Tk. Venkatachalam et al., Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity, ANTIVIR CHE, 11(5), 2000, pp. 329-336
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.