New Copper (II) Complexes Based on 1,4-Disubstituted-1,2,3-Triazole Ligands with Promising Antileishmanial Activity

<b>Background/Objectives:</b> Leishmaniasis constitutes one of the most fatal parasitic diseases globally, adversely impacting the health of individuals residing in both intertropical and temperate zones. In these geographical areas, the administration of treatment is often inconsistent and largely ineffective with the available pharmaceuticals, as these exhibit more pronounced side effects than the therapeutic advantages they purport to provide. <b>Methods</b>: Consequently, the current investigation seeks to engage in molecular modeling of novel pharmacological candidates incorporating 1,2,3 disubstituted triazole moieties, coordinated with Cu^II metal centers, in pursuit of promising bioactive properties. <b>Results</b>: Two complexes were prepared and X-ray analysis revealed a comparable structural configuration surrounding the copper (II) atom. The planar square coordination geometry was elucidated through the assessment of the τ4=0 (tau four) parameters. The comprehensive characterization encompasses HRMS-ESI (+), NMR, elemental analyses, mid-infrared, and UV-vis spectroscopic techniques. Time-dependent density functional theory (TD-DFT) analyses will substantiate the findings obtained through UV-vis spectroscopy. Crucially, the biological assays against <i>Leishmania</i> (<i>L.</i>) <i>amazonensis</i> revealed that Complex 1 exhibited outstanding potency against the intracellular amastigote form, demonstrating a half-maximal inhibitory concentration (IC₅₀) of 0.4 µM. This activity was 6-fold higher than that of amphotericin B (IC₅₀ = 2.5 µM) and 33-fold higher than pentamidine (IC₅₀ = 13.3 µM). Furthermore, Complex 1 showed a promising selectivity index (SI = 9.7) against amastigotes, surpassing the reference drugs and meeting the criteria for a lead compound. While less active on promastigotes, both complexes demonstrated high stability in DMSO solution, a prerequisite for biological testing. <b>Conclusions</b>: These results unequivocally identify Complex 1 as a highly promising candidate for the development of new antileishmanial therapies, warranting further in vivo studies.