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

Abstract

Towards optimization of the pyrrolizine-5-carboxamide scaffold, a novel series of six derivatives (4a-c and 5a-c) was prepared and evaluated for their anti-inflammatory, analgesic and anticancer activities. The (EZ)-7-cyano-6-((4-hydroxybenzylidene)amino)-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4b) and (EZ)-6-((4-chlorobenzylidene)-amino)-7-cyano-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5b) bearing the electron donating methyl group showed the highest anti-inflammatory activity while (EZ)-6-((4-chlorobenzylidene)amino)-7-cyano-N-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5a) was the most active analgesic agent. Cytotoxicity of the new compounds was evaluated against the MCF-7, A2780 and HT29 cancer cell lines using the MTT assay. Compounds 4b and 5b displayed high anticancer activity with IC50 in the range of 0.30–0.92 μmol L−1 against the three cell lines, while compound (EZ)-N-(4-chlorophenyl)-7-cyano-6-((4-hydroxybenzylidene)-amino)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4c) was the most active against MCF-7 cells (IC50 = 0.08 μmol L−1). Both the anti-inflammatory and anticancer activities of the new compounds were dependent on the type of substituent on the phenyl rings. Substituents with opposite electronic effects on the two phenyl rings are preferable for high cytotoxicity against the MCF-7 and A2780 cells. COX inhibition was suggested as the molecular mechanism of the anti-inflammatory activity of the new compounds while no clear relationship could be observed between COX inhibition and anticancer activity. Compound 5b, the most active against the three cell lines, induced dose-dependent early apoptosis with 0.1–0.2 % necrosis in MCF-7 cells. New compounds showed promising drug-likeness scores while the docking study revealed high binding affinity to COX-2. Taken together, this study highlighted the significant impact of the substituents on the anti-inflammatory and anticancer activity of pyrrolizine-5-carboxamides, which could help in further optimization to discover good leads for the treatment of cancer and inflammation.

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.…”

“…The study was performed using both SwissADME (http://www. swiss adme.ch/), developed by the Molecular Modeling Group of the Swiss Institute of Bioinformatics [27], and Molsoft (http://molso ft.com/mprop /) which was developed by Molsoft LLC according to our previous reports [12,31]. The study revealed that all the selected compounds displayed molecular weight, molecular volume in the range of 257.26-382.56 (< 500), log P values (MlogP) in the range of 2.94 -5.49, hydrogen bond donors range (H D ) ≤ 5 and hydrogen bond acceptors (H A ) ≤ 10 ( Table 7).…”

“…Although coxibs displayed safe GIT profile, but their use was associated with cardiovascular and renal side effects [9]. However, selective COX-2 inhibitors still attract the attention due to their antiproliferative activity [10][11][12].…”

Proapoptotic Activity of Achillea membranacea Essential Oil and Its Major Constituent 1,8-Cineole against A2780 Ovarian Cancer Cells

“…The induction of apoptosis activity of A. membranacea EO and 1,8-cineole was investigated by annexin V FITC/Propidium iodide protocol as described in the literature [44]. Briefly, A2780 cells were seeded at 1 × 10 5 cells/well in 6-well plate overnight before treatment with either A. membranacea EO or 1,8-cineole at four concentrations, ranging from 0 to 50 µg/mL, or 0-1 µM, respectively (representing IC 50 : 0, ×1, ×2 and ×4).…”

Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities

“…The quantitative elemental analyses were done in the microanalytical centre, Cairo University. Compounds 12 37 , 14a-c [38][39][40] , 15a-c 41 were prepared according to the previous reports. Copies of spectral data including IR, 1 H-NMR, 13 C-NMR, 13 C-NMR, DEPT C 135 , and mass spectra of the new compounds are provided in supplementary ( Figures S43-S137).…”