Anti-leishmanial click modifiable thiosemicarbazones: Design, synthesis, biological evaluation and in silico studies

Mohamed G. Temraz, Perihan A. Elzahhar, Alaa El-Din A. Bekhit, Adnan A. Bekhit, Hala F. Labib, Ahmed S.F. Belal

Index: 10.1016/j.ejmech.2018.04.003

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Abstract

Leishmaniasis is a devastating tropical disease with limited therapeutic options. Depending on recently reported active anti-leishmanial compounds, we designed and synthesized a series of click modifiable 1,2,3-triazole and thiosemicarbazone hybrids. Most of the synthesized compounds showed comparable to superior activity to a well-established anti-leishmanial drug miltefosine. Compounds 2 and 10a showed nanomolar IC50s against promastigotes of L. major (227.4 nM and 140.3 nM respectively, vs 7.8 μM for miltefosine). Their antiamastigote IC50s were 1.4 μM and 1 μM respectively, which are 6 and 8 times the activity of miltefosine (IC50 8.09 μM). Folic and folinic acids reversed the anti-leishmanial effects of compounds 2 and 10a and hence we anticipate they act via an anti-folate mechanism. They exhibited better safety profiles than that of miltefosine on VERO cell lines. Also they were relatively safe on experimental mice when administered via oral and parenteral routes. Docking experiments on PTR1 identified preferential binding interactions and docking scores. Finally, drug-likeness and ligand efficiency were assessed indicating that both 2 and 10a are promising hits and/or leads as anti-leishmanial chemotherapeutic agents.