Total Synthesis and Microbiological Evaluation of Leopolic Acid A and Analogues

Abstract

New antimicrobial scaffolds are scarce, and there is a great need for the development of novel therapeutics. In this study, we report a convergent 9-step synthesis of leopolic acid A and a series of targeted analogues. The designed compounds allowed for incorporation of non-natural ureido dipeptide moieties and 4- and 5-position substituents around the 2,3-pyrrolidinedione of leopolic acid A. Leopolic acid A displayed modest antimicrobial activity (32 μg/mL) against MRSA, while the most active analogues displayed slightly improved activity (8-16 μg/mL). Additionally, several of the leopolic acid A analogues displayed promising antibiofilm activity, most notably having an MBEC:MIC ratio of ∼1. Overall, this work represents an initial SAR of the natural product and a framework for further optimization of these bioactive scaffolds within the context of bioactive pyrrolidinediones.