Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11-HSD1 Molecular Docking and ADMET Prediction

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1-3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P2(1)/c, P2(1) and P2(1)/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H center dot center dot center dot O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H center dot center dot center dot N, C-H center dot center dot center dot S and C-H center dot center dot center dot pi interactions. The energy frameworks for crystal structures of 1-3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1-3 were determined using in silico techniques. Molecular docking of the compounds into the 11 beta-HSD1 active site showed comparable binding affinity scores (-7.50 to 8.92 kcal/mol) to the 11 beta-HSD1 co-crystallized ligand 4YQ (-8.48 kcal/mol, 11 beta-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.