Over the past decades, emergence of resistant bacterial strains has created havoc to the human health resulting in increased morbidity and mortality, including in developed countries. In order to enhance armamentarium against these resistant strains, we synthesized 1,2,3-triazole and sulfonate derivatives of natural bioactive precursors. In vitro antibacterial evaluation against six sensitive bacterial strains (Pseudomonas aeruginosa, Salmonella enterica, Streptococcus pneumoniae, Enterococcus faecalis, Klebsiella pneumoniae, Enterococcus coli) showed very promising results specially 14, 19 and 22 emerged as potent antibacterial agents against S. pneumoniae (IC50: 0.178, 0.021 and 0.104 µM), E. faecalis (IC50: 0.104, 0.018 and 0.162 µM) and E. coli (IC50: 0.043, 0.037 and 0.060 µM), respectively. Moreover, these lead inhibitors also demonstrated considerable activity against multidrug resistant E. coli strain. Growth curve analysis for 14, 19 and 22 exhibited their bacteriostatic nature. Selected compounds did not show significant cytotoxicity up to 100 µg/mL concentration on HEK293 cell line. TEM micrographs of bacterial cells (S. pneumoniae and E. coli) exposed to 14 and 22 clearly revealed membrane disruption leading to cell death. Studies on the larvae of Galleria mellonella showed that the selected inhibitors 14 and 22 did not cause an alteration in the hemocyte density thereby did not provoke an immune response and were non-toxic up to the conc. of 3.0 mg/ml. Our study revealed that better activity and toxicity profiles of the lead compounds (14 and 22) make them suitable candidates for further structural optimization for the development of potent and safe antibacterial agents.

Design and synthesis of small molecule inhibitors bearing 1,2,3-triazole/sulfonate pharmacophore from natural precursors for the treatment of bacterial infections

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.