Spiro-Lactams as Novel Antimicrobial Agents

INTRODUCTION: Structural modulation of previously identified lead spiro-beta-lactams with antimicrobial activity was carried out. OBJECTIVE: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. METHODS: The target chiral spiro-gamma-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-gamma-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-beta-lactams and spiro-gamma-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 microM) were identified. RESULTS: A novel synthetic route to chiral spiro-gamma-lactams has been established. The studied beta- and gamma- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. CONCLUSION: The designed structural modulation of biologically active spiro-beta-lactams involved the replacement of the four-membered beta-lactam ring by a five-membered gamma-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between beta- and gamma- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the beta-lactamic core is a requirement for the activity against both HIV and Plasmodium.