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Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers.

Abstract：

:In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivativesusing 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 Cav3.2 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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Nam Y,Ryu KD,Jang C,Moon YH,Kim M,Ko D,Chung KS,Gandini MA,Lee KT,Zamponi GW,Lee JY

doi

10.1016/j.bmc.2020.115491

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

115491

issue

11

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(20)30312-6

journal_volume

28

pub_type

杂志文章

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