Pharmacophore-linked pyrazolo[3,4-d]pyrimidines as EGFR-TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies

Ahmed A Gaber; Ahmed M El-Morsy; Farag F Sherbiny; Ashraf H Bayoumi; Kamal M El-Gamal; Khaled El-Adl; Ahmed A Al-Karmalawy; Rogy R Ezz Eldin; Marwa A Saleh; Hamada S Abulkhair

doi:10.1002/ardp.202100258

Pharmacophore-linked pyrazolo[3,4-d]pyrimidines as EGFR-TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies

Arch Pharm (Weinheim). 2021 Aug 31:e2100258. doi: 10.1002/ardp.202100258. Online ahead of print.

Authors

Ahmed A Gaber¹, Ahmed M El-Morsy^{1

2}, Farag F Sherbiny^{1

3}, Ashraf H Bayoumi¹, Kamal M El-Gamal¹, Khaled El-Adl^{4

5}, Ahmed A Al-Karmalawy⁶, Rogy R Ezz Eldin⁷, Marwa A Saleh⁸, Hamada S Abulkhair^{1

6}

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Nasr City, Egypt.
² Pharmaceutical Chemistry Department, College of Pharmacy, The Islamic University, Najaf, Iraq.
³ Department of Chemistry, Basic Science Center and Pharmaceutical Organic Chemistry College of Pharmaceutical Science & Drug Manufacturing, Misr University for Science and Technology (MUST), Al-Motamayez District, 6th of October City, Egypt.
⁴ Department of Medicinal Chemistry & Drug Design, Faculty of Pharmacy, Al-Azhar University, Cairo, Nasr City, Egypt.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt.
⁶ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.
⁷ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said, Egypt.
⁸ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.

PMID: 34467546
DOI: 10.1002/ardp.202100258

Abstract

Targeting the epidermal growth factor receptors (EGFRs) with small inhibitor molecules has been validated as a potential therapeutic strategy in cancer therapy. Pyrazolo[3,4-d]pyrimidine is a versatile scaffold that has been exploited for developing potential anticancer agents. On the basis of fragment-based drug discovery, considering the essential pharmacophoric features of potent EGFR tyrosine kinase (TK) inhibitors, herein, we report the design and synthesis of new hybrid molecules of the pyrazolo[3,4-d]pyrimidine scaffold linked with diverse pharmacophoric fragments with reported anticancer potential. These fragments include hydrazone, indoline-2-one, phthalimide, thiourea, oxadiazole, pyrazole, and dihydropyrazole. The synthesized molecules were evaluated for their anticancer activity against the human breast cancer cell line, MCF-7. The obtained results revealed comparable antitumor activity with that of the reference drugs doxorubicin and toceranib. Docking studies were performed along with EGFR-TK and ADMET profiling studies. The results of the docking studies showed the ability of the designed compounds to interact with key residues of the EGFR-TK through a number of covalent and noncovalent interactions. The obtained activity of compound 25 (IC₅₀ = 2.89 µM) suggested that it may serve as a lead for further optimization and drug development.

Keywords: EGFR; SAR; Schiff bases; antitumor; docking; pyrazolo[3,4-d]pyrimidine.