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Center for Drug Discovery and College of Pharmacy, University of Georgia, Athens, GA 30602, USA





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Academic Editor: Jean Jacques Vanden Eynde

Abstract HIV integrase, encoded at the 3′-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of -no-return- in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are β-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer ST step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity EC50 improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC50 and IC90 ST enzymology data for 96 6 nM and 97 nM, respectively and the EC50 and EC90 anti-HIV data for its prodrug 116 9 nM and 94 nM, respectively. Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96. View Full-Text

Keywords: prodrugs; HIV-1 integrase inhibitors; antiviral activity prodrugs; HIV-1 integrase inhibitors; antiviral activity





Author: Vasu Nair * and Maurice Okello

Source: http://mdpi.com/



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