Antileishmanial potential of thiourea-based derivatives: design, synthesis and biological activity†

Leishmaniasis is a neglected tropical disease caused by protozoan parasites and transmitted to humans by the sandfly vector. Currently, the disease has limited therapeutic alternatives. Thiourea derivatives were designed, synthesized, and screened for antileishmanial activity. The synthesized compounds 4g, 20a, and 20b demonstrated significant in vitro potency against L. major, L. tropica, and L. donovani promastigotes with IC₅₀ values at low submicromolar concentrations. Compound 4g showed the highest activity against the amastigotes of L. major. In enzyme inhibition assays, compounds 4g, 20a, and 20b demonstrated good inhibitory potential against L. major dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). Reversal of the antileishmanial effect by adding folic acid revealed that the compounds 4g, 20a, and 20b act through an antifolate mechanism. Cytotoxicity data on normal human embryonic kidney cells (HEK-293) showed that the synthesized compounds displayed better safety profiles. Docking experiments on the enzymes L. major DHFR and PTR1 demonstrated the significant interactions with the active pocket residues of the target enzymes.