ly-73497 and 2-phenyl-6-(2--(4--(ethoxycarbonyl)thiazolyl))thiazolo(3-2-b)(1-2-4)triazole

HIV-1 (Human Immunodeficiency Virus Type-1) is the pathogenic retrovirus and causative agent of AIDS. HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as NNRTIs and NRTIs. NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTIs category, there is a set of inhibitors commonly referred to as phenyl ethyl thiazolyl thiourea (PETT) derivatives. The present 3D QSAR study attempts to explore the structural requirements of phenyl ethyl thiazolyl thiourea (PETT) derivatives for anti-HIV activity. Based on the structures and biodata of previous PETT analogs, 3D-QSAR (CoMFA) study has been performed with a training set consisting of 60 molecules, which resulted in a reliable computational model with q(2)=0.657, S(PRESS)=0.957, r(2)=0.938, and standard error of estimation (SEE)=0.270 with the number of partial least square (PLS) components being 5. It is shown that the steric and electrostatic properties predicted by CoMFA contours can be related to the anti-HIV activity. The predictive ability of the resultant model was evaluated using a test set comprised of 11 molecules and the predicted r(2)=0.893. This model is a more significant guide to trace the features that really matter especially with respect to the design of novel compounds.

Topics: Anti-HIV Agents; Computational Biology; Drug Design; Humans; Models, Molecular; Quantitative Structure-Activity Relationship; Reverse Transcriptase Inhibitors; Static Electricity; Thiazoles; Thiourea; Triazoles

A series of potent specific HIV-1 RT inhibitory compounds is described. The compounds are urea analogs of PETT (PhenylEthylThiazoleThiourea) derivatives and the series includes derivatives with an ethyl linker (1-6) and conformationally restricted analogs (7-13). The antiviral activity is determined both at the RT level and in cell culture on both native and mutant forms of HIV-1. Many compounds display activity in the nM range against wt-RT.

Topics: Anti-HIV Agents; Blood Proteins; Cell Line; HIV-1; Humans; Microbial Sensitivity Tests; Protein Binding; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Thiazoles; Triazoles

To identify the minimal structural elements necessary for biological activity, the rigid tricyclic nucleus of the known human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydroimidazobenzodiazepinthione was subjected to systematic bond disconnection to obtain simpler structures. A rational selection and testing of modeled analogs containing these potential pharmacophoric moieties led to the discovery of a new series of nonnucleoside inhibitors of RT. The lead compound of this new PETT series of nonnucleoside RT inhibitors, N-(2-phenylethyl)-N'-(2-thiazolyl)thiourea (LY73497), was found to inhibit HIV-1 but not HIV-2 or simian immunodeficiency virus in cell culture at micromolar concentrations. This derivative was also found to inhibit HIV-1 RT. Through an integrated effort involving synthesis and molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed. In these studies, LY300046-HCl was identified as a potent nonnucleoside inhibitor of HIV-1 RT possessing favorable pharmacokinetic properties.

Topics: Animals; Antiviral Agents; Base Sequence; Benzodiazepines; Brain; Cattle; Cells, Cultured; DNA-Directed DNA Polymerase; Drug Resistance, Microbial; HIV-1; Humans; Imidazoles; Intercalating Agents; Male; Molecular Sequence Data; Pyridines; Rats; Rats, Inbred F344; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Thiazoles; Thiourea; Triazoles