Synthesis and biological evaluation of pyrazole linked benzothiazole-β-naphthol derivatives as topoisomerase I inhibitors with DNA binding ability

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 5; pp. 708 - 720
• Main Authors: Nagaraju, Burri, Kovvuri, Jeshma, Kumar, C. Ganesh, Routhu, Sunitha Rani, Shareef, Md. Adil, Kadagathur, Manasa, Adiyala, Praveen Reddy, Alavala, Sateesh, Nagesh, Narayana, Kamal, Ahmed
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2019; Elsevier
• Subjects: Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Benzothiazole; Benzothiazoles - chemical synthesis; Benzothiazoles - metabolism; Benzothiazoles - pharmacology; Betanaphthol; Biochemistry & Molecular Biology; Bisbenzimidazole - pharmacology; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; DNA - chemistry; DNA - metabolism; DNA binding; Doxorubicin - pharmacology; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints - drug effects; Humans; Intercalating Agents - chemical synthesis; Intercalating Agents - metabolism; Intercalating Agents - pharmacology; Life Sciences & Biomedicine; Molecular Docking Simulation; Naphthols - chemical synthesis; Naphthols - metabolism; Naphthols - pharmacology; Pharmacology & Pharmacy; Physical Sciences; Pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - metabolism; Pyrazoles - pharmacology; Science & Technology; Topoisomerase; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - metabolism; Topoisomerase I Inhibitors - pharmacology; Viscosity; Topoisomerase; Betanaphthol; Anticancer; Benzothiazole; Pyrazole; DNA binding; COMPLEXES; ANTICONVULSANT; MECHANISMS; IDENTIFICATION; ANTITUMOR; CANCER; POTENT; LIGANDS; FLUORESCENCE; ANTAGONISTS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.01.011

[Display omitted] •A series of pyrazole linked benzothiazole-β-naphthol derivatives were synthesized by using catalyst-free reaction conditions.•The synthesized derivatives were tested for their anti-proliferative activity against human cancer cell lines.•Topoisomerase I inhibition assay demonstrates that these derivatives inhibit topoisomerase I activity.•Spectroscopic studies and molecular docking studies revealed that these derivatives exhibit DNA minor groove binding. A series of new pyrazole linked benzothiazole-β-naphthol derivatives were designed and synthesized using a simple, efficient and ecofriendly route under catalyst-free conditions in good to excellent yields. These derivatives were evaluated for their cytotoxicity on selected human cancer cell lines. Among those, the derivatives 4j, 4k and 4l exhibited considerable cytotoxicity with IC50 values ranging between 4.63 and 5.54 µM against human cervical cancer cells (HeLa). Structure activity relationship was elucidated by varying different substituents on benzothiazoles and pyrazoles. Further, flow cytometric analysis revealed that these derivatives induced cell cycle arrest in G2/M phase and spectroscopic studies such as UV–visible, fluorescence and circular dichroism studies showed that these derivatives exhibited good DNA binding affinity. Additionally, these derivatives can effectively inhibit the topoisomerase I activity. Viscosity studies and molecular docking studies demonstrated that the derivatives bind with the minor groove of the DNA.