Abstract
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.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed drugs for the treatment of inflammatory conditions worldwide [1]
The energy framework was outlined as red cylinders for Eelec, green cylinders for Edis, and blue cylinders for Etot, as shown in (Figure 8b–d), and the relative strength of molecular packing was expressed in various directions by these tubes
5d, studies substituted with a methoxy functionalin group the 3-position of Molecular docking are considered an invaluable silicoatapproach to corthe benzoyl ring,structure–activity displayed the least inhibitory (SAR)
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed drugs for the treatment of inflammatory conditions worldwide [1]. NSAIDs exhibit their anti-inflammatory activity via inhibition of cyclooxygenase (COX), an enzyme involved in the biosynthesis of prostaglandin G2 (PGG2). In persistence of our interest in pharmacologically active heterocyclic compounds [40,41,42,43,44,45,46,47,48], polymorphism studies [49,50,51,52], and the discovery of anti-inflammatory agents [53,54,55,56,57,58,59], in the present investigation, we synthesized a range of 7-methoxy indolizine derivatives as indomethacin analogues (Figure 1 and Scheme 1) to evaluate their potential as antiinflammatory agents. The title compounds (5a–e) were evaluated for their pharmacological activity against the COX-2 enzyme in order to study the influence of ethyl ester at the 1and 2-positions, ethyl at the 2-position, and the diverse substituent on the benzoyl ring at the 3-positions of the indolizine core on the biological action
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