The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase

Abstract

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.

Synthesis and biological evaluation of some new 1,3,4-thiadiazole and 1,2,4-triazole derivatives from L-methionine as antituberculosis and antiviral agents

“…Some novel 1,3,4-thiadiazole [5][6][7][8] and 1,2,4-triazole [9][10][11][12] derivatives carrying amino acid moiety were synthesized starting from L-methionine. 1,3,4-Thiadiazole and 1,2,4-triazole scaffolds were prepared by cyclocondensation of the corresponding thiosemicarbazide and finally converted to their thiourea derivatives.…”

“…1,3,4-Thiadiazole and 1,2,4-triazole scaffolds were prepared by cyclocondensation of the corresponding thiosemicarbazide and finally converted to their thiourea derivatives. Structures of the synthesized compounds [4][5][6][7][8][9][10][11][12] were confirmed by IR, 1 H-NMR and 13 C-NMR spectral data and elemental analysis. …”

Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: Synthesis and Biological Evaluation of Novel Quinoxalinylethylpyridylthioureas as Potent Antiviral Agents

“…Early studies showed that the potent inhibitor of HIV-1 reverse transcriptase N-(2-pyridylethyl)-N′-2-(5-bromopyridinyl)thiourea(LY73497) readily crosses the blood-brain barrier in rats (Ahgren et al, 1995). Similarly, 6-FQXPT 23f, which we found to have subnanomolar potency against HIV-1 in cell culture assays, rapidly enters the mouse brain, reaching mean maximum concentrations (C max ) at the same time as in plasma, 30 min after subcutaneous dosing (20 mg/kg).…”

“…(2) (Hargrave et al, 1991), TIBO (3) (Pauwels et al, 1990), pyridinones (4) (Goldman et al, 1991), PBO (5) (Campiani et al, 1996(Campiani et al, , 1999a) and trovirdine (6) (Ahgren et al, 1995;Bell et al, 1995;Cantrell et al, 1996). Herein we report the synthesis and biological evaluation as NNRTIs of a series of thiourea derivatives structurally related to trovirdine.…”

Syntheses and reactions of methyl [3-(4-phenyl-thiazol-2-yl)-thioureido] alkanoates and related compounds

“…Several heterocyclic thioureas have been reported as a new class of potent NNRTIs such phenethylthiazolyl-thiourea (PETT) derivatives. [6][7][8][9] Uckun et al 10 described the synthesis of a series of thiazole thioureas with alkyl, aryl, heteroaryl substituents as newly identified NNRTI of HIV, including mutant strains of HIV, and effective in the treatment of multi-drug resistant HIV infection.…”