| Abstract
| - Based on data derived from a large number of HIV-1 integraseinhibitors, similar structuralfeatures can be observed, which consist of two aryl units separated bya central linker. Formany inhibitors fitting this pattern, at least one aryl ring alsorequires ortho bis-hydroxylationfor significant inhibitory potency. The ability of such catecholspecies to undergo in situoxidation to reactive quinones presents one potential limitation totheir utility. In an effort toaddress this problem, a series of inhibitors were prepared which didnot contain ortho bis-hydroxyls. None of these analogues exhibited significantinhibition. Therefore an alternateapproach was taken, whose aim was to increase potency rather thaneliminate catecholsubstructures. In this latter study, naphthyl nuclei were utilizedas aryl components, since aprevious report had indicated that fused bicyclic rings may affordhigher affinity relative tomonocyclic phenyl-based systems. In preliminary work withmonomeric units, it was foundthat the 6,7-dihydroxy-2-naphthoic acid (17)(IC50 = 4.7 μM) was approximately 10-foldmorepotent than its 5,6-dihydroxy isomer 19 (IC50= 62.4 μM). Of particular note was the dramaticdifference in potency between free acid 17 and its methylester 21 (IC50> 200 μM). Thenearlytotal loss of activity induced by esterification strongly indicatesthat the free carboxylic −OHis important for high potency of this compound. This contrastswith the isomeric 5,6-dihydroxyspecies 19, where esterification had no effect on inhibitorypotency (23, IC50 = 52.7 μM).Thesedata provide evidence that the monomeric 6,7- and5,6-dihydroxynaphthalenes may beinteracting with the enzyme in markedly different fashions.However, when these naphthylnuclei were incorporated into dimeric structures, significantenhancements in potencies eachrelative to the monomeric acids were observed, with bis-6,7-dihydroxyanalogue 49 and bis-5,6-dihydroxy analogue 51 both exhibiting approximately equalpotencies (IC50 values of 0.81and 0.11 μM, respectively).
|
