Supramolecular Self-Assembly Built by Weak Hydrogen, Chalcogen, and Unorthodox Nonbonded Motifs in 4-(4-Chlorophenyl)-3-[(4-fluorobenzyl)sulfanyl]-5-(thiophen-2-yl)-4 H-1,2,4-triazole, a Selective COX-2 Inhibitor: Insights from X-ray and Theoretical Studies

Lamya H Al-Wahaibi; Bavanandan Rahul; Ahmed A B Mohamed; Mohammed S M Abdelbaky; Santiago Garcia-Granda; Ali A El-Emam; M Judith Percino; Subbiah Thamotharan

doi:10.1021/acsomega.0c06287

Supramolecular Self-Assembly Built by Weak Hydrogen, Chalcogen, and Unorthodox Nonbonded Motifs in 4-(4-Chlorophenyl)-3-[(4-fluorobenzyl)sulfanyl]-5-(thiophen-2-yl)-4 H-1,2,4-triazole, a Selective COX-2 Inhibitor: Insights from X-ray and Theoretical Studies

ACS Omega. 2021 Mar 3;6(10):6996-7007. doi: 10.1021/acsomega.0c06287. eCollection 2021 Mar 16.

Authors

Lamya H Al-Wahaibi¹, Bavanandan Rahul², Ahmed A B Mohamed³, Mohammed S M Abdelbaky⁴, Santiago Garcia-Granda⁴, Ali A El-Emam³, M Judith Percino⁵, Subbiah Thamotharan²

Affiliations

¹ Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia.
² Biomolecular Crystallography Laboratory, Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India.
³ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁴ Department of Physical and Analytical Chemistry, Faculty of Chemistry, Oviedo University-CINN, Oviedo 33006, Spain.
⁵ Unidad de Polímeros y Electrónica Orgánica, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Val3-Ecocampus Valsequillo, Independencia O2 Sur 50, San Pedro Zacachimalpa, Puebla C.P. 72960, Mexico.

Abstract

A selective triazole-based COX-2 inhibitor, 4-(4-chlorophenyl)-3-[(4-fluorobenzyl)sulfanyl]-5-(thiophen-2-yl)-4H-1,2,4-triazole, C₁₉H₁₃ClFN₃S₂, has been synthesized, and its crystal structure was determined at 150 K. Single-crystal X-ray diffraction analysis revealed that the thiophene ring was disordered over two orientations. The crystal structure is stabilized by weak hydrogen and chalcogen bonds and unorthodox F···π and S···C(π) contacts. These noncovalent interactions cooperatively generate the supramolecular self-assembly in the crystalline state. The Hirshfeld surface and its associated two-dimensional (2D)-fingerprint plots were obtained to analyze the role of different noncovalent interactions in the crystal packing. Further, the enrichment ratio was obtained from different atom···atom pairs to calculate the propensity of these pairs to form noncovalent interactions. The strength of different dimeric motifs formed in the crystal structure and lattice energies was calculated by the PIXEL method. Furthermore, the topological analysis of the charge density of intermolecular interactions was described. A CSD survey of C-H···F hydrogen bond, C-S···Cl chalcogen bond, and unorthodox nonbonded contacts (F···π and S···C(π)) is presented. The title compound possesses selective inhibitory activity against human COX-2 enzyme rather than COX-1. The quantum mechanics (QM) polarized ligand docking analysis was used to predict the binding pose and study the title compound's selectivity against COX-1/2 enzymes.