Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors

• Published in: Bioorganic chemistry Vol. 78; pp. 158 - 169
• Main Authors: Akhtar, Md. Jawaid, Khan, Ahsan Ahmed, Ali, Zulphikar, Dewangan, Rikeshwer Prasad, Rafi, Md, Hassan, Md. Quamrul, Akhtar, Md. Sayeed, Siddiqui, Anees Ahmad, Partap, Sangh, Pasha, Santosh, Yar, M. Shahar
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.08.2018; Elsevier
• Subjects: Anticancer; Apoptosis; Benzimidazole linked pyrazole; Biochemistry & Molecular Biology; Cardiomyopathy studies; Chemistry; Chemistry, Organic; Docking studies; Life Sciences & Biomedicine; Physical Sciences; Science & Technology; Docking studies; Anticancer; Cardiomyopathy studies; Benzimidazole linked pyrazole; Apoptosis; TK INHIBITORS; DNA-BINDING; DESIGN; REVERSIBLE INHIBITOR; CANCER; TYROSINE KINASE INHIBITORS; GROWTH-FACTOR RECEPTOR; BIOLOGICAL EVALUATION; DUAL INHIBITORS; CYTOTOXIC AGENTS
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.03.002

[Display omitted] •A series of novel benzimidazole linked pyrazole derivatives were synthesized and characterized.•All the compounds were screened for their anticancer and in vitro EGFR inhibition assay.•The most potent compound 5a emerged as most promising candidate as anticancer agents against A549.•The compounds 5a showed EGFR inhibition; induce apoptosis; G2/M cell cycle arrest.•A detailed docking and cardiomyopathy study of the compound 5a is reported. A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC50 = 2.2 µM) and EGFR binding (IC50 = 0.97 µM) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G2/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds and two π-π interaction with binding energies ΔG = −34.581 Kcal/mol.