Recent advances in the discovery and development of novel HIV-1 NNRTI platforms: 2006-2008 update.

Currently, the long-term usage of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIVAIDS patients eventually leads to the development of drug resistance and severe side effect. Therefore, it is imperative to look for the novel NNRTIs with potent and broad spectrum anti-mutant activity that are also safe and have excellent pharmacokinetic profiles. In this article, newly emerging NNRTIs scaffolds in recent three years, together with the underlying strategies for developing new generation HIV-1 NNRTIs with improved resilience to current drug resistant mutants, are reviewed and analysed.

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

[2]  L. Boone,et al.  Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1. , 2004, Journal of medicinal chemistry.

[3]  J. Deschamps,et al.  New HIV-1 reverse transcriptase inhibitors based on a tricyclic benzothiophene scaffold: synthesis, resolution, and inhibitory activity. , 2006, Bioorganic & medicinal chemistry letters.

[4]  William L. Jorgensen,et al.  Search for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase Using Chemical Similarity, Molecular Docking, and MM-GB/SA Scoring , 2007, J. Chem. Inf. Model..

[5]  J. Caldwell,et al.  Design, synthesis, and biological evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. Part 2. , 2006, Bioorganic & medicinal chemistry letters.

[6]  Synthesis and evaluation of N-aryl pyrrolidinones as novel anti-HIV-1 agents. Part 1. , 2006, Bioorganic & medicinal chemistry letters.

[7]  M. Radi,et al.  Towards novel S-DABOC inhibitors: synthesis, biological investigation, and molecular modeling studies. , 2008, Bioorganic & medicinal chemistry letters.

[8]  William L. Jorgensen,et al.  Optimization of azoles as anti-human immunodeficiency virus agents guided by free-energy calculations. , 2008, Journal of the American Chemical Society.

[9]  R. Hamatake,et al.  Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase , 2006, Antimicrobial Agents and Chemotherapy.

[10]  Discovery of novel benzimidazolones as potent non-nucleoside reverse transcriptase inhibitors active against wild-type and mutant HIV-1 strains. , 2007, Bioorganic & medicinal chemistry letters.

[11]  A. Bergamini,et al.  Arylthiopyrrole (AThP) Derivatives as Non‐Nucleoside HIV‐1 Reverse Transcriptase Inhibitors: Synthesis, Structure–Activity Relationships, and Docking Studies (Part 2) , 2006, ChemMedChem.

[12]  Hwangseo Park,et al.  Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors , 2005, J. Comput. Aided Mol. Des..

[13]  Zhengqiang Wang,et al.  Synthesis of pyrimidine and quinolone conjugates as a scaffold for dual inhibitors of HIV reverse transcriptase and integrase. , 2008, Bioorganic & medicinal chemistry letters.

[14]  Marcela Madrid,et al.  Effect of a bound non-nucleoside RT inhibitor on the dynamics of wild-type and mutant HIV-1 reverse transcriptase. , 2005, Journal of the American Chemical Society.

[15]  Julian Tirado-Rives,et al.  Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2006, Bioorganic & medicinal chemistry letters.

[16]  P. Fernandes,et al.  The Current Status of the NNRTI Family of Antiretrovirals Used Against HIV Infection , 2008 .

[17]  J. Caldwell,et al.  Design, synthesis, and biological evaluations of novel quinolones as HIV-1 non-nucleoside reverse transcriptase inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[18]  Taraneh Mirzadegan,et al.  Design of annulated pyrazoles as inhibitors of HIV-1 reverse transcriptase. , 2008, Journal of medicinal chemistry.

[19]  F. Maggiolo,et al.  Rilpivirine, a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. , 2008, Current opinion in investigational drugs.

[20]  L. Zhang,et al.  Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[21]  M. Radi,et al.  Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants. , 2009, Journal of medicinal chemistry.

[22]  L. Boone,et al.  Antiviral Activity of GW678248, a Novel Benzophenone Nonnucleoside Reverse Transcriptase Inhibitor , 2005, Antimicrobial Agents and Chemotherapy.

[23]  Peng Zhan,et al.  Sulfanyltriazole/tetrazoles: a promising class of HIV-1 NNRTIs. , 2009, Mini reviews in medicinal chemistry.

[24]  C. Salomon,et al.  Rationally designed dual inhibitors of HIV reverse transcriptase and integrase. , 2007, Journal of medicinal chemistry.

[25]  Y. Li,et al.  Diphenyl Ether Non‐Nucleoside Reverse Transcriptase Inhibitors with Excellent Potency Against Resistant Mutant Viruses and Promising Pharmacokinetic Properties , 2009, ChemMedChem.

[26]  Jan Balzarini,et al.  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 , 2007 .

[27]  S. Binford,et al.  In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor. , 2006, Antiviral research.

[28]  E. De Clercq,et al.  1,2,3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[29]  M. Allan,et al.  Tri-substituted triazoles as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase. , 2006, Bioorganic & medicinal chemistry letters.

[30]  C. Mowbray,et al.  A concise and selective synthesis of novel 5-aryloxyimidazole NNRTIs. , 2006, Organic letters.

[31]  T. Dahl,et al.  Capravirine, a nonnucleoside reverse-transcriptase inhibitor in patients infected with HIV-1: a phase 1 study. , 2004, The Journal of infectious diseases.

[32]  L. Boone,et al.  Anti-Human Immunodeficiency Virus Type 1 Activity of the Nonnucleoside Reverse Transcriptase Inhibitor GW678248 in Combination with Other Antiretrovirals against Clinical Isolate Viruses and In Vitro Selection for Resistance , 2005, Antimicrobial Agents and Chemotherapy.

[33]  William L. Jorgensen,et al.  FEP-guided selection of bicyclic heterocycles in lead optimization for non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2006 .

[34]  D. Jochmans Novel HIV-1 reverse transcriptase inhibitors. , 2008, Virus research.

[35]  William L Jorgensen,et al.  Optimization of diarylamines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2006, Bioorganic & medicinal chemistry letters.

[36]  S. Teague Implications of protein flexibility for drug discovery , 2003, Nature Reviews Drug Discovery.

[37]  M. Erion,et al.  Relative binding affinities of fructose-1,6-bisphosphatase inhibitors calculated using a quantum mechanics-based free energy perturbation method. , 2007, Journal of the American Chemical Society.

[38]  Zhengqiang Wang,et al.  Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine. , 2008, Bioorganic & medicinal chemistry.

[39]  K. Kuhen,et al.  Synthesis and biological evaluations of sulfanyltriazoles as novel HIV-1 non-nucleoside reverse transcriptase inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[40]  D. Green,et al.  Benzophenone derivatives: a novel series of potent and selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase. , 1995, Journal of medicinal chemistry.

[41]  L. Boone,et al.  Next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors. , 2006, Current opinion in investigational drugs.

[42]  A. Mai,et al.  5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones, a series of anti-HIV-1 agents of the dihydro-alkoxy-benzyl-oxopyrimidine family with peculiar structure-activity relationship profile. , 2008, Journal of medicinal chemistry.

[43]  Roland Marquet,et al.  HIV-1 reverse transcriptase inhibitors , 2007, Applied Microbiology and Biotechnology.

[44]  Y. Li,et al.  Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2008, Bioorganic & medicinal chemistry letters.

[45]  D. Stammers,et al.  Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors. , 2008, Journal of medicinal chemistry.

[46]  S. Sarafianos,et al.  Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. , 2004, Current opinion in structural biology.

[47]  R. Hamatake,et al.  A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors , 2006, Antimicrobial Agents and Chemotherapy.

[48]  G. McGaughey,et al.  Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): a potent, orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitor with improved potency against key mutant viruses. , 2008, Journal of medicinal chemistry.

[49]  J. Duan,et al.  Thiotetrazole alkynylacetanilides as potent and bioavailable non-nucleoside inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases. , 2007, Bioorganic & medicinal chemistry letters.

[50]  William L Jorgensen,et al.  From docking false-positive to active anti-HIV agent. , 2007, Journal of medicinal chemistry.

[51]  William L Jorgensen,et al.  Optimization of pyrimidinyl- and triazinyl-amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2006, Bioorganic & medicinal chemistry letters.

[52]  D. Hazuda,et al.  Antiviral Activity of MK-4965, a Novel Nonnucleoside Reverse Transcriptase Inhibitor , 2009, Antimicrobial Agents and Chemotherapy.

[53]  Maurizio Botta,et al.  A Multidisciplinary Approach for the Identification of Novel HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors: S‐DABOCs and DAVPs , 2008, ChemMedChem.

[54]  D. Stammers,et al.  Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor. , 2006, Journal of medicinal chemistry.

[55]  Z. Sweeney,et al.  Improving non-nucleoside reverse transcriptase inhibitors for first-line treatment of HIV infection: the development pipeline and recent clinical data. , 2008, Current opinion in drug discovery & development.

[56]  G. McGaughey,et al.  The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutations. , 2008, Bioorganic & medicinal chemistry letters.

[57]  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.

[58]  P. Bonneau,et al.  Scaffold hopping in the rational design of novel HIV-1 non-nucleoside reverse transcriptase inhibitors. , 2007, Bioorganic & medicinal chemistry letters.