Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects

• Published in: Bioorganic & medicinal chemistry 2017-09, Vol.25 (17), p.4656-4664
• Main Authors: Kim, Jin Han, Jeong, Hui Rak, Jung, Da Woon, Yoon, Hong Bin, Kim, Sun Young, Kim, Hyoung Ja, Lee, Kyung-Tae, Gadotti, Vinicius M., Huang, Junting, Zhang, Fang-Xiong, Zamponi, Gerald W., Lee, Jae Yeol
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroquinazoline; A549 Cells; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - toxicity; Animals; Bioisostere; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - toxicity; Calcium Channels, T-Type - chemistry; Calcium Channels, T-Type - genetics; Calcium Channels, T-Type - metabolism; Cell Survival - drug effects; Cytotoxic activity; Drug Stability; Fluorine - chemistry; HEK293 Cells; Humans; Inflammatory pain; Inhibitory Concentration 50; Liver microsomal stability; Microsomes, Liver - metabolism; Patch-Clamp Techniques; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - toxicity; Quinidine - analogs & derivatives; Quinidine - chemical synthesis; Quinidine - chemistry; Quinidine - toxicity; Rats; T-type calcium channel
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.07.010

[Display omitted] As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC50=5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav3.2 channels.