Introduction: Structural modulation of previously identified lead spiro-β-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-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction
of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium
of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one
derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM)
Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ-
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-β-lactams involved the replacement
of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational
and superimposition computational studies revealed no significant differences between β- and γ-
lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a
similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the
activity against both HIV and Plasmodium.