Discovery and Preliminary Structure-Activity Investigation of 3-Sub stituted-1H-imidazol-5-yl-1H-indoles with In Vitro Activity towards Methicillin-Resistant Staphylococcus aureus

Antibiotics have been the cornerstone of modern medicine saving lives by virtue of being able to cure infectious diseases and to prevent infections in those who are immune compromised. Their intense use has led to a surging increase in the incidence of antibiotic-resistant bacteria resulting in a desperate need for antibiotics with new mechanisms of action. As part of our search for new antimicrobials we have screened an in-house library of compounds and identified two 3-substituted-1H-imidazol-5-yl-1H-indoles as weak growth inhibitors (MIC 16 mu g/mL) against methicillin-resistant Staphylococcus aureus (MRSA). An extensive library of analogues was prepared using the Van Leusen three-component reaction, biological evaluation of which led to the identification of two analogues (26 and 32) with favorable anti-MRSA activity (MIC <= 0.25 mu g/mL) which also lacked cytotoxic or hemolytic properties. The screening campaign also identified two derivatives, a phenethyl-indoleimidazole 57 and a 5-phenyl-1H-imidazole 111 that were non-toxic selective antifungals towards Cryptococcus neoformans. These results have identified 3-substituted-1H-imidazol-5-yl-1H-indoles and 5-phenyl-1H-imidazoles as new structural scaffolds for further investigation as anti-MRSA and anti-C. neoformans agents, respectively.

Automated summary

Antibiotics have played a crucial role in modern medicine, but the increasing prevalence of antibiotic-resistant bacteria has highlighted the urgent need for new antibiotics with novel mechanisms of action. In this study, researchers screened a library of compounds and identified two weak growth inhibitors that showed potential against methicillin-resistant Staphylococcus aureus (MRSA). Further evaluation led to the discovery of two analogues with favorable anti-MRSA activity and no cytotoxic or hemolytic properties. Additionally, the study also identified two derivatives that showed selective antifungal activity against Cryptococcus neoformans. These findings suggest that 3-substituted-1H-imidazol-5-yl-1H-indoles and 5-phenyl-1H-imidazoles could serve as promising structural scaffolds for the development of new anti-MRSA and anti-C. neoformans agents, respectively.