Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy

Farheen Shamsi, Phool Hasan, Aarfa Queen, Afzal Hussain, Parvez Khan, Bushra Zeya, Hannah M. King, Sandeep Rana, Jered Garrison, Mohamed F. Alajmi, M. Moshahid Alam Rizvi, Muhammad Zahid, Md Imtaiyaz Hassan, Mohammad Abid

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

A diverse series of 1,2,4-oxadiazoles based substituted compounds were designed, synthesized and evaluated as anticancer agents targeting carbonic anhydrase IX (CAIX). Initial structure-activity analysis suggested that the thiazole/thiophene-sulfonamide conjugates of 1,2,4-oxadiazoles exhibited potent anticancer activities with low μM potencies. Compound OX12 exhibited antiproliferative activity (IC50 = 11.1 µM) along with appreciable inhibition potential for tumor-associated CAIX (IC50 = 4.23 µM) isoform. Therefore, OX12 was structurally optimized and its SAR oriented derivatives (OX17-27) were synthesized and evaluated. This iteration resulted in compound OX27 with an almost two-fold increase in antiproliferative effect (IC50 = 6.0 µM) comparable to the clinical drug doxorubicin and significantly higher potency against CAIX (IC50 = 0.74 µM). Additionally, OX27 treatment decreases the expression of CAIX, induces apoptosis and ROS production, inhibited colony formation and migration of colon cancer cells. Our studies provide preclinical rational for the further optimization of identified OX27 as a suitable lead for the possible treatment of CRC.

Original languageEnglish (US)
Article number103754
JournalBioorganic Chemistry
Volume98
DOIs
StatePublished - May 2020

Keywords

  • 1,2,4-Oxadiazoles
  • Apoptosis
  • Colorectal cancer
  • Inhibitors
  • Sulfonamides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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    Shamsi, F., Hasan, P., Queen, A., Hussain, A., Khan, P., Zeya, B., King, H. M., Rana, S., Garrison, J., Alajmi, M. F., Rizvi, M. M. A., Zahid, M., Imtaiyaz Hassan, M., & Abid, M. (2020). Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy. Bioorganic Chemistry, 98, [103754]. https://doi.org/10.1016/j.bioorg.2020.103754