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

Bioorg Med Chem. 2017 Sep 1;25(17):4656-4664. doi: 10.1016/j.bmc.2017.07.010. Epub 2017 Jul 8.

Abstract

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.

Keywords: 3,4-Dihydroquinazoline; Bioisostere; Cytotoxic activity; Inflammatory pain; Liver microsomal stability; T-type calcium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / toxicity
  • Animals
  • 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
  • Drug Stability
  • Fluorine / chemistry
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Microsomes, Liver / metabolism
  • Patch-Clamp Techniques
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / toxicity
  • Quinidine / analogs & derivatives*
  • Quinidine / chemical synthesis
  • Quinidine / chemistry
  • Quinidine / toxicity
  • Rats

Substances

  • Analgesics
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • KCP10068F
  • KYS 05090
  • Quinazolines
  • Fluorine
  • hydroquinidine
  • Quinidine

Grants and funding