Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors

Peng, Cheng-Kang; Zeng, Ting; Xu, Xingjun; Chang, Yiqun; Hou, Wen; Lu, Kuo‐Shyan; Lin, Hui Yi; Sun, Ping‐Hua; Lin, Jing; Chen, Weimin

doi:10.1016/j.ejmech.2016.12.035

Cited by 17 publications

(2 citation statements)

References 27 publications

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“…Cancer is a major health obstacle in the world threating the life of millions of people annually 1 , 2 . The universal burden of cancer has been expected to rise to 21.6 million in 2023 compared to 14.1 million in 2012 and was predicted to increase to 28.4 million in 2040 with 47% increment relative to 2020 3–5 .…”

Section: Introductionmentioning

confidence: 99%

2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

Elbadawi

Eldehna

El-Hafeez

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this study, different assortments of 2-arylquinolines and 2,6-diarylquinolines have been developed. Recently, we have developed a new series of 6,7-dimethoxy-4-alkoxy-2-arylquinolines as Topoisomerase I (TOP1) inhibitors with potent anticancer activity. Utilising the SAR outputs from this study, we tried to enhance anticancer and TOP1 inhibitory activities. Though target quinolines demonstrated potent antiproliferative effect, specifically against colorectal cancer DLD-1 and HCT-116, they showed weak TOP1 inhibition which may be attributable to their non-coplanarity. Thereafter, screening against kinase panel revealed their dual inhibitory activity against EGFR and FAK. Quinolines 6f , 6h , 6i , and 20f were the most potent EGFR inhibitors (IC 50 s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h , 6i , 16d , and 20f exerted the best FAK inhibition (IC 50 s = 22.68, 14.25, 18.36, 17.36, and 15.36 nM, respectively). Finally, molecular modelling was employed to justify the promising EGFR/FAK inhibition. The study outcomes afforded the first reported quinolines with potent EGFR/FAK dual inhibition.

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Section: Introductionmentioning

confidence: 99%

2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

Elbadawi

Eldehna

El-Hafeez

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…After the MD, analysis was performed with the ptraj analysis tool based on the last 2 ns trajectories of the simulation. The binding free energies of complexes were calculated using the MM-PBSA 40 .…”

Section: Methodsmentioning

confidence: 99%

New molecular insights into the tyrosyl-tRNA synthase inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

Fan

Peng

et al. 2017

Sci Rep

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Drug resistance caused by excessive and indiscriminate antibiotic usage has become a serious public health problem. The need of finding new antibacterial drugs is more urgent than ever before. Tyrosyl-tRNA synthase was proved to be a potent target in combating drug-resistant bacteria. In silico methodologies including molecular docking and 3D-QSAR were employed to investigate a series of newly reported tyrosyl-tRNA synthase inhibitors of furanone derivatives. Both internal and external cross-validation were conducted to obtain high predictive and satisfactory CoMFA model (q 2 = 0.611, r 2 pred = 0.933, r 2 m = 0.954) and CoMSIA model (q 2 = 0.546, r 2 pred = 0.959, r 2 m = 0.923). Docking results, which correspond with CoMFA/CoMSIA contour maps, gave the information for interactive mode exploration. Ten new molecules designed on the basis of QSAR and docking models have been predicted more potent than the most active compound 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (15) in the literatures. The results expand our understanding of furanones as inhibitors of tyrosyl-tRNA synthase and could be helpful in rationally designing of new analogs with more potent inhibitory activities.

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Synthesis, in vitro cytotoxicity, ADME, and molecular docking studies of benzimidazole‐bearing furanone derivatives

Husain

Bhutani

Parveen

et al. 2020

J Chinese Chemical Soc

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A series of benzimidazole‐derived–furanones (4a–l) were synthesized, characterized, and explored for their in vitro anticancer activities. The pharmacokinetic parameters assessed revealed that all the compounds followed the Lipinski's rule of five, making them potential drug candidates. Further, the results of anticancer activity revealed that (E)‐5‐(1H‐benzo[d]imidazol‐2‐yl)‐3‐(3,4,5‐trimethoxybenzylidene)furan‐2(3H)‐one (4a), was active against A549, MCF7, and DU145 with an IC50 values of 10.4 ± 0.39, 11.1 ± 0.43, and 10.7 ± 0.19 μM, respectively. While another compound (E)‐5‐(1H‐benzo[d]imidazol‐2‐yl)‐3‐([5‐phenyl]furan‐2‐yl)furan‐2(3H)‐one (4k) also exhibited good activity against A549, MCF7, and DU145 with IC50 values of 11.4 ± 0.39, 9.1 ± 0.43, and 12.7 ± 0.19 μM, respectively. Doxorubicin was used as the standard drug. Further, molecular docking studies were carried out to provide binding mode into the binding sites of vascular endothelial growth factor receptor (VEGFR). Docking scores and binding energies corroborated well with the results of experimental anticancer activity. Pharmacokinetic (ADME) parameters of the potent derivatives were also found to be in an acceptable range. The benzimidazole‐furanonone conjugates seem to be a potential source for the further development of potent cytotoxic agents.

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Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors

Cited by 17 publications

References 27 publications

2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

New molecular insights into the tyrosyl-tRNA synthase inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

Synthesis, in vitro cytotoxicity, ADME, and molecular docking studies of benzimidazole‐bearing furanone derivatives

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