Arylamide inhibitors of HIV-1 integrase.
Based on data derived from a large number of HIV-1 integrase inhibitors, similar structural features can be observed, which consist of two aryl units separated by a central linker. For many inhibitors fitting this pattern, at least one aryl ring also requires ortho bis-hydroxylation for significant inhibitory potency. The ability of such catechol species to undergo in situ oxidation to reactive quinones presents one potential limitation to their utility. In an effort to address this problem, a series of inhibitors were prepared which did not contain ortho bishydroxyls. None of these analogues exhibited significant inhibition. Therefore an alternate approach was taken, whose aim was to increase potency rather than eliminate catechol substructures. In this latter study, naphthyl nuclei were utilized as aryl components, since a previous report had indicated that fused bicyclic rings may afford higher affinity relative to monocyclic phenyl-based systems. In preliminary work with monomeric units, it was found that the 6,7-dihydroxy-2-naphthoic acid (17) (IC50 = 4.7 microM) was approximately 10-fold more potent than its 5,6-dihydroxy isomer 19 (IC50 = 62.4 microM). Of particular note was the dramatic difference in potency between free acid 17 and its methyl ester 21 (IC50 > 200 microM). The nearly total loss of activity induced by esterification strongly indicates that the free carboxylic -OH is important for high potency of this compound. This contrasts with the isomeric 5,6-dihydroxy species 19, where esterification had no effect on inhibitory potency (23, IC50 = 52.7 microM). These data provide evidence that the monomeric 6,7- and 5,6-dihydroxynaphthalenes may be interacting with the enzyme in markedly different fashions. However, when these naphthyl nuclei were incorporated into dimeric structures, significant enhancements in potencies each relative to the monomeric acids were observed, with bis-6,7-dihydroxy analogue 49 and bis-5,6-dihydroxy analogue 51 both exhibiting approximately equal potencies (IC50 values of 0.81 and 0.11 microM, respectively).
Zhao
H
H
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Neamati
N
N
Mazumder
A
A
Sunder
S
S
Pommier
Y
Y
Burke
T R
TR
D002109:Caffeic Acids / Q000737:chemistry* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D003603:Cytotoxins / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011809:Quinones / Q000378:metabolism; D013329:Structure-Activity Relationship
D002109:Caffeic Acids; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D019428:HIV Integrase Inhibitors; D016328:NF-kappa B; D011809:Quinones; D019427:HIV Integrase; C055494:caffeic acid phenethyl ester; D003474:Curcumin; D010626:Phenylethyl Alcohol