Synthesis of 1,2,3‐Triazole‐Methyl‐Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood‐Dwelling Parasites

Abstract This study explores the synthesis and evaluation of novel 1,2,3‐triazole‐methyl‐1,4‐naphthoquinone hybrids, focusing on their electrochemical properties and antiparasitic efficacies against two human blood‐dwelling parasites Plasmodium falciparum and Schistosoma mansoni . Using copper‐catalyzed azide‐alkyne cycloaddition (CuAAC), a well‐established tool in click chemistry, two synthetic routes were assessed to develop α‐ and β‐[triazole‐methyl]‐menadione derivatives. By optimizing the CuAAC reaction conditions, yields were significantly improved, reaching up to 94 % for key intermediates and resulting in the formation of a library of approximately 30 compounds. Biological evaluation of the compounds in antiparasitic drug assays demonstrated notable antischistosomal potencies, while no significant activity was observed for the same series against P. falciparum parasites. Electrochemical and ‘benzylic’ oxidation studies confirmed that the active ‘benzoyl’ metabolite responsible for the antiplasmodial activity of plasmodione cannot be generated. These findings highlight the potential of triazole‐linked menadione hybrids as promising early candidates for antischistosomal drug development, and provides insights into structure‐activity relationships crucial for future therapeutic strategies.