Carbothioamide functionalized paroxetine analogues as antiparasitic agents targeting the hypoxanthine-guanine-xanthine phosphoribosyltransferase enzyme: Synthesis, characterization, biochemical, biophysical, and in silico studies.

Hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) is one of the central enzymes of purine salvage pathway of protozoan parasites, including Plasmodium. These parasites are purine auxotrophs, and rely on purine salvage pathway for nucleic acid synthesis. Inhibiting the enzymatic activity can effectively reduce the parasite- induced infections, including malaria. In this context, a library of new carbothioamide derivatives 1-17 of paroxetine was synthesized via single-step chemical transformation strategy with a series of substituted phenyl isothiocyanates. All compounds were purified, and their structures were deduced by using spectroscopic techniques, such as mass, FT-IR, UV, and 1H-, and 13C-NMR. These compounds were evaluated for their HGXPRT inhibitory activity via in vitro UV-based spectrophotometric assay. All derivatives 1-17 showed varying potential to inhibit the enzyme activity with IC50 values between 19.0 to 76.9 µM, with highest activity showed by compound 13 (IC50 = 19.0 ± 2.09 µM) within the series, but remained less potent than the standard (9-deazaguanine, IC50 = 12.00 ± 1.0 µM). Biophysical, molecular docking, and molecular simulation studies were carried out further to analyse the enzyme-inhibitor interaction, and stability. These compounds were predicted to occupy the putative allosteric site of enzyme. Furthermore, cytotoxic profile of these compounds were also evaluated via ADMET analysis and MTT assay, and found to be largely non-cytotoxic. The current study has identified potential hits against HGXPRT enzyme that could further be investigated as anti-parasitic drugs.