Small molecule

Receptor

Organic chemistry

Combinatorial chemistry

In silico

EGFR inhibitors

Epidermal growth factor receptor

Lipinski's rule of five

Stereochemistry

Biology

Gene

Cancer

Nursing

Chemistry

Pyrazole

Quinazoline

Pyrimidine

Fulvestrant

Thiourea

Breast cancer

Drug discovery

Docking (animal)

Genetics

Biochemistry

Pharmacophore

Medicine

Estrogen receptor

Pharmacology

Archiv der Pharmazie

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.

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

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