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

Abstract

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 μM, 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.

Pharmacophore model, docking, QSAR, and molecular dynamics simulation studies of substituted cyclic imides and herbal medicines as COX-2 inhibitors

“…In addition, more investigations in the role of COX-2 inhibitors in cancer chemotherapy [ 6 , 7 ] and neurological diseases such as Parkinson [ 8 ] and Alzheimer's diseases are still needed [ 9 , 10 ]. Many valuable studies on COX-2 inhibitors have still published until now, as, these inhibitors are still subject to the interest of researchers worldwide [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Investigation of Antifungal Properties of Synthetic Dimethyl-4-Bromo-1-(Substituted Benzoyl) Pyrrolo[1,2-a] Quinoline-2,3-Dicarboxylates Analogues: Molecular Docking Studies and Conceptual DFT-Based Chemical Reactivity Descriptors and Pharmacokinetics Evaluation

“…However, in organic chemistry, the maximum heterocyclic compounds possess significant biological activity [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Recent reports suggest that indolizine is a very attractive molecule among the heterocyclic compounds and possesses two fused ring structures with carbon and nitrogen bridging atoms.…”

“…Recent reports suggest that indolizine is a very attractive molecule among the heterocyclic compounds and possesses two fused ring structures with carbon and nitrogen bridging atoms. Further, the numerous indolizine derivatives show potential biological activities [ 16 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], which includes antioxidant [ 42 , 43 , 44 ], antimicrobial [ 42 , 43 , 44 , 45 , 46 ], anti-inflammatory [ 47 ], anticancer [ 48 , 49 ] and antituberculosis [ 50 ] activities.…”

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

“…Synthetic indolizine derivatives have been shown to interact with a wide range of drug targets such as calcium channels [10], histamine receptors [11], and phospholipase A2 [12]. In addition, they have shown numerous pharmacological properties [13] such as analgesic [14], COX-2-inhibitory [15][16][17][18], anticancer [19,20], antidiabetic [21], antihistaminic [11], antileishmanic [22], antimicrobial [23], antimutagenic [24], antioxidant [25], antiviral [26], larvicidal [27,28], herbicidal [29], antitubercular [30][31][32][33][34][35][36][37], and alpha-7 nicotinic acetylcholine receptor (α-7 nAChR)- [38], N-meningitidis-, N-acetylneuraminic acid synthese (NmeNANAS)-inhibitory activities [39].…”