Abstract
Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to inhibit the replication of the HIV-1 strain HTLVIIIB in human peripheral blood 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 μM. However, the thiourea derivatives that contain a bromo- or chloro-substituted pyridyl group, compounds 2 and 5, inhibited HIV-1 replication at nanomolar concentrations. The addition of a methyl group onto the piperidine ring significantly altered the potency of these compounds; while methyl substitution at the 3-position of the piperidine ring reduced the activity, methyl substitution at the 2-position enhanced the anti-HIV activity. The IC50 value of the lead piperidinyl compound, N-[2-(2-methylpiperidinylethyl)]-N′-[2-(5-bromopyridyl)] thiourea (4) was >0.001 μM. All three phenoxyethyl derivatives, including the unsubstituted parent phenoxyethyl pyridyl thiourea compound N-[2-(phenoxy)ethyl]-N-[2-(pyridyl)]thiourea (8) and the bromo-/chloro-substituted phenoxyethyl halopyridyl thiourea compounds N-[2-(phenoxy)ethyl]-N-[2-(5-chloropyridyl)]thiourea (9) and N-[2-(phenoxy)ethyl]-N-[2-(5-bromopyridyl)]thiourea (10) exhibited potent anti-HIV activity with nanomolar IC50 values. The corresponding fluoroethyl halopyridyl thiourea compounds β-fluoro[2-phenethyl]-N′[2-(5-chloropyridyl)]thiourea (11) and β-fluoro[2-phenethyl]-N′[2-(5-bromopyridyl)]thiourea (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 fluorothiourea compounds 11 and 12 were both substantially more active against the NNRTI-resistant HIV strains RT-MDR (V106A) and A17 (Y181C) than nevirapine or delavirdine. Taken together, our results provide additional experimental evidence that the structural features of the ‘linker unit” between the pyridyl and phenyl moieties and changes in the phenyl group of PETT-related thiourea compounds significantly affects their biological activity as NNRTIs of HIV-1 RT.