Design and synthesis of substituted (1-(benzyl)-1 H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone conjugates: study on their apoptosis inducing ability and tubulin polymerization inhibition

  • RSC Med Chem. 2020 Sep 8;11(11):1295-1302. doi: 10.1039/d0md00162g.
Kesari Lakshmi Manasa  1  2 ,  Sowjanya Thatikonda  3 ,  Dilep Kumar Sigalapalli  1  2 ,  Sowmya Vuppaladadium  4 ,  Ganthala Parimala Devi  1 ,  Chandraiah Godugu  3 ,  Mallika Alvala  2 ,  Narayana Nagesh  4 ,  Bathini Nagendra Babu  1
Affiliations
  • 1. Department of Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology Hyderabad-500007 India [email protected].
  • 2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Hyderabad-500037 India.
  • 3. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad-500037 India.
  • 4. CSIR-Centre for Cellular and Molecular Biology Hyderabad 500007 India.
PMID: 34095841 DOI: 10.1039/d0md00162g
Abstract

A library of substituted (1-(benzyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone derivatives were designed, synthesized and screened for their in vitro cytotoxic activity against BT-474, HeLa, MCF-7, NCI-H460 and HaCaT cells by employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized analogues, compound 10ec displayed the highest cytotoxicity with the IC50 value of 0.99 ± 0.01 μM towards BT-474 Cancer cell line. The target compound (10ec) was also evaluated for its tubulin polymerization inhibition study. Detailed biological studies such as acridine orange/ethidium bromide (AO/EB), DAPI and annexin V-FITC/propidium iodide staining assay suggested that compound 10ec induced the Apoptosis of BT-474 cells. The clonogenic assay revealed that the inhibition of colony formation in BT-474 cells by 10ec in concentration-dependent manner. Moreover, the flow cytometric analysis revealed that 10ec induced Apoptosis via cell cycle arrest at the sub-G1 and G2/M phase. In silico studies of sulfonyl piperazine-integrated triazole conjugates unveil that they possess drug-like properties. According to the molecular modelling studies, compound 10ec binds to the colchicine binding site of the tubulin.