Bioactivity of beta lactam substitued polycyclic fused pyrrolidine pyrrolizidine derivatives in vitro in vivo and in silico studies

Abstract

Quest for new anti fungal compounds with proven mechanisms of action arises due to resistance and dose limiting toxicity of existing agents beta lactam derived polycyclic fused pyrrolidine pyrrolizidine derivatives synthesized by 1 3 dipolar cycloaddition reaction were evaluated against a panel of microbes involved in human dental infections Thirty compounds were screened among them compound 3 showed efficient antimicrobial activity against E faecalis and C albicans and also showed activity in an ex vivo dentinal tubule and in vivo mice infectious disease models Compound 3 was also found to be active against resistant E faecalis strains isolated from failed root canal treatment cases Mechanism of action of compound 3 on E faecalis was deciphered and found to act by binding to penicillin binding protein resulting in cell damage Mechanism of action studied for compound 3 on C albicans showed that it inhibited the enzyme 14 demethylase involved in ergosterol biosynthesis pathway and repressed the virulence by preventing the yeast to hyphae conversion involving the cAMP pathway Further compound 3 was found to be hemocompatible not cytotoxic to normal mammalian cells and non mutagenic The study concluded that beta lactam compound 3 exhibited promising antimicrobial activity against E faecalis and C albicans involved in root canal infections and the mechanism of action was deciphered The results of this research can be further implicated in the development of potent antimicrobial medicaments with applications in dentistry newline