In Vitro and In Silico Assessment of Antileishmanial Potential of Novel Tri‐ and Penta‐Valent Antimony Complexes With Phenolic Ligands

Leishmaniasis, caused by protozoan parasites of the genus Leishmania, affects nearly 12 million people annually worldwide, and has limited, highly toxic therapeutic options. This study reports the synthesis, in vitro and in silico evaluations of four novel antimony complexes (3a-3d) as potent and safe antileishmanial agents. The complexes were synthesized using Sb-salts with different phenolic ligands and characterized by elemental analysis, FT-IR and NMR spectroscopic techniques. Structural parameters were further evaluated via DFT studies. The antileishmanial activity of these complexes (3a-3d) was assessed in vitro against promastigote and axenic amastigote forms of Leishmania tropica, showing promising potential as antileishmanial agents. Complex 3a and 3c were particularly active, with IC₅₀ values of 10.8 ± 2.1 and 11.0 ± 2.0 μmol/L against promastigotes, and 20.14 ± 6.11 and 27.72 ± 0.13 μmol/L against amastigotes, respectively. Molecular docking analysis against receptor protein (PDB ID: 8FI6) from genus Leishmania revealed high binding conformations of synthesized molecules within the active cavity of the target protein. With the lowest Ki value of 1.25 and a pattern of hydrophobic π-interactions and strong conventional hydrogen bonds, complex 3d demonstrated excellent binding affinities within the active pocket. Notably, these complexes exhibited low cytotoxicity, compared to the standard antileishmanial drugs, TA (potassium antimonyl tartrate) and AmB (Amphotericin B), with hemolysis rates of < 12% for all complexes. Our findings suggest that these complexes (3a-3d) are promising candidates for the development of new, safer antileishmanial therapies, combining potent activity against L. tropica with significantly lower cytotoxicity compared to existing treatments.