Synthesis of the pyrimidine analog of 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)one (TIBO) potential for HIV-1 inhibition

Bioorganic & Medicinal Chemistry Letters
1991.0

Abstract

Efficient synthesis of the pyrimidine TIBO analog 3, starting from 9-benzyl-6-chloropurine and testing of its ability to inhibit the replication of the HIV-1 virus in MT-4 cells are described. We have reported that members of a novel series of tetrahydro-imidazo[4,5,1-ik][1,4]-benzodiazepin-2(1H)one and -thione (TIBO), such as 1 and 2, inhibit the replication of HIV-1 [1,2] (the main etiological agent of AIDS), but not of HIV-2, or of any other DNA or RNA viruses tested to date [3-5]. The unprecedented specificity of these compounds is believed to result from an interaction with reverse transcriptase, the unique viral enzyme responsible for translation of HIV-1 viral RNA into DNA which is incorporated into host cells' genomic DNA. Previous studies have established that 2 inhibits the isolated reverse transcriptase [6]. In laboratory tests, TIBO derivatives inhibited reproduction of the HIV-1 virus at concentrations far below those toxic to uninfected cells. Compound 2 is currently being evaluated in clinical trials as another drug to add to anti-AIDS therapy. In the course of SAR studies to find even more potent analogs, phenyl substituents were varied and those studies will be published in the future. Additionally, substitution of heteroaromatics for the benzo portion of the TIBO structure was undertaken. This report describes the synthesis and anti-HIV-1 testing result of pyrimidine analog 3, an example of that type of change.

Knowledge Graph

Similar Paper

Synthesis of the pyrimidine analog of 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)one (TIBO) potential for HIV-1 inhibition
Bioorganic & Medicinal Chemistry Letters 1991.0
Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives
Journal of Medicinal Chemistry 1991.0
Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 2
Journal of Medicinal Chemistry 1991.0
Synthesis and Anti-HIV-1 Activity of 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TlBO) Derivatives. 4
Journal of Medicinal Chemistry 1995.0
Synthesis of 1-(2-aminopropyl)benzimidazoles, structurally related to the TIBO derivative R82150, with activity against human immunodeficiency virus
Bioorganic & Medicinal Chemistry Letters 1993.0
Synthesis and HIV-1 inhibition of novel benzimidazole derivatives
Bioorganic & Medicinal Chemistry Letters 1995.0
Novel 1,3-dihydro-benzimidazol-2-ones and their analogues as potent non-nucleoside HIV-1 reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry 2010.0
Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry Letters 2010.0
Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines
Journal of Medicinal Chemistry 1993.0
Synthesis and Anti-HIV-1 Activity Evaluation of 5-Alkyl-2-alkylthio-6-(arylcarbonyl or α-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-ones as Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors
Journal of Medicinal Chemistry 2007.0