TitleCrystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives.
Publication TypeJournal Article
Year of Publication2021
AuthorsVenugopala KN, Chandrashekharappa S, Tratrat C, Deb PKishore, Nagdeve RD, Nayak SK, Morsy MA, Borah P, Mahomoodally FM, Mailavaram RPrasad, Attimarad M, Aldhubiab BE, Sreeharsha N, Nair AB, Alwassil OI, Haroun M, Mohanlall V, Shinu P, Venugopala R, Kandeel M, Nandeshwarappa BP, Ibrahim YF
Date Published2021 Jun 10
KeywordsAnti-Inflammatory Agents, Crystallography, X-Ray, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Humans, Hydrophobic and Hydrophilic Interactions, Indolizines, Indomethacin, Structure-Activity Relationship

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 (-) 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 () emerged as a promising COX-2 inhibitor with an IC of 5.84 µM, as compared to indomethacin (IC = 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 () was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule () crystallizes in the monoclinic crystal system with space group 2/n with = 12.0497(6)Å, = 17.8324(10)Å, = 19.6052(11)Å, = 90.000°, = 100.372(1)°, = 90.000°, and V = 4143.8(4)Å. In addition, with the help of 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.

Alternate JournalMolecules
PubMed ID34200764
PubMed Central IDPMC8230391
Grant List186333 / / Deanship of Scientific Research, King Faisal University /