Aminopyridone-linked benzimidazoles: a fragment-based drug design for the development of CDK9 inhibitors-Reference-Cited by-同舟云学术

Aminopyridone-linked benzimidazoles: a fragment-based drug design for the development of CDK9 inhibitors

Published:2023-07 Issue:14 Volume:15 Page:1213-1232
ISSN:1756-8919
Container-title:Future Medicinal Chemistry
language:en
Short-container-title:Future Medicinal Chemistry

Author:

Husseiny Ebtehal M¹^ORCID,Abulkhair Hamada S²³^ORCID,El-Hddad Sanadelaslam SA⁴,Osama Nada⁵,El-Zoghbi Mona S⁶^ORCID

Affiliation:

1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, 11754, Egypt

2. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11884, Egypt

3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University – Egypt, New Damietta, 34518, Egypt

4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Omar Almukhtar University, Al Bayda, 102345, Libya

5. Biochemistry Department, Faculty of Pharmacy, Menoufia University, Shibin Elkom, Menoufia, 32511, Egypt

6. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Shebin El-Koum, 32511, Egypt

Abstract

Aim: A fragment-based design and synthesis of three novel series of aminopyridone-linked benzimidazoles as potential anticancer candidates with significant CDK9 inhibition was implemented. Materials & methods: All synthesized compounds were submitted to National Cancer Institute, 60 cell lines and seven-dose cytotoxicity toward three cancer cells. Results: Compounds 2, 4a, 4c, 4d, 6a and 8a exhibited significant cytotoxicity and selectivity with IC50 range of 7.61–57.75 μM. Regarding the mechanism either in vitro or in silico, 4a, 6a and 8a displayed potent CDK9 inhibition with IC50 value of 0.424–8.461 μM. Compound 6a arrested the cell cycle at S phase and induced apoptosis in MCF-7 cells. Conclusion: Compound 6a is a promising CDK9 inhibitor that warrants additional research for cancer treatment.

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

Link

https://www.future-science.com/doi/pdf/10.4155/fmc-2023-0139

Reference97 articles.

1. American Cancer Society. Cancer Facts and Figures 2022 (2023). www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html#:∼:text=Estimated numbers of new cancer,incidence%2C mortality%2C and survival statistics

2. Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations

3. The effect of novel synthetic semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles on the apoptotic markers, VEGFR-2, and cell cycle of myeloid leukemia

4. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies

Cited by 3 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Design, synthesis, and mechanistic insight of novel imidazolones as potential EGFR inhibitors and apoptosis inducers;Bioorganic Chemistry;2024-03

2. Novel benzochromenes: design, synthesis, cytotoxicity, molecular docking and mechanistic investigations;Future Medicinal Chemistry;2024-01

3. Molecular overlay-guided design of new CDK2 inhibitor thiazepinopurines: Synthesis, anticancer, and mechanistic investigations;Bioorganic Chemistry;2023-11