title: Design and synthesis of imidazo[2,1-b]thiazole-chalcone conjugates: microtubule-destabilizing agents.
abstract: A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 μM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.
authors.affiliation: Medicinal Chemistry & Pharmacology, Council of Science and Industrial Research, Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500 007 (India); Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad-500 037 (India). ahmedkamal@iict.res.in.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: Moku
authors.initials: M
authors.lastname: Balakrishna
authors.forename: V Lakshma
authors.initials: VL
authors.lastname: Nayak
authors.forename: Thokhir Basha
authors.initials: TB
authors.lastname: Shaik
authors.forename: Shaikh
authors.initials: S
authors.lastname: Faazil
authors.forename: Vijaykumar D
authors.initials: VD
authors.lastname: Nimbarte
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000737:chemistry*; D053938:DNA Fragmentation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007150:Immunohistochemistry; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; D002599:Chalcone; C029899:imidazole; D053148:Caspase 3
keywords: antiproliferation; apoptosis; cell-cycle arrest; chalcones; molecular docking; tubulin polymerization