Pharmacophore‐linked pyrazolo[3,4‐<i>d</i>]pyrimidines as EGFR‐TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies
Ahmed A. Abdel Gaber, Ahmed 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
Abstract
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 (IC 50 = 2.89 µM) suggested that it may serve as a lead for further optimization and drug development.