Synthesis, characterization and antibacterial activity of benzimidazole Derivatives.
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Date
2018
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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.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.