Synthesis of Novel 2-(2-Cyclopentyl)- and 2-(2-Cyclohexyl) Substituted 1-Naphthol Derivatives with Anticyclooxygenase Activity

Abstract

Eight novel 2-(2'-cyclopentyl)- and 2-(2'-cyclohexyl) substituted 1-naphthol derivatives were synthesized in good yield starting from 1-hydroxy-2-naphthoic acid. Two of them, 2-((1-(hydroxymethyl)cyclopentyl)methyl)naphthalene-1-ol (8) and 2-((1-(hydroxymethyl)cyclohexyl)methyl)-naphthalene-1-ol (9) showed anticyclooxygenase activity on COX-2 with IC(50) values of 19.90 microM and 7.77 microM, respectively and 9 also inhibited COX-1 (5.55 microM), while the other six were inactive on both isozymes. Molecular docking experiments indicated that the orientation of the active naphthols is different from that of the inactive ones. Two evidences playing important roles for the inhibition by the active compounds, are 1) C-1 and C-3' hydroxyl groups formed hydrogen bonds with COX-2/COX-1 Val523/Ile523 and Arg120, respectively, 2) hydrogen at C-5 of the naphthalene nucleus was attracted rather close to the phenolic group of Tyr385 due to van der Waals interaction.

Rearrangements of Cycloalkenyl Aryl Ethers

“…Naphthols and their methyl ethers also possess useful biologically activities. They show inhibitory activity with preferential inhibition on cyclooxygenase I and II [11,12].…”

Methyl-1-hydroxy-2-naphthoate, a novel naphthol derivative, inhibits lipopolysaccharide-induced inflammatory response in macrophages via suppression of NF-κB, JNK and p38 MAPK pathways

“…Some naphthol derivatives have been reported to display a variety of biological activities. For instance, 2-substituted-1-naphthol derivatives were shown to inhibit the activities of cyclooxygenase and 5-lipooxygenase [15,16]. A metabolic naphthol derivative, 1,4-dihydroxy-2-naphthoic acid, from fermentation by Propionibacterium freudenreichii was reported to suppress bone resorption [17] and dextran sodium sulphate (DSS)-induced colitis [18].The 1-naphthol derivative NKH-7 was found to prevent the deleterious effect of external CaCl 2 on Zds1 Delta strain yeast through a-tubulin [19].…”