5-Arylidene-2,4-thiazolidinediones as Cysteine Protease Inhibitors against Leishmania Donovani

A series of 5-arylidene-2,4-thiazolidinediones were synthesized using Knoevenagel condensation and evaluated for their anti-leishmanial activity against L. donovani promastigotes and axenic amastigotes. Among the compounds tested, three were the most active, with IC50 values of 0.82-1.42 & mu;M against L. donovani promastigotes and 0.69-1.19 & mu;M against L. donovani amastigote. (Z)-5-(4-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione was the most prominent among all the tested compounds and demonstrated better anti-leishmanial properties when compared to the standard drug miltefosine (1.26 & mu;M against L. donovani promastigotes and 1.17 & mu;M against L. donovani amastigotes). It was insignificantly toxic compared to the standard miltefosine in THP-1 human monocytic cells. It was further evaluated for its in vitro cysteine protease (papain) inhibitory activity using Z-RR-AMC fluorogenic peptide substrate. It demonstrated promising inhibitory activity with the IC50 value of 3.42 & mu;M. In silico docking studies also supported that the (Z)-5-(4-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione is bound to cysteine protease proteins & PRIME; catalytic active binding site. Anti-leishmanial properties of this class of compounds have been evaluated for the first time, and (Z)-5-(4-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione emerged as a lead molecule from the library of compounds tested. This may serve as a template for further drug discovery in Leishmania.