Anti-human immunodeficiency virus type 1 activity of novel 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives.
نویسندگان
چکیده
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 in vitro. 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.
منابع مشابه
Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives with potential anti-HIV activity.
BACKGROUND Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1. METHODS Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil by other functional groups or N(1)-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil. RESULTS These compounds showed only micromolar potency against HIV-1 in MT-4, tho...
متن کاملDifferential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains.
A series of 23 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives that were highly potent inhibitors of wild-type human immunodeficiency virus type 1 strain IIIB (HIV-1/IIIB) replication in CEM cells were evaluated against a panel of HIV-1 mutant strains containing the replacement of leucine by isoleucine at position 100 (100-Leu-->Ile), 103-Lys-->Asn, 106-Val-->Ala, 138-Glu-->Lys, 1...
متن کامل[Synthesis and evaluation of novel nucleic acid derivatives as bioactive substances].
This review describes the synthesis and evaluation of novel nucleic acid derivatives performed by our research group to date. We developed a new method for the synthesis of 2-alkoxyadenosine analogs via nonaqueous diazotization-dediazoniation reactions. By applying these reactions, we effectively synthesized four types of carbocyclic oxetanocin analogs (2-alkoxy-C.OXT-A). The angiogenic activit...
متن کاملVenom Components of Iranian Scorpion Hemiscorpius lepturus Inhibit the Growth and Replication of Human Immunodeficiency Virus 1 (HIV-1)
Background: During the recent years, significant progress has been achieved on development of novel anti-viral drugs. Natural products are assumed as the potential sources of novel anti-viral drugs; therefore, there are some previous studies reporting the anti-viral compounds from venomous animals. Based on the significant value for tracing of non-toxic anti-viral agents from natural resources,...
متن کاملSynthesis of N2-(substituted benzyl)-3-(4-methylphenyl)indazoles as novel anti-angiogenic agents.
To search for novel compounds with potent anti-angiogenic activity, a series of N(1)-(substituted benzyl)-3-(4-methylphenyl)-1H-indazoles (16, 18, 20, 22, 24, 26, 28, 30, 32) and N(2)-(substituted benzyl)-3-(4-methylphenyl)-2H-indazoles (17, 19, 21, 23, 25, 27, 29, 31, and 33) were synthesized. The structures of these regioisomers were established by IR, UV, and NMR spectral data. 3-(4-Methylph...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Antimicrobial agents and chemotherapy
دوره 56 5 شماره
صفحات -
تاریخ انتشار 2012