Details

Autor(en) / Beteiligte

• Othman, Ismail M.M.
• Alamshany, Zahra M.
• Tashkandi, Nada Y.
• Gad-Elkareem, Mohamed A.M.
• Anwar, Manal M.
• Nossier, Eman S.

Titel

New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: Synthesis, anticancer, antimicrobial evaluation and computational studies

Ist Teil von

• Bioorganic chemistry, 2021-09, Vol.114, p.105078, Article 105078

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] •New pyrimidine and pyrazole derivatives 4a, b–6a, b as ATP mimicking tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized.•The cytotoxic activity of new compounds was evaluated in vitro against human breast cancer (MCF-7) and hepatocellular carcinoma (HepG-2).•The most promising compounds 4a, 4b were examined as inhibitors against EGFRWT and its mutated isoforms EGFRL858R and EGFRT790M.•Antimicrobial assay of all compounds was carried against different types of pathogenic gram-positive, gram-negative bacteria and fungi.•Molecular docking results of compounds 4a and 4b proved their good binding interactions with EGFRWT and EGFRT790M. In silico ADMET studies proved drug-likeness properties of the new compounds. 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.