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 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.
Kongkathip
Ngampong
N
Natural Products and Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand. fscibk@ku.ac.th
Hasitapan
Komkrit
K
Pradidphol
Narathip
N
Kirtikara
Kanyawim
K
Jongkona
Nipa
N
Kongkathip
Boonsong
B
D000818:Animals; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D014709:Vero Cells
D016861:Cyclooxygenase Inhibitors; D009284:Naphthols; C029350:1-naphthol