Affiliations 

  • 1 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
  • 2 Faculty of Life Sciences and Biology, South Asian University, New Delhi 110021, India
  • 3 Faculty of Pharmacy, AIMST University, Semeling Campus, Jalan Bedong-Semeling, Bedong, Kedah Darul Aman 08100, Malaysia
  • 4 Faculty of Applied Science, AIMST University, Semeling Campus, Jalan Bedong-Semeling, Bedong, Kedah Darul Aman 08100, Malaysia
  • 5 Faculty of Medical Sciences, AIMST University, Semeling Campus, Jalan Bedong-Semeling, Bedong, Kedah Darul Aman 08100, Malaysia
  • 6 Department of Chemistry, School of Chemical and Life Science, Jamia Hamdard, New Delhi, India. Electronic address: syedshafi@jamiahamdard.ac.in
  • 7 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India. Electronic address: yarmsy@rediffmail.com
Bioorg Chem, 2020 01;95:103519.
PMID: 31884140 DOI: 10.1016/j.bioorg.2019.103519

Abstract

A set of two series of 1,3,4-oxadiazole (11a-n) and 1,2,4-Triazole (12a, c, e, g, h, j-n) based topsentin analogues were prepared by replacing imizadole moiety of topsentin through a multistep synthesis starting from indole. All the compounds synthesized were submitted for single dose (10 µM) screening against a NCI panel of 60-human cancer cell lines. Among all cancer cell lines, colon (HCC-2998) and Breast (MCF-7, T-47D) cancer cell lines were found to be more susceptible for this class of compounds. Among the compounds tested, compounds 11a, 11d, 11f, 12e and 12h, were exhibited good anti-proliferative activity against various cancer cell lines. Compounds 11d, 12e and 12h demonstrated better activity with IC50 2.42 µM, 3.06 µM, and 3.30 µM respectively against MCF-7 human cancer cell line than that of the standard drug doxorubicin IC50 6.31 µM. Furthermore, 11d induced cell cycle arrest at G0/G1 phase and also disrupted mitochondrial membrane potential with reducing cell migration potential of MCF-7 cells in dose dependent manner. In vitro microtubule polymerization assays found that compound 11d disrupt tubulin dynamics by inhibiting tubulin polymerization with IC50 3.89 μM compared with standard nocodazole (IC50 2.49 μM). In silico docking studies represented that 11d was binding at colchicine binding site of β-tubulin. Compound 11d emerged as lead molecule from the library of compounds tested and this may serve as a template for further drug discovery.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.