Leishmaniasis, classified by the World Health Organization as one of the 20 neglected tropical diseases, impacts around 12 million individuals across four continents and poses significant challenges to public health. The limited treatment choices, compounded by issues of drug toxicity and growing resistance to existing medications, underscore the critical need for novel therapeutic agents. This study seeks to deepen understanding of the key structural elements driving the anti-leishmanial activity in derivatives of 2-aminothiophene. To achieve this, a series of novel molecules were designed and prepared, incorporating targeted alterations at positions 3, 4, and 5 on the thiophene core, along with bioisosteric replacement of sulfur with selenium. Multiple derivatives of 2-aminothiophene (2-AT) and the corresponding 2-aminoselenophene (2-AS) analogs were prepared in sequence using the Gewald multicomponent reaction. These compounds were subsequently tested in vitro to assess their inhibitory effects on Leishmania amazonensis parasites and their potential toxic impact on mammalian macrophages. Various compound libraries were successfully generated, revealing specific structural trends that enhance potency. Notably, several analogs exhibited IC₅₀ values under 10 µM. Key insights include the dispensability of a cyano substituent at position 3; the critical role of cycloalkyl or piperidinyl substituents at positions 4 and 5, where chain length and type significantly influence efficacy; and the beneficial effect of sulfur-to-selenium bioisosteric exchange, which improved activity while preserving low cytotoxicity. Collectively, the results reinforce the promising outlook for 2-aminothiophene scaffolds as sources of viable anti-leishmanial candidates and provide valuable guidance for optimizing future compounds to address the ongoing challenges posed by leishmaniasis more effectively.
