Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase

• Published in: Journal of medicinal chemistry 2007-07, Vol.50 (15), p.3416-3419
• Main Authors: Wang, Zhengqiang, Bennett, Eric M, Wilson, Daniel J, Salomon, Christine, Vince, Robert
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Crystallography, X-Ray; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV Reverse Transcriptase - antagonists & inhibitors; HIV-1 - drug effects; HIV-1 - enzymology; Humans; In Vitro Techniques; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - virology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Structure-Activity Relationship; Thymine - analogs & derivatives; Thymine - chemical synthesis; Thymine - chemistry; Thymine - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070512p

Bifunctional inhibitors were designed and synthesized based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) a non-nucleoside reverse transcriptase (RT) inhibitors and diketoacid (DKA) integrase (IN) inhibitors. Biochemical studies revealed activity against RT and IN at low nanomolar and low micromolar concentrations, respectively. Exceptionally low IC50 values from a cell-based assay were achieved along with remarkably high therapeutic indices. Compound 7 was identified as the best compound of the series (IC50:  24 nM against RT, 4.4 μM against IN, and 10 nM against HIV-1).