Design, synthesis and antitumor activity evaluation of novel indole acrylamide derivatives as IMPDH inhibitors

[Display omitted] •Thirty-seven novel indole acrylamide derivatives were synthesized as hIMPDH2 inhibitors.•It was confirmed that the introduction of cyano group at the 3-position of indole was more favorable than dihydrothiazolyl group for the inhibitory activity of hIMPDH2.•Compounds 14e and 14n, which have exhibited outstanding hIMPDH2 inhibitory activities (IC50 = 4.207 and 2.948 μM, respectively) and tumor cell proliferation inhibitory activities (for SW480 human colon cancer cells, IC50 = 15.34 ± 0.06 and 15.31 ± 0.09 μM, respectively), were promising preferred agents for the development of antitumor drugs. Inosine 5′-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) is the rate-limiting enzyme of GMP biosynthesis. The inhibition of IMPDH limits the growth and survival of tumors. Based on the systematic summary of clinical IMPDH inhibitors, 38 acrylamide derivatives with differently substituted indoles at the 3-position as the core scaffold were designed and synthesized. In addition, the actions of these compounds at the enzyme and cellular levels were evaluated. An MTT assay with different kinds of cells was used to assess the cytotoxic activities of compounds 14e and 14n, which displayed potent hIMPDH2 inhibitory activities (IC50 = 4.207 and 2.948 μM, respectively). Biological evaluation indicated that target compounds 14e and 14n displayed the most significant effects on SW480 human colon cancer cells (IC50 = 15.34 ± 0.06 and 15.31 ± 0.09 μM, respectively), and it was determined that these compounds are effective and valuable IMPDH inhibitors for cancer intervention.