Synthesis and cytotoxic effects of 2-thio-3, 4-dihydroquinazoline derivatives as novel T-type calcium channel blockers. Issue 11 (1st June 2020) - Nam, Yunchan
Graphical abstract: Abstract: In our previous work, a series of 2-amino-3, 4-dihydroquinazoline derivatives using an electron acceptor group was reported to be potent T -type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3, 4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3, 4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T -type calcium channel blocking activity and cytotoxic effects against two human cancerous cell lines (lung cancer A549 and colon cancer HCT-116). Among them, compound 6g showed potent inhibition of Cav 3.2 currents (83% inhibition) at 10 µM concentrations. The compound also exhibited IC50 values of 5.0 and 6.4 µM against A549 and HCT-116 cell lines, respectively, which are comparable to the parental lead compound KYS05090 . These results indicate that the isothiourea moiety similar to the guanidine moiety of 2-amino-3, 4-dihydroquinazoline derivatives may be an essential pharmacophore for the desired biological activities. Therefore, our preliminary work can provide the opportunity to expand a chemical repertoire to improve affinity and selectivity for T -type calcium channels.