Chem. Pharm. Bull. 54(5) 682—686 (2006)

bition of virus adsorption, virus-cell fusion, reverse transcription, integration, translation, proteolytic cleavage, glycosylation, assembly, or release. Because the integration is essential for the replication of HIV and the integrase, the enzyme responsive for integration, appears to be absent in the mammalian host, HIV-1 integrase (HIV-1 IN) represents a potential target for the development of non-toxic antiviral therapeutic agents. Recently numerous coumarin compounds have been evaluated for inhibitory effects against HIV replication, and some of them have been found to inhibit different stages in the HIV replication cycle. A natural tetrameric coumarin (I) shown potent integrase inhibitory activity (IC50 0.8 mM for integration and 1.5 mM for 3 -processing) was first reported by Mazumder et al. and the parent compound was then modified into simple components to determine the minimum active pharmacophore essential for potency. They disclosed a biscoumarin unit linked by a phenyl ring (II) was required for activity. Our previous studies focused mainly on the linker of phenyl ring. Replacement of the phenyl ring by aniline mustard (III) was achieved. We reasoned the mustard moiety might react with nearby nucleophile of the binding site to form a covalent bonding and to improve the inhibitory activity. However, these compounds failed to enhance activity. We also prepared biscoumarins with a diversified modification on the linker. Structure–activity relationship studies enabled us to know that the benzoyloxyphenyl linker (IV) seemed important for the inhibitory activity. These encouraging results prompted us to modify these lead compounds. Thus, we examined the effects of substitutions on the benzene ring of benzoyloxyphenyl linker. In the present paper, we report the synthesis and biological evaluation of a novel benzoyloxyphenyl linker (V) having either a monohydroxy or bishydroxy groups on the benzoyl ring. Chemistry A general synthetic route for the preparation of target compounds (30—47) is depicted in Charts 2 and 4. Protection of the phenolic hydroxyl groups of commercially available polyphenolic acids (1—8) by acetylation with acetic anhydride in pyridine in the dark at room temperature gave (9—16). Key intermediate 17 was prepared from 4hydroxybenzaldehyde with 4-hydroxycoumarin in ethanol under reflux. The first attempt to prepare target compounds by esterification of 17 with protected polyphenolic acids (14) in the presence of coupling reagents dicyclohexylcarbodiimide (DCC) and catalyst 4-dimethylaminopyridine (4DMAP) in dichloromethane, followed by 3 N HCl hydrolysis to remove the protected phenols was unfruitful (Chart 3). The product was unexpected 18 other than 45. Alternative synthesis of target compounds was successful by esterification of 4-hydroxybenzaldehyde with protected polyphenolic acids (9—16, 19) and lipoic acid in the presence of coupling 682 Vol. 54, No. 5