title: Rational design and synthesis of 2-anilinopyridinyl-benzothiazole Schiff bases as antimitotic agents.
abstract: Based on our previous results and literature precedence, a series of 2-anilinopyridinyl-benzothiazole Schiff bases were rationally designed by performing molecular modeling experiments on some selected molecules. The binding energies of the docked molecules were better than the E7010, and the Schiff base with trimethoxy group on benzothiazole moiety, 4y was the best. This was followed by the synthesis of a series of the designed molecules by a convenient synthetic route and evaluation of their anticancer potential. Most of the compounds have shown significant growth inhibition against the tested cell lines and the compound 4y exhibited good antiproliferative activity with a GI50value of 3.8µM specifically against the cell line DU145. In agreement with the docking results, 4y exerted cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, comparable to E7010. Detailed binding modes of 4y with colchicine binding site of tubulin were studied by molecular docking. Furthermore, 4y induced apoptosis as evidenced by biological studies like mitochondrial membrane potential, caspase-3, and Annexin V-FITC assays.
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Biotechnology, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India.
authors.forename: Thokhir B
authors.initials: TB
authors.lastname: Shaik
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: S M Ali
authors.initials: SMA
authors.lastname: Hussaini
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: V Lakshma
authors.initials: VL
authors.lastname: Nayak
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India.
authors.forename: M Lakshmi
authors.initials: ML
authors.lastname: Sucharitha
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: M Shaheer
authors.initials: MS
authors.lastname: Malik
authors.affiliation: Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037, India. Electronic address: ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
mesh_terms: D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D001667:Binding, Competitive; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D012545:Schiff Bases / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D050256:Antimitotic Agents; D052160:Benzothiazoles; D012545:Schiff Bases; D014404:Tubulin; D050257:Tubulin Modulators; C005465:benzothiazole
keywords: Benzothiazole; Cell cycle; Cytotoxicity; E7010; Tubulin polymerization