182205-62-5Relevant articles and documents
Arylamide inhibitors of HIV-1 integrase
Zhao, He,Neamati, Nouri,Mazumder, Abhijit,Sunder, Sanjay,Pommier, Yves,Burke Jr., Terrence R.
, p. 1186 - 1194 (2007/10/03)
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 orth obis-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 μM) was approximately 10-fold more potent than its 5,6-dihydroxy isomer 19 (IC50 = 62.4 μM). Of particular note was the dramatic difference in potency between free acid 17 and its methyl ester 21 (IC50 > 200 μM). 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 μM). 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 μM, respectively).
Hydroxylated aromatic inhibitors of HIV-1 integrase
Burke Jr.,Fesen,Mazumder,Wang,Carothers,Grunberger,Driscoll,Kohn,Pommier
, p. 4171 - 4178 (2007/10/03)
Efficient replication of HIV-1 requires integration of a DNA copy of the viral genome into a chromosome of the host cell. Integration is catalyzed by the viral integrase, and we have previously reported that phenolic moieties in compounds such as flavones, caffeic acid phenethyl ester (CAPE, 2), and curcumin confer inhibitory activity against HIV-1 integrase. We now extend these findings by performing a comprehensive structure-activity relationship using CAPE analogues. Approximately 30 compounds have been prepared as HIV integrase inhibitors based on the structural lead provided by CAPE, which has previously been shown to exhibit an IC50 value of 7 μM in our integration assay. These analogues were designed to examine specific features of the parent CAPE structure which may be important for activity. Among the features examined for their effects on inhibitory potency were ring substitution, side chain length and composition, and phenyl ring conformational orientation. In an assay which measured the combined effect of two sequential steps, dinucleotide cleavage and strand transfer, several analogues have IC50 values for 3'-processing and strand transfer lower than those of CAPE. Inhibition of strand transfer was assayed using both blunt-ended and 'precleaved' DNA substrates. Disintegration using an integrase mutant lacking the N-terminal zinc finger and C-terminal DNA-binding domains was also inhibited by these analogues, suggesting that the binding site for these compounds resides in the central catalytic core. Several CAPE analogues were also tested for selective activity against transformed cells. Taken together, these results suggest that the development of novel antiviral agents for the treatment of acquired immune deficiency syndrome can be based upon inhibition of HIV-1 integrase.
