First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific anti-vaccinia and adenovirus agents via ‘privileged scaffold’ refining approach

Abstract A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) method. The biological significance of the novel synthesized quinazolines was highlighted by evaluating them in vitro for antiviral activity, wherein several compounds exhibited excellent activity specifically against vaccinia and adenovirus. Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with an EC50 value of 1.7μM, which was 15 fold than that of the reference drug Cidofovir (EC50 =25μM). 24b13 was the most potent compound against adenovirus-2 with an EC50 value of 6.2μM, which proved lower than all the reference drugs. Preliminary structure–activity relationships were also discussed. To the best of our knowledge, no data are present in the literature on antiviral activity of 3-hydroxy-quinazoline-2,4(1H,3H)-diones against DNA-viruses. Thus, these findings warrant further investigations (library expansion and compound refinement) on this novel class of antiviral agents.

[1]  Y. Sham,et al.  The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus. , 2012, Bioorganic & medicinal chemistry.

[2]  M. Bray,et al.  Looking back at smallpox. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  F. Bailly,et al.  2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), novel inhibitors of HIV integrase with a high barrier to resistance. , 2013, ACS chemical biology.

[4]  B. Huck,et al.  The identification and optimization of a N-hydroxy urea series of flap endonuclease 1 inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[5]  E. De Clercq,et al.  Activity of the Anti-Orthopoxvirus Compound ST-246 against Vaccinia, Cowpox and Camelpox Viruses in Cell Monolayers and Organotypic Raft Cultures , 2007, Antiviral therapy.

[6]  F. Bailly,et al.  2-hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: influence of the alkylation of position 4. , 2011, European journal of medicinal chemistry.

[7]  F. Bailly,et al.  Magnesium chelating 2-hydroxyisoquinoline-1,3(2H,4H)-diones, as inhibitors of HIV-1 integrase and/or the HIV-1 reverse transcriptase ribonuclease H domain: discovery of a novel selective inhibitor of the ribonuclease H function. , 2011, Journal of medicinal chemistry.

[8]  F. Bailly,et al.  4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors. , 2013, ACS medicinal chemistry letters.

[9]  E. De Clercq,et al.  The discovery of antiviral agents: Ten different compounds, ten different stories , 2008, Medicinal research reviews.

[10]  G. Wadell.  Molecular epidemiology of human adenoviruses. , 1984, Current topics in microbiology and immunology.

[11]  P. Zhou,et al.  Deep RNA Sequencing Reveals Complex Transcriptional Landscape of a Bat Adenovirus , 2012, Journal of Virology.

[12]  Peng Zhan,et al.  "Old Dogs with New Tricks": exploiting alternative mechanisms of action and new drug design strategies for clinically validated HIV targets. , 2014, Molecular bioSystems.

[13]  Peng Zhan,et al.  Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries. , 2016, Drug discovery today.

[14]  Xiaohong Liu,et al.  Structural and Binding Analysis of Pyrimidinol Carboxylic Acid and N-Hydroxy Quinazolinedione HIV-1 RNase H Inhibitors , 2011, Antimicrobial Agents and Chemotherapy.

[15]  A. Geddes,et al.  The history of smallpox. , 2006, Clinics in dermatology.

[16]  T. Karcz,et al.  Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55. , 2013, ACS medicinal chemistry letters.

[17]  S. Khoo,et al.  Adenoviruses from Human Immunodeficiency Virus-Infected Individuals, Including Two Strains That Represent New Candidate Serotypes Ad50 and Ad51 of Species B1 and D, Respectively , 1999, Journal of Clinical Microbiology.

[18]  E. De Clercq,et al.  Clinical features and treatment of adenovirus infections , 2008, Reviews in medical virology.

[19]  T. Lion,et al.  Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation , 2008, Leukemia.

[20]  S. Moro,et al.  Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Synthesis, pharmacological, and molecular modeling studies. , 2006, Journal of medicinal chemistry.

[21]  Peng Zhan,et al.  "Old friends in new guise": exploiting privileged structures for scaffold re-evolution/refining. , 2014, Combinatorial chemistry & high throughput screening.

[22]  G. Wadell,et al.  DNA restriction analysis of adenovirus prototypes 1 to 41 , 2005, Archives of Virology.

[23]  Robert T. Chen,et al.  Safety profile of smallpox vaccine: insights from the laboratory worker smallpox vaccination program. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[24]  Peng Zhan,et al.  Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends. , 2016, Journal of medicinal chemistry.

[25]  P. Wang,et al.  Histone deacetylase inhibitors through click chemistry. , 2008, Journal of medicinal chemistry.

[26]  Peng Zhan,et al.  Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2011 – 2014) , 2014, Expert opinion on therapeutic patents.

[27]  F. Bailly,et al.  Development of a series of 3-hydroxyquinolin-2(1H)-ones as selective inhibitors of HIV-1 reverse transcriptase associated RNase H activity. , 2012, Bioorganic & medicinal chemistry letters.

[28]  M. Durkin,et al.  Multiple cases of life-threatening adenovirus pneumonia in a mental health care center. , 1998, American journal of respiratory and critical care medicine.

[29]  J. Sagartz,et al.  A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus , 2010, Journal of Virology.

[30]  F. Bailly,et al.  Design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain. , 2008, Journal of medicinal chemistry.

[31]  J. Kates,et al.  Vaccinia Virus Replication I. Requirement for the Host-Cell Nucleus , 1979, Journal of virology.