Since it appeared in the eighties, AIDS has been responsible for the death of more than 25 million people and has become the most challenging pandemic of the 21st century. The current standard of treatment, Highly Active Antiretroviral Treatment (HAART), consists of a cocktail of drugs which includes reverse transcriptase (RT) inhibitors, protease inhibitors (PI), and/or a fusion inhibitor. This regimen can achieve a significant reduction of the viral load in HIV-1 infected patients but is noticeably limited by the emergence of multidrug resistant viral strains. New strategies aimed at inhibiting virus replication are still necessary. In 2007, the FDA approved raltegravir A (IsentressTM, Meck & Co., Inc.), the first drug inhibiting the HIV-1 integrase (HIV-1 IN), led to strongly encouraging clinical results but resistant viral strains have already appeared after a 3 year use.1 Important therapeutic alternatives may consist of novel HIV-1 IN inhibitors with different profiles from that of raltegravir or of multi-targeted drugs. In our laboratory, we decided to investigate the last alternative by designing dual inhibitors of HIV-1 integrase and ribonuclease H function of reverse transcriptase.2 Integrase, the enzyme responsible for integration, catalyses the insertion of viral DNA within the host cell genome whereas the ribonuclease H function of reverse transcriptase catalyses the hydrolysis of the RNA strand in the RNA/DNA duplex. These two key steps of the viral replication are promoted by structurally-related catalytic cores, which are able to chelate two magnesium cations. We recently developed a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones B able to complex magnesium cations with a 1/1 stoichiometry.3 The majority of the synthesized compounds consisted of average dual inhibitors of RNase H and IN (micromolar IC50 values) with high cellular cytotoxicity. In the same field, we investigated a series of 3-hydroxyquinolin-2(1H)-ones C with metal complexing properties.4 Herein we present the synthesis and biological activities (integrase and RNase H inhibitory activities, viral replication inhibition and cytotoxicity on MT-4 cells) of some candidates of the series of 30 derivatives, together with their magnesium chelating properties

Development of 3-hydroxyquinolein-2(1H)-ones as inhibitors of HIV-1 integrase and ribonuclease H function of reverse transcriptase

TRAMONTANO, ENZO;ESPOSITO, FRANCESCA;CORONA, ANGELA;
2010

Abstract

Since it appeared in the eighties, AIDS has been responsible for the death of more than 25 million people and has become the most challenging pandemic of the 21st century. The current standard of treatment, Highly Active Antiretroviral Treatment (HAART), consists of a cocktail of drugs which includes reverse transcriptase (RT) inhibitors, protease inhibitors (PI), and/or a fusion inhibitor. This regimen can achieve a significant reduction of the viral load in HIV-1 infected patients but is noticeably limited by the emergence of multidrug resistant viral strains. New strategies aimed at inhibiting virus replication are still necessary. In 2007, the FDA approved raltegravir A (IsentressTM, Meck & Co., Inc.), the first drug inhibiting the HIV-1 integrase (HIV-1 IN), led to strongly encouraging clinical results but resistant viral strains have already appeared after a 3 year use.1 Important therapeutic alternatives may consist of novel HIV-1 IN inhibitors with different profiles from that of raltegravir or of multi-targeted drugs. In our laboratory, we decided to investigate the last alternative by designing dual inhibitors of HIV-1 integrase and ribonuclease H function of reverse transcriptase.2 Integrase, the enzyme responsible for integration, catalyses the insertion of viral DNA within the host cell genome whereas the ribonuclease H function of reverse transcriptase catalyses the hydrolysis of the RNA strand in the RNA/DNA duplex. These two key steps of the viral replication are promoted by structurally-related catalytic cores, which are able to chelate two magnesium cations. We recently developed a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones B able to complex magnesium cations with a 1/1 stoichiometry.3 The majority of the synthesized compounds consisted of average dual inhibitors of RNase H and IN (micromolar IC50 values) with high cellular cytotoxicity. In the same field, we investigated a series of 3-hydroxyquinolin-2(1H)-ones C with metal complexing properties.4 Herein we present the synthesis and biological activities (integrase and RNase H inhibitory activities, viral replication inhibition and cytotoxicity on MT-4 cells) of some candidates of the series of 30 derivatives, together with their magnesium chelating properties
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/86617
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