Synthesis and structure-activity relationships of new chiral spiro-β-lactams highly active against HIV-1 and Plasmodium

Abstract

The synthesis and antimicrobial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-β-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information. Among the tested compounds, two spirocyclopentenyl-β-lactams were identified as having remarkable nanomolar activity against HIV-1. Additionally, the same molecules showed promising antiplasmodial activity, inhibiting both the hepatic and blood stages of Plasmodium infection.

Keywords: 1,3-Dipolar cycloaddition; 2-Butynoates; Allenes; Anti-HIV agents; Antiplasmodial agents; Phosphane-catalyzed [3+2] annulations; Spiro-3H-pyrazole-β-lactams; Spiro-penicillanates; Spirocyclic compounds; Spirocyclopentenyl-β-lactams; β-Lactams.