Structure-based design of N-[2-(1-piperidinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase

• Published in: Bioorganic & medicinal chemistry letters 1998-08, Vol.8 (16), p.2213-2218
• Main Authors: Mao, Chen, Vig, Rakesh, Venkatachalam, T.K., Sudbeck, Elise A., Uckun, Fatih M.
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding Sites; Biological and medical sciences; Computer Simulation; Drug Design; HIV Core Protein p24 - biosynthesis; HIV Core Protein p24 - blood; HIV Infections - blood; HIV Infections - virology; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV-1 - drug effects; HIV-1 - physiology; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - physiology; Leukocytes, Mononuclear - virology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Thiourea - analogs & derivatives; Thiourea - chemical synthesis; Thiourea - chemistry; Thiourea - pharmacology; Virus Replication - drug effects
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(98)00384-9

A novel computer model of the HIV reverse transcriptase (RT) non-nucleoside inhibitor (NNI) binding pocket, which was generated using high resolution crystal structure information from 9 individual RT/NNI complexes, revealed previously unrecognized ligand derivatization sites for phenethylthiazolylthiourea (PETT) derivatives. Spatial gaps surrounding the pyridyl ring of the active PETT derivative trovirdine were discovered during modeling procedures. Docking studies using the computer-generated model of the binding pocket (composite binding pocket) suggested that the replacement of the planar pyridyl ring of trovirdine with a nonplanar piperidinyl or piperazinyl ring, which occupy larger volumes, would better fill the spacious Wing 2 region of the butterfly-shaped NNI binding pocket. The anti-HIV activity of the synthesized heterocyclic compounds N-[2-(1-piperidinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea was examined in HTLV iiib-infected peripheral blood mononuclear cells. Both compounds were more potent than trovirdine and abrogated HIV replication at nanomolar concentrations without any evidence of cytotoxicity. The synthesis and anti-HIV potency of the following compounds are reported.