Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole IN/I-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, IIn Silico/I 11β-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[sub.1] /c, P2[sub.1] and P2[sub.1] /n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2022-10, Vol.27 (21)
Main Authors: Al-Wahaibi, Lamya H, Macías, Mario A, Blacque, Olivier, Zondagh, Luke S, Joubert, Jacques, Thamotharan, Subbiah, Percino, María Judith, Mohamed, Ahmed A. B, El-Emam, Ali A
Format: Article
Language:English
Subjects:
Chemical properties
Chemical reactions
Drug metabolism
Health aspects
Methods
Organic compounds
Pharmaceutical research
Pharmacokinetics
Structure
Toxicity testing
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Summary: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[sub.1] /c, P2[sub.1] and P2[sub.1] /n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π 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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1–3 were determined using in silico techniques. Molecular docking of the compounds into the 11β-HSD1 active site showed comparable binding affinity scores (−7.50 to −8.92 kcal/mol) to the 11β-HSD1 co-crystallized ligand 4YQ (−8.48 kcal/mol, 11β-HSD1 IC[sub.50] = 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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27217403