In Silico Studies and Biological Evaluation of Thiosemicarbazones as Cruzain-Targeting Trypanocidal Agents for Chagas Disease

TL;DR

Scientists tested new compounds that inhibit a key enzyme in Chagas disease parasites, showing strong effectiveness and low toxicity.

Contribution

The study identifies thiosemicarbazone derivatives as potent cruzain inhibitors with favorable drug properties for treating Chagas disease.

Findings

Compounds H7, H10, and H11 inhibited cruzain with IC50 values below 0.5 µM.

These compounds showed low cytotoxicity in human fibroblasts with CC50 > 64 µM.

Structure–activity analysis revealed that aromatic systems and electron-donating groups enhance cruzain binding.

Abstract

Background/Objectives: Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided hit prioritization and correlated with enzyme inhibition; validation by redocking supported the protocol’s reliability. Results: The top compounds—H7, H10 and H11—showed potent cruzain inhibition (IC50 = 0.306, 0.512 and 0.412 µM, respectively) and low-micromolar trypanocidal activity, with negligible cytotoxicity in human fibroblasts (CC50 > 64 µM) and favorable selectivity. Structure–activity insights highlighted the role of expanded aromatic systems and electron-donating groups in enhancing binding within S2/S1′ subsites, while nitro substituents were associated with higher cytotoxicity. In silico ADMET parameters supported oral drug-likeness and acceptable metabolic liabilities. Conclusions: Overall, these data position TSCs as promising anti-T. cruzi leads and underscore the value of rational design against cruzain.

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