7‐(Chloroquinolin‐4‐yl) Sulfanyl Derivatives, Optimization of the Synthesis, In Silico ADMET Profiling Studies, and Evaluation of the Biological Activity Against Leishmania mexicana

Leishmaniasis is a parasitic human infection that constitutes a major global health challenge due to limited therapeutic options, toxicity, resistance, and high costs of the drugs approved as therapy. In this study, a group of 7‐chloroquinoline derivatives ( 5 – 12 ) was synthesized via an optimized route and evaluated against the human parasite Leishmania mexicana . Compounds were fully characterized and showed favorable in silico ADME/Tox profiles, including high predicted gastrointestinal absorption (>93%), although limited solubility and potential hepatotoxicity were observed for several derivatives. Biological assays demonstrated significant antileishmanial activity. Interestingly, intracellular amastigote assays revealed nanomolar potency and very high selectivity index (SI), with compound 12 exhibiting IC 50 = 2.5 nM (SI = 21.030) and compound 9 IC 50 = 5.2 nM (SI = 7.384). Mechanistic studies demonstrated concentration‐dependent mitochondrial membrane depolarization and acidocalcisome alkalinization. Since these two organelles are both involved in bioenergetics and in parasite intracellular Ca 2+ homeostasis, the results support the notion that intracellular Ca 2+ disruption is an essential target for different drug actions. Overall, these findings support a multitarget mechanism and position these quinoline derivatives as promising chemical scaffolds for the development of improved antileishmanial strategies.