Next Article in Journal
Non-Nucleosidic Analogues of Polyaminonucleosides and Their Influence on Thermodynamic Properties of Derived Oligonucleotides
Next Article in Special Issue
Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?
Previous Article in Journal
Simultaneous Fitting of Absorption Spectra and Their Second Derivatives for an Improved Analysis of Protein Infrared Spectra
Previous Article in Special Issue
Evaluation of Novel Antibacterial N-Halamine Nanoparticles Prodrugs towards Susceptibility of Escherichia coli Induced by DksA Protein
Article Menu

Export Article

Open AccessReview
Molecules 2015, 20(7), 12623-12651;

Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids

Center for Drug Discovery and College of Pharmacy, University of Georgia, Athens, GA 30602, USA
Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 29 May 2015 / Revised: 6 July 2015 / Accepted: 7 July 2015 / Published: 13 July 2015
(This article belongs to the Special Issue Prodrugs)
Full-Text   |   PDF [1550 KB, uploaded 13 July 2015]   |  


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

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Share & Cite This Article

MDPI and ACS Style

Nair, V.; Okello, M. Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids. Molecules 2015, 20, 12623-12651.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top