Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity

Citation
Tk. Venkatachalam et al., Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity, ANTIVIR CHE, 11(5), 2000, pp. 329-336
Citations number
20
Categorie Soggetti
Microbiology
Journal title
ANTIVIRAL CHEMISTRY & CHEMOTHERAPY
ISSN journal
09563202 → ACNP
Volume
11
Issue
5
Year of publication
2000
Pages
329 - 336
Database
ISI
SICI code
0956-3202(200009)11:5<329:PPAFBT>2.0.ZU;2-Q
Abstract
Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcrip tase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to in hibit the replication of the HIV-1 strain HTLVIIIB in human peripheral bloo d mononuclear cells. The unsubstituted parent pyridyl thiourea compound N-[ 2-(1-piperidine)ethyl]-N'-[2-(pyridyl)] thiourea (1) exhibited no anti-HIV activity, even at 100 muM. However, the thiourea derivatives that contain a bromo- or chloro-substituted pyridyl group, compounds 2 and 5, inhibited H IV-1 replication at nanomolar concentrations. The addition of a methyl grou p onto the piperidine ring significantly altered the potency of these compo unds; while methyl substitution at the 3-position of the piperidine ring re duced the activity, methyl substitution at the 2-position enhanced the anti -HIV activity. The IC50 value of the lead piperidinyl compound, N-[2-(2-met hylpiperidinylethyl)]-N'-[2-(5-bromopyridyl)] thiourea (4) was <0.001 <mu>M . All three phenoxyethyl derivatives, including the unsubstituted parent ph enoxyethyl pyridyl thiourea compound N-[2-(phenoxy)ethyl]N'-[2-(pyridyl)]th iourea (8) and the bromo-/chlorosubstituted phenoxyethyl halopyridyl thiour ea compounds N-[2-(phenoxy)ethyl]-N'-[2-(5-chlorepyridyl)]thiourea (9) and N-[2-(phenoxy)ethyl]-N'-[2(5-bromopyridyl)]thiourea (10) exhibited potent a nti-HIV activity with nanomolar IC50 values. The corresponding fluoroethyl halopyridyl thiourea compounds beta -fluouo[2-phenethyl]-N'[2-(5-chloropyri dyl)]thiourea (11) and beta -fluoro[2-phenethyl]-N'[2(5-bromopyridyl)]thiou rea (12) inhibited HIV-1 replication in PBMC with subnanomolar IC50 values and selectivity indices >30000. Compared to the corresponding phenoxyethyl thiourea compounds 9 and 10, these compounds were >4-5-fold more active as anti-HIV agents. Notably, the lead flourothiourea compounds 11 and 12 were both substantially more active against the NNRTI-resistant HIV strains RT-M DR (V106A) and A17 (Y181C) than nevirapine or delavirdine. Taken together, our results provide additional experimental evidence that the structural fe atures of the 'linker unit' between the pyridyl and phenyl moieties and cha nges in the phenyl group of PETT-related thiourea compounds significantly a ffects their biological activity as NNRTIs of HIV-1 RT.