Design, synthesis, and biological evaluation of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile.

Because the emergence of drug-resistant mutants has limited the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs), it is essential to develop new antivirals with better drug resistance and pharmacokinetic profiles. Here we designed and synthesized a series of 1-[(2-benzyloxyl/alkoxyl)methyl]-5-halo-6-aryluracils, the HEPT analogues, and evaluated their biological activity using nevirapine and 18 (TNK-651) as reference compounds. Most of these compounds, especially 6b, 7b, 9b, 11b, and 7c, exhibited highly potent anti-HIV-1 activity against both wild-type and NNRTI-resistant HIV-1 strains. Compound 7b, which had the highest selectivity index (SI = 38 215), is more potent than nevirapine and 18. These results suggest that the introduction of a halogen at the C-5 position may contribute to the effectiveness of these compounds against RTI-resistant variants. In addition, meta substituents on the C-6 aromatic moiety could significantly enhance activity against NNRTI-resistant HIV-1 strains. These compounds can be further developed as next-generation NNRTIs with an improved antiviral efficacy and drug-resistance profile.

[1]  H. Xing,et al.  Genotypic and phenotypic cross-drug resistance of harboring drug-resistant HIV type 1 subtype B' strains from former blood donors in central Chinese provinces. , 2010, AIDS research and human retroviruses.

[2]  Ying Guo,et al.  The design and synthesis of N-1-alkylated-5-aminoarylalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors. , 2007, Bioorganic & medicinal chemistry.

[3]  H. Xing,et al.  Genotype and Phenotype Patterns of Drug-Resistant HIV-1 Subtype B′ (Thai B) Isolated From Patients Failing Antiretroviral Therapy in China , 2007, Journal of acquired immune deficiency syndromes.

[4]  Stephen H Hughes,et al.  Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. , 2005, Progress in biophysics and molecular biology.

[5]  A. Debnath,et al.  N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion , 2004, Antimicrobial Agents and Chemotherapy.

[6]  Ivet Bahar,et al.  Conformational changes in HIV-1 reverse transcriptase induced by nonnucleoside reverse transcriptase inhibitor binding. , 2004, Current HIV research.

[7]  C. Tarby.  Recent advances in the development of next generation non-nucleoside reverse transcriptase inhibitors. , 2004, Current topics in medicinal chemistry.

[8]  H. M. Vinkers,et al.  Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. , 2004, Journal of medicinal chemistry.

[9]  C. Nielsen,et al.  Synthesis of Furoannelated Analogues of Emivirine (MKC‐442) , 2004, Archiv der Pharmazie.

[10]  G. Weverling,et al.  TMC125 exerts similar initial antiviral potency as a five-drug, triple class antiretroviral regimen , 2003, AIDS.

[11]  J. Tronchet,et al.  Nonnucleoside inhibitors of HIV-1 reverse transcriptase: from the biology of reverse transcription to molecular design. , 2003, Current topics in medicinal chemistry.

[12]  I. Lavandera,et al.  Novel and efficient syntheses of 3′,5′-diamino derivatives of 2′,3′,5′-trideoxycytidine and 2′,3′,5′-trideoxyadenosine. Protonation behavior of 3′,5′-diaminonucleosides , 2003 .

[13]  Kenneth A Jacobson,et al.  Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A(2A)- and A(3)-adenosine receptor antagonists. , 2002, Journal of medicinal chemistry.

[14]  Ettore Novellino,et al.  Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives. , 2002, Current pharmaceutical design.

[15]  A. Napoli,et al.  Simple and Efficient Routes for the Preparation of Isoxazolidinyl Nucleosides Containing Cytosine and 5-Methyl-cytosine as New Potential Anti-HIV Drugs. , 2002 .

[16]  A. Napoli,et al.  Simple and efficient routes for the preparation of isoxazolidinyl nucleosides containing cytosine and 5-methyl-cytosine as new potential anti-HIV drugs , 2001 .

[17]  E. De Clercq.  New developments in anti-HIV chemotherapy , 2001, Current medicinal chemistry.

[18]  E. De Clercq,et al.  The HIV‐1 Reverse Transcription (RT) Process as Target for RT Inhibitors , 2000, Medicinal research reviews.

[19]  E. Novellino,et al.  5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3, 4-dihydropyrimidin-4(3H)-ones: novel potent and selective dihydro-alkoxy-benzyl-oxopyrimidine derivatives. , 1999, Journal of medicinal chemistry.

[20]  C. Monneret,et al.  A 3D QSAR study of a series of HEPT analogues: the influence of conformational mobility on HIV-1 reverse transcriptase inhibition. , 1997, Journal of medicinal chemistry.

[21]  D I Stuart,et al.  Models which explain the inhibition of reverse transcriptase by HIV-1-specific (thio)carboxanilide derivatives. , 1997, Biochemical and biophysical research communications.

[22]  D I Stuart,et al.  Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  K. Danel,et al.  Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. , 1996, Journal of medicinal chemistry.

[24]  Richard T. Walker,et al.  Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. , 1996, Journal of medicinal chemistry.

[25]  E. Pedersen,et al.  Easy Synthesis of 5,6‐Disubstituted Acyclouridine Derivatives. , 1995 .

[26]  R. T. Walker,et al.  Hept Derivatives: 6-Benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442) , 1995 .

[27]  Henri Moereels,et al.  Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors , 1995, Nature Structural Biology.

[28]  A. D. Clark,et al.  Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution , 1995 .

[29]  Yvonne Jones,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors , 1995, Nature Structural Biology.

[30]  Yvonne Jones,et al.  High resolution structures of HIV-1 RT from four RT–inhibitor complexes , 1995, Nature Structural Biology.

[31]  K A Johnson,et al.  Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors , 1995, Science.

[32]  J. Coffin,et al.  HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy , 1995, Science.

[33]  T. Steitz,et al.  Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. De Clercq,et al.  Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[35]  S. Hannick,et al.  An improved procedure for the Blaise reaction: a short, practical route to the key intermediates of the saxitoxin synthesis , 1983 .

[36]  W. Sung.  Synthesis of 4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one ribonucleotide and its application in synthesis of oligoribonucleotides , 1982 .

[37]  R. C. Elderfield,et al.  Communications- Application of the Mannich Reaction with β, β-Dichlorodiethylamine to Derivatives of Uracil , 1961 .

[38]  D. Stammers,et al.  HIV reverse transcriptase structures: designing new inhibitors and understanding mechanisms of drug resistance. , 2005, Trends in pharmacological sciences.

[39]  E. Pedersen,et al.  Three Routes for the Synthesis of 6-Benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde , 2001 .