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

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 (5a–e) 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 (5a) 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 (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer 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.

Download Full-text

Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies

Biomolecules ◽

10.3390/biom9110661 ◽

2019 ◽

Vol 9 (11) ◽

pp. 661 ◽

Cited By ~ 4

Author(s):

Venugopala ◽

Al-Attraqchi ◽

Tratrat ◽

Nayak ◽

Morsy ◽

...

Keyword(s):

Molecular Modeling ◽

Therapeutic Agents ◽

Cox Inhibitors ◽

Lead Compounds ◽

Important Target ◽

Pharmacokinetic Properties ◽

Molecular Modeling Studies ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 2 Inhibitors

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 M, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents.

Download Full-text

Design and synthesis of new 1,4,5-trisubstituted triazole-bearing benzenesulphonamide moiety as selective COX-2 inhibitors

Medicinal Chemistry Research ◽

10.1007/s00044-021-02716-7 ◽

2021 ◽

Author(s):

Mohamed S. Bekheit ◽

Hanan A. Mohamed ◽

Bakr F. Abdel-Wahab ◽

Marwa A. Fouad

Keyword(s):

Design And Synthesis ◽

Cox 2 ◽

Cox 2 Inhibitors

Download Full-text

COX-2: A Pivotal Enzyme in Mucosal Protection and Resolution of Inflammation

The Scientific World JOURNAL ◽

10.1100/tsw.2006.122 ◽

2006 ◽

Vol 6 ◽

pp. 577-588 ◽

Cited By ~ 50

Author(s):

John L. Wallace

Keyword(s):

Digestive System ◽

Intestinal Inflammation ◽

Mucosal Protection ◽

Cox Inhibitors ◽

Gastrointestinal Injury ◽

Inflammatory Drugs ◽

Long Term Consequences ◽

Cox 2 ◽

Cox 2 Inhibitors

The discovery of a second form of cyclooxygenase, COX-2, led to a burst of research aimed at the development of nonsteroidal anti-inflammatory drugs that would not damage the gastrointestinal tract. In the years since, this promise has only been partially fulfilled. Selective COX-2 inhibitors cause less gastric damage than conventional, nonselective COX inhibitors, but their use is still associated with significant gastrointestinal injury, and with toxicity in the renal and cardiovascular systems. COX-2 is now recognized as a source of mediators that produce many beneficial and detrimental effects in the digestive system. In this review, the roles of COX-2 in mucosal defense and injury are discussed. Furthermore, contributions of COX-2derived products to the long-term consequences of intestinal inflammation, including cancer, are reviewed.

Download Full-text