New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with <i>in silico</i> docking, ADMET, toxicity, and DFT studies

Alanazi, Mohammed M.; Elkady, Hazem; Alsaif, Nawaf A.; Obaidullah, Ahmad J.; Alkahtani, Hamad M.; Alanazi, Manal M.; Alharbi, Madhawi A.; Eissa, Ibrahim H.; Dahab, Mohammed A.

doi:10.1039/d1ra05925d

Cited by 54 publications

(29 citation statements)

References 80 publications

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“…Then, the carboxylic group of compound 5 was activated via the formation of acyl chloride derivative 6 . This reaction was performed using thionyl chloride and a catalytic amount of DMF as reported [ 57 ]. Next, compound 6 was subjected to amide formation (compounds 7a – e) through its stirring with deferent amines in the presence of TEA in acetonitrile as a solvent at room temperature ( Scheme 2 ).…”

Section: Resultsmentioning

confidence: 99%

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

et al. 2022

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This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative of our previous work concerned with the development of VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast cancer (MCF-7), colorectal carcinoma (HCT116), and hepatocellular carcinoma (HepG2). The synthesized compounds were also evaluated against VEGFR-2 kinase activity. The biological testing fallouts showed that compound 8d was more potent than standard sorafenib. Such compound showed IC50 values of 3.43, 2.79, and 2.43 µM against the aforementioned cancer cell lines, respectively, compared to IC50 values of 4.21, 5.30, and 3.40 µM reported for sorafenib. Compound 8d also was found to exert exceptional VEGFR-2 inhibition activity with an IC50 value of 0.0554 μM compared to sorafenib (0.0782 μM). In addition, compound 8h revealed excellent cytotoxic effects with IC50 values of 3.53, 2.94, and 2.76 µM against experienced cell lines, respectively. Furthermore, compounds 8a and 8e were found to inhibit VEGFR-2 kinase activity with IC50 values of 0.0579 and 0.0741 μM, exceeding that of sorafenib. Compound 8d showed a significant apoptotic effect and arrested the HepG2 cells at the pre-G1 phase. In addition, it exerted a significant inhibition for TNF-α (90.54%) and of IL-6 (92.19%) compared to dexamethasone (93.15%). The molecular docking studies showed that the binding pattern of the new compounds to VEGFR-2 kinase was similar to that of sorafenib.

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Section: Resultsmentioning

confidence: 99%

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

et al. 2022

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“…The final benzoxazoles 12a - l and 13a - c were synthesised as presented in Schemes 1–3 . The starting materials and key intermediates 2a-c , 3a - c , 5 , 6 , 7a - d , 9 , 10, and 11 were primarily prepared according to the reported methods 22–25 as delineated in Schemes 1 and 2 .…”

Section: Resultsmentioning

confidence: 99%

Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation

Taghour

Mahdy

Gomaa

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds ( 12d , 12f , 12i , 12l , and 13a ) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l ( IC 50 = 10.50 μM and 15.21 μM against HepG2 and MCF-7, respectively ) had the most promising VEGFR-2 inhibitory activity (IC 50 = 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.

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“…On the other hand, 4-aminobenzoic acid IV was reacted with chloroacetyl chloride in DMF to afford the chloroacetamide intermediate V . Then, treatment of compound V by thionyl chloride afforded 4-(2-chloroacetamido)benzoyl chloride VI 53 , 54 , which was then successively reacted with a set of commercially available amines namely, cyclohexylamine, aniline, 4-chloroaniline, 4-methoxyaniline in acetonitrile and triethylamine (TEA), to get the key intermediates VIIa-d . Finally, compounds VIIa-d were heated with the formerly prepared potassium salts IIIa-c in dry DMF to afford the final target compounds 1–12 ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

Eissa

El-Haggar

Dahab

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A novel series of 2-thioacetamide linked benzoxazole-benzamide conjugates 1 – 15 was designed as potential inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2). The prepared compounds were evaluated for their potential antitumor activity and their corresponding selective cytotoxicity was estimated using normal human fibroblast (WI-38) cells. Compounds 1 , 9 – 12 and 15 showed good selectivity and displayed excellent cytotoxic activity against both HCT-116 and MCF-7 cancer cell lines compared to sorafenib, used as a reference compound. Furthermore, compounds 1 and 11 showed potent VEGFR-2 inhibitory activity. The cell cycle progression assay showed that 1 and 11 induced cell cycle arrest at G2/M phase, with a concomitant increase in the pre-G1 cell population. Further pharmacological studies showed that 1 and 11 induced apoptosis and inhibited the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in both cell lines. Therefore, compounds 1 and 11 might serve as promising candidates for future anticancer therapy development.

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New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies

Abstract: A new series of 3-methylquinoxaline-based derivatives having the same pharmacophoric features of VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against MCF-7 and HepG-2 cells.

Cited by 54 publications

References 80 publications

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation

Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

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