Adamantane-thiazole hybrids and related derivatives: synthesis, crystal structures, in vitro antibacterial, antifungal, and anti-proliferative activities

Series of 2-(adamantan-2-ylidene)-N-substituted hydrazine-1-carbothioamide derivatives 5a-d and (E)-2-[(adamantan-2-ylidene)hydrazono]-3,4-diaryl-2,3-dihydrothiazole derivatives 7a-l were prepared and their structures were confirmed. In vitro antimicrobial evaluation of compounds 5a-d and 7a-l against different pathogenic bacterial and fungal strains revealed that compounds 5a, 5b, 5c, 7a, 7f, 7i and 7k displayed notable effectiveness against the Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and the Gram-negative Escherichia coli, and all compounds lacked antifungal activity. In addition, compounds 5a, 5b, 5c, 7f and 7 L displayed marked anti-proliferative activity particularly against HepG-2 and MCF-7 cancer cell lines (IC₅₀ < 25 µM). The structures of compounds 5c, 7a and 7f were confirmed by single-crystal X-ray diffraction studies. Compound 5c crystallized with a lattice water molecule and is stabilized by N-H···Cl/S, and C-H···O/Cl/π interactions. The crystal packing features of 7a and 7f are very similar, despite the presence of a methoxy substituent in 7f. Compound 7a is stabilized by C-H···N/S/π interactions and a chalcogen bond (S···π), whereas compound 7f is stabilized by C-H···N/S/π interactions as well as C-H···O interactions involving the methoxy oxygen as an acceptor. Molecular docking studies of the most potent antibacterial adamantane-thiazole derivatives 7f and 7i showed good affinity towards dehydrosqualene synthase (SaCrtM) from Staphylococcus aureus. Meanwhile, potent anti-proliferative compounds 5a, 5b, and 7f showed marked affinity the urokinase-type plasminogen activator receptor (uPAR).