N-[2-(4-methylphenyl)ethyl]-N '-[2-(5-bromopyridyl)]-thiourea as a potent inhibitor of NNRTI-resistant and multidrug-resistant human immunodeficiencyvirus type 1

The composite non-nucleoside reverse transcriptase inhibitor (NNRTI) bindin g pocket model was used to study a number of thiourea analogues with differ ent substitutions at the 4-phenyl position including N-[2-(4-methylphenyl)e thyl]-N'-[2(5-bromopyridyl)l-thiourea (compound Hl-244), which inhibited re combinant RT better than trovirdine or compound HI-275 with an unsubstitute d phenyl ring. HI-244 effectively inhibited the replication of HIV-1 strain HTLVIIIB in human peripheral blood mononuclear cells with an IC50 value of 0.007 mu M, which is equal to the IC50 value of trovirdine. Notably, HI-24 4 was 20 times more effective than trovirdine against the multidrug-resista nt HIV-1 strain RT-MDR with a V106A mutation las well as additional mutatio ns involving the RT residues 74V, 41L and 215Y) and seven times more potent than trovirdine against the NNRTI-resistant HIV-1 strain A17 with a Y181C mutation.