Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed anti-inflammatory and pain relief medications. However, their use is associated with many drawbacks, including mainly serious gastric and renal complications. In an attempt to circumvent these risks, a set of N-(4-bromophenyl)-7-cyano-6-substituted-H-pyrrolizine-5-carboxamide derivatives were designed, synthesized and evaluated as dual COX/5-LOX inhibitors. The structural elucidation, in vivo anti-inflammatory and analgesic activities using a carrageenan-induced rat paw edema model and hot plate assay, were performed, respectively. From the results obtained, it was found that the newly synthesized pyrrolizines exhibited IC 50 values in the range of 2.45-5.69 µM and 0.85-3.44 µM for COX-1 and COX-2, respectively. Interestingly, compounds 12, 13, 16 and 17 showed higher anti-inflammatory and analgesic activities compared to ibuprofen. Among these derivatives, compounds 16 and 19 displayed better safety profile than ibuprofen in acute ulcerogenicity and histopathological studies. Furthermore, the docking studies revealed that compound 17 fits nicely into COX-1 and COX-2 binding sites with the highest binding affinity, while compound 16 exerted the highest binding affinity for 5-LOX. In light of these findings, these novel pyrrolizine-5-carboxamide derivatives represent a promising scaffold for further development into potential dual COX/5-LOX inhibitors with safer gastric profile.

Carprofen: a theoretical mechanistic study to investigate the impact of hydrophobic interactions of alkyl groups on modulation of COX-1/2 binding selectivity

“…The crystal structure of the two enzymes were obtained from protein data bank (http://www.rcsb.org/pdb). The preparation of the ligands was done according to our previous reports [4,12]. The study was performed after validation of the docking scenario by re-docking the native ligands into their corresponding COX enzymes.…”

“…Development of selective cyclooxygenase-2 (COX-2) inhibitors was suggested as an attractive strategy to overcome GIT side effects of traditional NSAIDs [1][2][3][4][5]. Diverse scaffolds with potential COX inhibitory activity were reported with the great advances in heterocyclic synthesis [6,7].…”

Pyrrolizine-5-carboxamides: Exploring the impact of various substituents on anti-inflammatory and anticancer activities

“…Experimental procedures were performed following our previous report (10). Induction of inflammation was performed by a subcutaneous (s.c.) injection of 50 µL of 0.5 % carrageenan-sodium gel (Sigma-Aldrich, USA) into the sub-plantar region of the right hind paw.…”

“…The standard drug, ibuprofen (100 mg kg -1 bm), and the test compounds (both 0.48 mmol kg -1 bm) were given orally. Experimental procedures were performed following a previous report (10). Analgesic effect of the tested compounds was calculated as the percentage of the maximal protective effect.…”

“…Recently, several reports have focused on the anti-inflammatory and anticancer activities of the pyrrolizine derivatives (8)(9)(10). Licofelone (Fig.…”