Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent

Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human im munodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (R T) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies base d on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Sever al compounds proved to be potent broad-spectrum enzyme inhibitors and signi ficantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the eth yl spacer, and structure-activity relationships are discussed in terms of t he possible interaction with the RT binding site. Although the new QXPTs an alogues show potent antiviral activity, none of the compounds tested overco me the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic an tiviral agents, which in general have very low oral bioavailability. Throug h an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic seri es of antivirals. Replacing the ethylthioureidic moiety with a hydrazine li nker led to a new antiviral lead, offering promising pharmacological and ph armacokinetic properties in terms of antiviral activity and oral bioavailab ility.