) by adding thionyl chloride (5.21 mL, 0.0714 mol) drop by drop over 30 min and refluxed for 2 h. It was cooled to room temperature and the excess ethanol was distilled using rotavap. The residue was stirred for 30 min with 100 mL cold water to get solid, filtered (8.8 g, 98%); m.p. 132-134°C; IR (KBr ν cm-1): 892, 961, 991, 1128 (C−O str), 1599, 1710 (C=O), 2995, 3203 (NH); 1HNMR (DMSO-d6) δ (ppm): 1.17 (t, 3H), 2.85 (t, 2H, -CH2CH2), 3.06 (t, 2H, -CH2CH2-), 4.06 (q, 2H, -CH3), 7.14 (dd, 1H, J=8.4 and 1.8 Hz, Ar-H), 7.48 (d, 1H, J =8.4 Hz, Ar-H), 7.52 (d, 1H, J =1.5 Hz, Ar-H); MS (m/z): 274.98 (M+Na) Anal. calcd. General procedure for the synthesis of 3-(6-chloro-1H-benzo[d] imidazol-2-yl) propane hydrazide (3): A mixture of 2 (8 g, 0.031 mol) and hydrazine hydrate (7.8 mL, 0.155 mol) in toluene (15 mL) was refluxed for 2 h and it was cooled filtered to get a white solid (5 g, 66%); m.p. 180-182°C; IR (KBr ν cm-1): 1138, 1225, 1307, 1343, 1395, 1449, 1599, 1670 (C=O), 2965, 3206 (NH); 1HNMR (DMSO-d6) δ (ppm): 2.57 (t, 2H,-CH2CH2-), 3.00 (t, 2H, -CH2CH2), 3.61 (s, 2H, -NH2), 7.14 (dd, 1H, J=8.7 and 1.8 Hz, Ar-H), 7.47 (d, 1H, J= 8.7 Hz, Ar-H), 7.51 (d, 1H, J=1.5Hz, Ar-H), 9.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ (ppm): 24.30, 30.97, 114.35, 115.37, 121.34, 125.53, 137.07, 140.13, 155.90, 170.39 (aromatic and quaternary carbons); MS (m/z): 238.8 (M+1) Anal. calcd. General procedure for the synthesis of 6-chloro-2-(5(substituted phenyl)-(1,3,4)oxadiazol-2,41methyl)-1-phenyl-1Hbenzimidazole (4a-4n): A mixture of acid hydrazide 3 (500 mg, 0.0021 mol) and substituted benzoic acid (0.0021 mol) was added POCl3 (3 mL) and refluxed for 2 h. The total reaction mixture was cooled to 0-5C and water was added at pH 9. Filtered the solid and recrystalized in methanol:water (70:30). 6-Chloro-2-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)ethyl)1H-benzo[d]imidazole (4a): Yellow colour solid (646 mg, 86%); m.p. 168-170°C; IR (KBr ν cm-1): 1023, 1190, 1482, 1640, 2829 (C-H str), 3060 (=CH str), 3210 (NH); 1HNMR (DMSO-d6) δ (ppm): 3.37 (t, 2H,