Synthesis, characterization and antibacterial activity of benzimidazole Derivatives.

Abstract

Three series of benzimidazole hybrids were synthesised, two of which contained either thiazolidinone or amino acids tethered to the benzimidazole at C-2 by a phenyl linker and the third contained a thiazolidinone moiety at C-5 on the core structure of the benzimidazole. A total of 35 new compounds were synthesised. Variety was introduced into the molecules by using different benzaldehydes when forming the thiazolidinones or different amino acids substituted on the phenyl linker. Many of the reaction steps were carried out using microwave reactions and in one series, a comparative study was carried out between conventional synthesis and microwave irradiation. In all cases, the microwave methods had many advantages over conventional methods, having shorter reaction times, improved yields and use of green solvents. The synthesized compounds were characterised using mainly Nuclear Magnetic Resonance Spectroscopy and confirmed by High Resolution Mass Spectroscopy. All compounds were tested for their antimicrobial properties against two Gram positive bacteria (Staphylococcus aureus ATCC 25923 and Staphylococcus aureus Rosenbach ATCC BAA-1683 (methicillin resistant S. aureus)) and four Gram negative bacteria (Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumonia ATCC 31488, Escherichia coli ATCC 25922 and Salmonella typhimurium ATCC 14026). A disc diffusion assay was used to first screen the compounds for bacterial activity, followed by the Minimum Bactericidal Concentration (MBC) assay. Among the three series, the thiazolidinones linked to the benzimidazole via the phenyl group at C-2 showed the lowest activity in the mM range. Both the amino acid derivatives linked to the phenyl group at C-2 and the thiazolidinone attached to C-5 of the benzimidazole showed antimicrobial activity in the M range. Although the benzimidazole amino acid hybrids were inactive against the Gram positive bacteria, B7c and B7d (the methionine derivatives) showed excellent inhibitory activity against S. typhimurium (MBC = 0.25 and 0.05 μM respectively), along with compounds B7a (valine derivative) and B7j (tryptophan derivative) which were active against K. pneumoniae with MBC values of 0.27 and 0.10 μM respectively. The benzimidazole–thiazolidinone hybrids, containing a trifluoromethyl group at C-2 and a thiazolidinone group at C-5, showed excellent activity with most compounds exhibiting activity ranging from 3 to over 100 fold higher than the standards. Among these, C3d, C3f and C3j (0.14-35.46 μM), containing bromine and nitro groups, displayed broad range activity against all strains tested. These findings are a major contribution and a good lead to developing new and better antimicrobial drugs.