Design, synthesis, 99mTc labeling, and biological evaluation of a novel pyrrolizine derivative as potential anti-inflammatory agent

Attallah, K. M.; Gouda, Ahmed M.; Ibrahim, I. T.; Abou-Zeid, Laila A.

doi:10.1134/s10663622170600121

Cited by 11 publications

(7 citation statements)

References 28 publications

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Gouda

Almalki

2019

SN Appl. Sci.

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Development of selective COX-1 and COX-2 was successfully used to overcome GIT side effects of the classical NSAIDs. Currently, virtual screening and docking study were extensively used to design of new potent and safe drug candidates. In this study, four series of carprofen derivatives were designed by isosteric replacement of the-NH-with-O- ,-Sand-CH 2-groups. More than 90 derivatives bearing different alkyl substituents were designed in this study. AutoDock software was used to explore the binding mode, affinity and selectivity of the designed analogs to COX1/2. The results revealed that position and length of alkyl substituents have remarkable effect on the binding mode. Substitution with alkyl groups at C1 and C6 of the four scaffolds improved binding to COX-1, while at C4 enhanced COX-2 binding affinity. Compound 66 displayed the highest binding affinity for COX-1 and COX-2 with ΔG b of 11.2 and 10.15 kcal/mol, respectively. Compound 56 and 99 displayed the highest potential selectivity to COX-1 and COX-2, respectively. Drug-likeness study and synthetic accessibility were evaluated for the most promising analogs. Compound 29 displayed drug-likeness score (DLS) of 0.96 compared to 0.3 for carprofen. Taken together, these results highlighted the importance of hydrophobic interactions in modulation of COX-1/2 binding selectivity of new potential NSAIDs.

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Section: Introductionmentioning

confidence: 99%

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

Gouda

Almalki

2019

SN Appl. Sci.

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“…Elemental analyses were done in the microanalytical centre, Cairo University (Giza, Egypt). Compounds 11 14 , 13a–e 15 , 16 , 14a–e 17 , 18 15 , and 19 15 were prepared according to the previous report 13 . Copies of spectral data including IR, 1 H NMR, 13 C NMR, 13 C NMR, DEPT C 135 , and mass spectra for each of the new compounds are provided in Supplementary (Figs.…”

Section: Methodsmentioning

confidence: 99%

“…480 (1), 450(6), 436 (4), 400(7), 396(5), 387(7), 372(6), 352(20), 340(14), 339(11), 329(17), 328(7), 327(9), 313(13), 299(12), 298(15), 280 (4), 279(11), 273(21), 269(15), 268 (48), 254 (20), 240 (26), 228 (30), 210 (40), 196 (23), 195 (31), 174 (100), 169 (31), 147 (29), 145 (17), 123 (31), 117 (29), 107 (44), 92 (36), 77 (14). Anal.…”

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Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

Shawky

Ibrahim

Abdalla

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a-e showed higher cytotoxicity than their corresponding Schiff bases 15a-e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC 50 in the range of 0.52-6.26 lM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC 50 ¼0.155-17.08 lM). Mechanistic studies revealed the ability of compounds 16a,b,d to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds 16a,b,d induced preG 1 and G 2 /M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds 16a,b,d into the active site in tubulin, CDK-2, and EGFR proteins revealed higher binding affinities compared to the co-crystallised ligands. These preliminary results suggested that compounds 16a,b,d could serve as promising lead compounds for the future development of new potent anticancer agents. HIGHLIGHTS 1. Two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized. 2. Compounds 16a,b,d displayed the highest cytotoxicity against the three cancer cell lines. 3. Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds 16a,b,d. 4. Compounds 16a,b,d exhibited weak to moderate inhibition of tubulin-polymerization. 5. Compounds 16a,b,d induced preG 1 and G 2 /M cell cycle arrest and early apoptosis in MCF-7 cells. 6. Docking studies revealed high binding affinities for compounds 16a,b towards tubulin and CDK-2.

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“…The docking studies were done using AutoDock 4.2 46 . Preparation of ligands, proteins, grid, and docking parameter files was done following our previous reports [47][48][49] . The study was performed according to the previous report 25 .…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

“…The docking procedures were performed according to the previous report 25 . The grid and docking parameter files were prepared according to the previous reports [47][48][49] . Visualisation of the binding interactions of the new compounds in the active sites of CDK-2 was performed by Discovery studio visualizer 50 .…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

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

Shawky

Ibrahim

Abourehab

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC 50 ¼ 0.16-34.13 lM). The drug-likeness study revealed that all the new compounds conform to Lipinski's rule. Mechanistic studies of compounds 18 b, 19a, and 20a revealed the induction of apoptosis and cell cycle arrest at the G 1 phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC 50 ¼ 25.53-115.30 nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents.

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Design, synthesis, 99mTc labeling, and biological evaluation of a novel pyrrolizine derivative as potential anti-inflammatory agent

Cited by 11 publications

References 28 publications

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

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

Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

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

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