Synthesis and antiplasmodial activity of indole-2-carboxamides

Malaria is caused by Plasmodium parasites and kills more than 500,000 people each year, with the greatest burden in Africa. The continuing risk of resistance to current antimalarial therapies highlights the need for new treatment options. Our lab collaborates with Medicines for Malaria Venture (MMV), a non-profit organization developing accessible medicines for malaria treatment and prevention. Together, we are developing compounds with potential for single-encounter radical cure and prophylaxis (SERCAP). Our approach focuses on optimizing the potency, metabolism, toxicity, and physicochemical properties from a hit compound identified from a Plasmodium falciparum asexual blood stage high-throughput screen (HTS). The hit series was developed from an indole-2-carboxamide with structural novelty and drug-like properties. Analogues were synthesized using reductive amination or nucleophilic displacement, followed by HATU-mediated amidation and Boc deprotection. Although potency, metabolic stability, and hERG activity improved, cross-resistance in drug-resistant malaria strains led us to discontinue the series.