Design and synthesis of novel pyrazolopyrimidine candidates as promising EGFR-T790M inhibitors and apoptosis inducers.

Autor: Gaber AA; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt., Sharaky M; Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt., Elmaaty AA; Medicinal Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt., Hammouda MM; Department of Chemistry, College of Science & Humanities in Al-Kharj, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia.; Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt., Mourad AA; Pharmacology & Toxicology Department, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt., Elkhawaga SY; Biochemistry & Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt., Mokhtar MM; Biochemistry & Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt., Abouzied AS; Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail, 81442, Saudi Arabia.; Department of Pharmaceutical Chemistry, National Organization for Drug Control & Research, Giza, 12553, Egypt., Mourad MA; Medicinal Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt., Al-Karmalawy AA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt.
Jazyk: angličtina
Zdroj: Future medicinal chemistry [Future Med Chem] 2023 Oct; Vol. 15 (19), pp. 1773-1790. Date of Electronic Publication: 2023 Oct 26.
DOI: 10.4155/fmc-2023-0156
Abstrakt: Aim: Our objective was to design and synthesize a new range of pyrazolopyrimidines while maintaining the key pharmacophoric features of EGFR tyrosine kinase inhibitors. Materials & methods: Percentage inhibition in 14 human cancer cell lines and IC 50 values were recorded. Compounds 6c , 7e and 7f were examined against both wild and mutant (T790M) EGFR subtypes. Apoptosis markers, cell cycle arrest, apoptosis assay and molecular docking were performed. Results: Compounds 6c , 7e and 7f demonstrated superior inhibitory potentials against wild and mutant (T790M) EGFR subtypes. A molecular docking study showed that compounds 6c and 7e had the best fit. Conclusion: The designed candidates demonstrated superior inhibitory potential as promising EGFR-T790M inhibitors that agrees with the proposed rationale.
Databáze: MEDLINE