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

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 IC50 values of 19.90 μM and 7.77 μM, respectively and 9 also inhibited COX-1 (5.55 μM), 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.