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  • Title: New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: Synthesis, anticancer, antimicrobial evaluation and computational studies.
    Author: Othman IMM, Alamshany ZM, Tashkandi NY, Gad-Elkareem MAM, Anwar MM, Nossier ES.
    Journal: Bioorg Chem; 2021 Sep; 114():105078. PubMed ID: 34161878.
    Abstract:
    This study was focused on the synthesis of new pyrimidines 4a,b, 5a,b and pyrazoles 6a, b as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). The new compounds were assessed as cytotoxic candidates against human breast cancer cells (MCF-7) and hepatocellular carcinoma cells (HepG-2). All the new compounds appeared as more potent cytotoxic agents than erlotinib, while only compound 4a exhibited more potency than 5-flourouracil and 4b analogue was equipotent to it. Accordingly, the kinase suppression effect of 4a and 4b was further evaluated against EGFRWT, EGFRL858R and EGFRT790M. Both pyrimidine analogues 4a and 4b displayed outstanding inhibitory activity against EGFRWT and its two mutated isoforms EGFRL858R and EGFRT790M in comparing to erlotinib and osimertinib as reference drugs. Additionally, all the new analogues were subjected to antimicrobial assay. Interestingly, both 4a and 4b represented the most promising activity of wide spectrum antimicrobial effect against the examined microbes in comparison to gentamycin and ketoconazole as standard drugs. Moreover, docking results proved the good binding interactions of the compounds 4a and 4b with EGFRWT and EGFRT790M which were in accordance with the results of the in vitro enzyme assay. Additional in silico ADMET studies were performed for the new derivatives which represented their good oral absorption, good drug-likeness properties and low toxicity risks in human.
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