Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives

• Main Authors: Katharigatta N. Venugopala, Sandeep Chandrashekharappa, Christophe Tratrat, Pran Kishore Deb, Rahul D. Nagdeve, Susanta K. Nayak, Mohamed A. Morsy, Pobitra Borah, Fawzi M. Mahomoodally, Raghu Prasad Mailavaram, Mahesh Attimarad, Bandar E. Aldhubiab, Nagaraja Sreeharsha, Anroop B. Nair, Osama I. Alwassil, Michelyne Haroun, Viresh Mohanlall, Pottathil Shinu, Rashmi Venugopala, Mahmoud Kandeel, Belakatte P. Nandeshwarappa, Yasmine F. Ibrahim
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: Molecules
• Subjects: indolizine derivatives; molecular modeling; COX-2 inhibition; crystal structure; Hirshfeld surface analysis; energy framework
• Online Access: https://www.mdpi.com/1420-3049/26/12/3550

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (<b>5a</b>–<b>e</b>) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (<b>5a</b>) emerged as a promising COX-2 inhibitor with an IC₅₀ of 5.84 µM, as compared to indomethacin (IC₅₀ = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (<b>5c</b>) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (<b>5c</b>) crystallizes in the monoclinic crystal system with space group <i>P</i> 2₁/n with <i>a</i> = 12.0497(6)Å, <i>b</i> = 17.8324(10)Å, <i>c</i> = 19.6052(11)Å, <i>α</i> = 90.000°, <i>β</i> = 100.372(1)°, <i>γ</i> = 90.000°, and V = 4143.8(4)ų. In addition, with the help of <i>Crystal Explorer</i> software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.