Data Sheet 1_Weak noncovalent interactions in 1,2,4-triazole-3-thione-linked adamantyl derivatives: experimental and computational insights into their potential as antiproliferative agents.docx

The synthesis, single-crystal X-ray structures, and antiproliferative activity of five adamantyl-linked 1,2,4-triazole-3-thione derivatives are presented. The crystal structures of the mono- and di-substituted chloro derivatives were analyzed in detail, revealing a variety of weak noncovalent interactions, including C–H···N, C–H···O, C–H···Cl, C–H···S, and π···π stacking, which contribute to the stability of their supramolecular assemblies. Notably, the crystal packing is also stabilized by σ-hole interactions, such as S···S and S···N chalcogen bonds, and by short, attractive Csp3–H···H–Csp3 contacts involving the adamantyl moieties. The nature and energetics of these interactions were investigated through a combination of Hirshfeld surface analysis, generalized Kohn-Sham energy decomposition analysis (GKS-EDA), and the quantum theory of atoms in molecules (QTAIM). The antiproliferative potential of these compounds was rationalized through molecular docking studies with urokinase plasminogen activator (uPA), which showed that the title compounds interact effectively with key catalytic residues. This work provides detailed insights into the role of weak noncovalent forces in the crystal engineering of adamantyl-triazole derivatives and supports their potential as uPA-directed anticancer agents.