Design, synthesis and biological evaluation of 1,3-diphenyl-1H-pyrazole derivatives containing benzimidazole skeleton as potential anticancer and apoptosis inducing agents

• Published in: European journal of medicinal chemistry Vol. 101; pp. 790 - 805
• Main Authors: Reddy, T. Srinivasa, Kulhari, Hitesh, Reddy, V. Ganga, Bansal, Vipul, Kamal, Ahmed, Shukla, Ravi
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 28-08-2015
• Subjects: Anti-proliferative activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzimidazole; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Cell Movement - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; HeLa Cells; Humans; MCF-7 Cells; Molecular Structure; Pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; RT-PCR; Structure-Activity Relationship; Tumor Cells, Cultured; Anti-proliferative activity; Benzimidazole; RT-PCR; Pyrazole; Apoptosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.07.031

A series of forty different pyrazole containing benzimidazole hybrids (6–45) have been designed, synthesized and evaluated for their potential anti-proliferative activity against three human tumor cell lines - lung (A549), breast (MCF-7), and cervical (HeLa). Some of the compounds, specifically 9, 17, and 28, showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.83–1.81 μM. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis inducing effect of compounds. The morphology, cell migration and long term clonogenic survival of MCF-7 breast cancer cells were severely affected by treatment with these compounds. Flow-cytometry revealed the compounds arrested MCF-7 cells in the G1 phase of the cell cycle via down regulation of cyclin D2 and CDK2. Fluorescent staining and DNA fragmentation studies showed that cell proliferation was inhibited by induction of apoptosis. Moreover, the compounds led to collapse of mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS) were noted. The ease of synthesis and the remarkable biological activities make these compounds promising new frameworks for the development of cancer therapeutics.
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•A series of forty pyrazole-benzimidazole hybrids were synthesized.•All compounds were screened for their anticancer activity.•Three compounds 9, 17 and 28 displayed promising activity.•These compounds induce cell cycle arrest and apoptosis in MCF-7 cells.