1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing ω-(2-benzyl- and 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These compounds displayed anti-HIV activity similar to that of nevirapine and several of them exhibited activity against the K103N/Y181C RT mutant HIV-1 strain. Further evaluation revealed that the inhibitors were active against most nevirapine-resistant mono- and di-substituted RTs with the exception of the V106A RT. Thus, the candidate compounds can be regarded as potential lead compounds against the wild-type virus and drug-resistant forms.

Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity

“…Two NNRTI (BPU Z007 and Z011) have already been tested as inhibitors of RNA-dependent DNA polymerase as well as DNA-dependent DNA polymerase activities of HIV-1 RT 18 , both of which are essential for retroviral replicative cycle. To perform EC50 measurements in solutions containing purified enzyme subunits, NNRTI had to be dissolved in DMSO while NNRTI/HC-PGC did not contain any organic solvents.…”

“…Z007 and Z011 have been previously shown to be efficient NNRTI 18 , while Z107 is new to this study.…”

“…1) family. These NNRTI are attractive active microbicide candidates since they have been previously proven efficient in tests involving both HIV-1 RT as well as its mutant forms, including a double mutant (K103N+Y181C) 18 . However, similar to many other first- and second- generation NNRTI (reviewed in 23 ), BPU are poorly soluble in water essentially limiting their efficacy in applications involving HIV-infected cells.…”

“…Z007 1-(2-(2-(3,5-dimethylbenzoyl)-4-methylphenoxy)ethyl)pyrimidine-2,4(1H,3H)-dione; and Z011 1-(2-(4-bromo-2-(3,5-dichlorobenzoyl)phenoxy)ethyl)pyrimidine-2,4(1H,3H)-dione, were described before 18 and one, i.e. Z107 1-(2-(4-chloro-2-(3,5-dimethylbenzoyl)phenoxy)ethyl)-1,5,6,7-tetrahydro- 2H -cyclopenta[ d ]pyrimidine-2,4(3H)-dione has not yet been tested extensively.…”

“…In this vein the goal of our work was to obtain and test stabilized water-soluble nano-formulations of a novel family of highly efficient but insoluble non-nucleoside reverse transcriptase inhibitors (NNRTI) 18, 19 (Figure 1) for their application as potential microbicides.…”