Enantiomer-Resolved Biological Profiling and Chiral Developability Assessment of Novel Naphthylethyl Thioureas

Molnár, Gergely and Simon, Balázs and Mirzahosseini, Arash and Dobó, Máté and Dombi, Gergely and Fiser, Béla and Mhammad, Ali and Bárdos, Vivien and Szolláth, Rita and Szabó, Zoltán István and Marton, András Dénes and Varga, Kamilla and Tábi, Tamás and Boldizsár, Imre and Horváth, Andrea and Dobay, Orsolya and Bősze, Szilvia and Balogh, György Tibor and Tóth, Gergő (2026) Enantiomer-Resolved Biological Profiling and Chiral Developability Assessment of Novel Naphthylethyl Thioureas. PHARMACEUTICS, 18. No. 1129. ISSN 1999-4923

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Abstract

Background/Objectives: Stereochemistry can substantially influence the biological activity and pharmaceutical properties of small molecules. This study investigated the stereochemistry-dependent biological activity and chiral recognition of novel naphthylethyl thiourea enantiomers using an integrated biological, chromatographic, and computational approach. Methods: Ten pairs of naphthylethyl thiourea enantiomers were synthesized from enantiomerically pure precursors and characterized. Antiproliferative and antibacterial activity, chiral HPLC behavior on polysaccharide- and protein-based stationary phases, molecular docking, and multivariate relationships were evaluated. Results: Target-dependent enantioselectivity and substituent-dependent activity patterns were observed. All enantiomeric pairs were chromatographically distinguished under at least one condition, and selected compounds showed selector- and mobile-phase-dependent changes in elution order. AGP-based chromatography showed stereoselective recognition for a subset of compounds, while computational analyses provided complementary support for the experimental trends. Conclusions: Stereochemistry and substitution jointly influence biological and chromatographic behavior in this thiourea series. Integrated biological, chromatographic, and computational profiling provides a useful framework for early enantiomer-resolved developability assessment.

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