Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation

Marzouk, Adel A.; Abdel‐Aziz, Salah A.; Abdelrahman, Kamal S; Wanas, Amira S.; Gouda, Ahmed M.; Youssif, Bahaa G.M.; Abdel‐Aziz, Mohamed

doi:10.1016/j.bioorg.2020.104090

Cited by 38 publications

(36 citation statements)

References 33 publications

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“…Continuing our quest to find a compound with improved antimicrobial properties [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], the current study describes the synthesis and structure elucidation of Fluoroquinolone(ciprofloxacin)-based hybrids containing various heterocycle derivatives, as well as antimicrobial activity evaluation using various strains of Gram-positive ( S. aureus and B. subtilis ), Gram-negative ( E. coli and P. aeruginosa ), and fungi ( A. flavus and C. albicans ). In addition, the inhibitory activity of the most active compounds against E. coli DNA gyrase and topoisomerase IV has been identified as a potential molecular target.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

et al. 2021

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A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1H NMR, 13C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1–21 were screened in vitro against Gram-positive bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa. As a result, many of the compounds examined had antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2–6, oxadiazole derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested had antifungal activity against Aspergillus flavus, but did have poor activity against Candida albicans, ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole). The most potent compounds, 3, 4, 5, and 6, displayed an IC50 of 86, 42, 92, and 180 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). Compounds 4, 5, and 6 showed IC50 values (1.47, 6.80, and 8.92 µM, respectively) against E. coli topo IV in comparison to novobiocin (IC50 = 11 µM).

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

et al. 2021

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“…At the M stage, nuclear division takes place. [ 52 ] Panc1 cells were incubated with the IC 50 concentration of 8d for 24 h. The cell line was examined using flow cytometry after it had been labeled with propidium iodide (PI)/annexin V. [ 53 ] According to the findings in Figure 4, Panc1 cells treated with 8d had a greater proportion of cell accumulation (41.53%) in the pre‐G1 phase than untreated control Panc1 cells (1.62%), indicating cell cycle arrest at the G1 transition. The percentages of cell accumulation in other stages (G0–G1, S, and G2/M phases) in Panc1 cells treated with 8d were comparable to those in untreated control Panc1 cells.…”

Section: Resultsmentioning

confidence: 99%

New 1,3,4‐oxadiazoles linked with the 1,2,3‐triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase

Mahmoud

Mohammed

Gomaa

et al. 2022

Archiv der Pharmazie

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A series of 1,3,4-oxadiazole-1,2,3-triazole hybrids bearing different pharmacophoric moieties has been designed and synthesized. Their antiproliferative activity was evaluated against four human cancer cell lines (Panc-1, MCF-7, HT-29, and A-549) using the MTT (3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide) assay. The preliminary activity test displayed that the most active compounds, 6d, 6e, and 8a-e, suppressed cancer cell growth (GI 50 = 0.23-2.00 µM) comparably to erlotinib (GI 50 = 0.06 µM).Compounds 6d, 6e, and 8a-e inhibited the epidermal growth factor receptor tyrosine kinase (EGFR-TK) at IC 50 = 0.11-0.73 µM, compared to erlotinib (IC 50 = 0.08 ± 0.04 µM).The apoptotic mechanism revealed that the most active hybrid 8d induced expression levels of caspase-3, caspase-9, and cytochrome-c in the human cancer cell line Panc-1 by 7.80-, 19.30-, and 13-fold higher than doxorubicin. Also, 8d increased the Bax level by 40fold than doxorubicin, along with decreasing Bcl-2 levels by 6.3-fold. Cell cycle analysis after treatment of Panc-1 cells with hybrid 8d revealed a high proportion of cell accumulation (41.53%) in the pre-G1 phase, indicating cell cycle arrest at the G1 transition.Computational docking of the 8d and 8e hybrids with the EGFR binding site revealed their ability to bind with EGFR similar to erlotinib. Finally, in silico absorption, distribution, metabolism, and excretion/pharmacokinetic studies for the most active hybrids are discussed.

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“…The ability of compounds 16a , b , d to induce apoptotic changes in MCF-7 cells was determined by Annexin V-FITC/PI staining according to the previous report 13 , 18 , 19 . Additionally, the morphological changes in MCF-7 cells were examined by microscope.…”

Section: Methodsmentioning

confidence: 99%

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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Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation

Cited by 38 publications

References 33 publications

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

New 1,3,4‐oxadiazoles linked with the 1,2,3‐triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase

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

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