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

Ahmed A Gaber; Marwa Sharaky; Ayman Abo Elmaaty; Mohamed M Hammouda; Ahmed Ae Mourad; Samy Y Elkhawaga; Mahmoud Mohamed Mokhtar; Amr S Abouzied; Mai Ae Mourad; Ahmed A Al-Karmalawy

doi:10.4155/fmc-2023-0156

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

Future Med Chem. 2023 Oct;15(19):1773-1790. doi: 10.4155/fmc-2023-0156. Epub 2023 Oct 26.

Authors

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
² Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
³ Medicinal Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt.
⁴ Department of Chemistry, College of Science & Humanities in Al-Kharj, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia.
⁵ Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt.
⁶ Pharmacology & Toxicology Department, Faculty of Pharmacy, Port Said University, Port Said, 42511, Egypt.
⁷ Biochemistry & Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt.
⁸ Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail, 81442, Saudi Arabia.
⁹ Department of Pharmaceutical Chemistry, National Organization for Drug Control & Research, Giza, 12553, Egypt.
¹⁰ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
¹¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt.

PMID: 37882053
DOI: 10.4155/fmc-2023-0156

Abstract

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 IC₅₀ 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.

Keywords: EGFR TKIs; EGFR-T790M; EGFR-WT; apoptosis markers; pyrazolopyrimidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents*
Apoptosis
Cell Line, Tumor
Cell Proliferation
ErbB Receptors
Humans
Lung Neoplasms* / drug therapy
Molecular Docking Simulation
Mutation
Protein Kinase Inhibitors

Substances

ErbB Receptors
Protein Kinase Inhibitors
Antineoplastic Agents
EGFR protein, human