2-Phenyl-1,2,6,7-Tetrahydrocyclopenta[D][1,3]Thiazine-4(5H)-Thione: Synthesis, Crystal Structure, Hirshfeld Surface Analysis, DFT Calculations, ADMET Prediction, and Molecular Docking†

Delgado G.E.; Cisterna J.; Coy C.; Mora A.J.; Guillen M.; Ávila E.; Contreras R.R.; Chacón C.; Marroquin G.; Márquez G. · Journal of Chemistry (2026) · DOI: 10.1155/joch/5818197

Resumen

The compound 2-phenyl-1,2,6,7-tetrahydrocyclopenta[d][1,3]thiazine-4(5H)-thione (I) was synthesized from benzylideneaniline and 2-amino-1-cyclopentene-dithiocarboxylic acid. Its molecular structure was confirmed by FT-IR and NMR spectroscopy, and the crystalline phase was verified by powder X-ray diffraction. Single-crystal X-ray diffraction revealed that (I) crystallizes in the monoclinic centrosymmetric space group P21/n (no. 14), with two independent molecules in the asymmetric unit, where the thiazine ring adopts a distorted boat conformation. The crystal packing is stabilized by N–H···S hydrogen-bond-forming D(2) dimers and C(6) one-dimensional chains. Hirshfeld surface analysis showed that H···H, S···H, and C···H contacts dominate the intermolecular interactions for both molecules. Energy framework calculations suggest that the intermolecular interactions are dominated by dispersion contributions, with secondary electrostatic components. DFT and DFTB calculations produce the experimental structural parameters with excellent agreement. ADMET prediction indicated favorable physicochemical and pharmacokinetic properties, including high gastrointestinal absorption, blood–brain barrier permeability, compliance with all major drug-likeness rules, and absence of pan-assay interference compounds (PAINS) alerts. The compound showed moderate lipophilicity, acceptable solubility, and low predicted risks of hepatic, renal, and cardiac toxicity. Molecular docking simulations against the serotonin 2B receptor (HTR2B) yielded a predicted binding affinity of −8.205 kcal/mol with a geometrically consistent binding mode involving residues. Asp351, Gln355, Arg74, and Val72; these findings are purely computational and should be regarded as preliminary indications requiring experimental validation. ADMET profiling revealed favorable physicochemical and pharmacokinetic properties, including compliance with all major drug-likeness criteria and absence of PAINS alerts. Overall, the combined crystallographic, computational, and in silico pharmacological analyses establish Compound (I) as a structurally well-defined thiazine scaffold whose predicted interaction profile warrants further experimental investigation. Copyright

Instituciones: Universidad Tecnológica del Perú