The use of classical synthetic methodologies in the synthesis of amide-pyrazole derivatives with antiplasmodial potential

Synthetic organic chemistry plays a fundamental role in the development of new therapeutic agents. Malaria is a life-threatening disease transmitted by the bite of infected Anopheles mosquitoes. In 2024, the malaria burden resulted in 210 million cases and 610 thousand deaths.¹ The demand for new chemotherapies for malaria treatment has risen due to the development of drug resistance emerging worldwide.² In this work, amide-pyrazole analogs are synthetized by a 5-step parallel-convergent route to afford derivatives with antiplasmodial activity. An aniline derivative is converted to hydrazine via a phenyldiazonium chloride as intermediate. In parallel, dioxopentanoates are synthesized to allow pyrazole formation by Knorr cyclization.³ Curtius’ rearrangement furnishes the substrate for amide coupling with carboxylic acids, providing an average global yield of 7%.⁴ Three distinct molecular cores were explored, with synthetic adaptation required for central core functionalization. Around 40 analogs were synthesized, reaching potency enhancement.