Green synthesis, <i>in vitro</i>, and <i>in silico</i> assessments of hydrazone-Schiff bases as potential antileishmanial agents

To synthesize and assess hydrazone Schiff bases using green chemistry principles for potential antileishmanial activity. Sixteen hydrazone Schiff bases, including seven novel compounds (SSB2, SSB4, SSB5, RSB4, SSB14, SSB15, and SSB31), were synthesized under solvent-free conditions using grinding technique. The compounds were structurally confirmed via FT-IR, ¹ H NMR, and ^{1 3} C NMR spectroscopy. Their in vitro antileishmanial activities were evaluated versus Leishmania tropica promastigotes and amastigotes. Molecular docking studies targeted leishmanolysin enzyme, while Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) and Density Functional Theory (DFT) analyses were used to predict pharmacokinetics, drug-likeness and stability. Most compounds showed moderate to good activity, with SSB28, SSB35, SSB36, and RSB4 displaying IC₅₀ values between 4 ± 0.5 and 8.0 ± 0.2 µg/mL. SSB28 was the most potent, with its IC₅₀ values of 4 ± 0.5 and 4.5 ± 0.4 µg/mL versus Promastigote and amastigote respectively as compared to the reference drug Amphotericin-B (IC₅₀ 2.0 and 2.3 ± 0.5 µg/mL). Docking studies indicated strong binding of SSB28 to leishmanolysin. ADMET and DFT results showed that SSB28 possesses favorable pharmacokinetics and low predicted toxicity. SSB28 is an encouraging antileishmanial lead derivative with potent activity, environmental compatibility, and predicted safety making it a feasible candidate for further drug development.