Synthesis and biological evaluation of structurally L-shaped carbostyril derivatives with integrated side chains as cyclooxygenase inhibitors.

In daily life, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs that elicit analgesic, antipyretic, anti-inflammatory, and antithrombotic activities. However, gastric ulceration is a serious side effect of these drugs, which results from cyclooxygenase-1 (COX-1) inhibition by oral NSAIDs in normal human gastric mucosa. Thus, COX-2-selective inhibitors should be developed to address this problem. Carbostyril (2-quinolinone and 2-quinolone) is a time-proven structural skeleton in pharmaceutical agents and physiologically active substances. The replacement of two fused-ring skeletons of lead or model compounds with carbostyril skeletons as bioisosteres without losing activities offers various advantages. Thus, promising pharmaceutical agents without serious pharmacodynamic and pharmacokinetic toxicities can be obtained using this strategy to incorporate carbostyrils into COX inhibitors. Herein, we report the synthesis and biological evaluation of carbostyril derivatives with integrated side chains, which form L-shaped structures like representative COX-2-selective inhibitors such as celecoxib.