Anti-Human Immunodeficiency Virus Type 1 Activity of Novel 6-Substituted 1-Benzyl-3-(3,5-Dimethylbenzyl)Uracil Derivatives

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replication<jats:italic>in vitro</jats:italic>. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound. After serial passages of the infected cells, escape viruses were obtained, and they were more than 500-fold resistant to the uracil derivatives compared to the wild type. Sequence analysis was conducted for RT of the escape viruses at passages 12 and 24. The amino acid mutation Y181C in the polymerase domain of RT was detected for all escape viruses. Docking studies using the crystal structure of RT showed that AmBBU requires the amino acid residues Leu100, Val106, Tyr181, and Trp229 for exerting its inhibitory effect on HIV-1. Four additional amino acid changes (K451R, R461K, T468P, and D471N) were identified in the RNase H domain of RT; however, their precise role in the acquisition of resistance is still unclear. In conclusion, the initial mutation Y181C seems sufficient for the acquisition of resistance to the uracil derivatives AzBBU and AmBBU. Further studies are required to determine the precise role of each mutation in the acquisition of HIV-1 resistance.</jats:p>

Selection Affects Genes Involved in Replication during Long-Term Evolution in Experimental Populations of the Bacteriophage φX174

“…Indeed, drugs that target the RNA polymerases of HIV and other eukaryotic viruses select for escape mutations that increase viral replication rates [57], [58]. Growing arboviruses only in an arthropod cell line, rather than switching between their arthropod and vertebrate hosts, selects for substitutions that increase the production of the reverse transcriptase needed for genome replication [59].…”

Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

“…The MKC-442 (emivirine) has HEPT origins ( Figure 3 ), even if it was very promising, it was abandoned after phase III of clinical trials [ 10 , 14 , 15 , 28 ].…”

“…The INI inhibitor: raltegravir (RAL, MK-0518) [ 12 , 13 , 14 , 15 , 17 , 18 , 19 , 24 ] (see Figure 1 ) [ 9 , 10 , 11 , 12 , 13 , 14 , 25 , 26 , 27 , 28 , 29 ].…”

“…The CRI inhibitor (SCH-D, SCH-417690) behaves like a CCR5 antagonist but another CRI inhibitor INCB-9471 acts like an uncompetitive allosteric antagonist of CCR5 ( Figure 2 ) [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 25 , 26 , 27 , 28 , 29 ].…”

Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives

“…10 We also continued the search for an anti-HIV-1 agent using the structure-activity relationships of the 1,3-disubstituted and 1,3,6-trisubstituted uracils. [11][12][13][14][15][16] We have demonstrated that the 3,5-dimethylbenzyl group at the N 3 -position and the amino group at the C6-position of the uracil skeleton play an important role in enhancing the anti-HIV-1 activity. Notably, substitution at the 1-position (with a benzyl or 4-picolyl group) of 6-amino-3-(3,5-dimethylbenzyl)uracil to obtain 1a-b (Table 1) yielded satisfactory anti-HIV-1 activity, with EC 50 values of 0.07 AE 0.01 mM and 0.03 AE 0.03 mM, respectively.…”