Synthesis and cytotoxic effects of 2-thio-3, 4-dihydroquinazoline derivatives as novel T-type calcium channel blockers. Issue 11 (1st June 2020)

• Record Type: Journal Article
• Authors: Nam, Yunchan; Ryu, Ki Deok; Jang, Changyoung; Moon, Yoon Hyoung; Kim, Misong; Ko, Dohyeong; Chung, Kyung-Sook; Gandini, Maria A.; Lee, Kyung-Tae; Zamponi, Gerald W.; Lee, Jae Yeol
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 11(2020)
• Publication Date: 2020-06-01
• Subjects: T-type calcium channel -- 2-thio-3, 4-dihydroquinazoline -- Current inhibition -- Cytotoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115491
• Languages: English
• ISSNs: 0968-0896

Abstract

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.