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Author Notes:

Correspondence to: Luigi A. Agrofoglio, luigi.agrofoglio@univ-orleans.fr

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Research Funding:

This work was supported in part by the NIH Intramural Research Program, Center for Cancer Research, National Cancer Institute (Z01 BC 007333-09LMP).

O.S. is grateful to the French Ministère de l’Enseignement Supérieur MNERST for a Ph.D. scholarship.

We thank the LABEX SynOrg (ANR-11-LABX-0029) for financial support.

RFS is supported in part by NIH Grant 5P30-AI-50409 (CFAR) and by the Department of Veterans Affairs.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • Dihydropyrimidine alpha, gamma-diketobutanoic acid
  • Synthesis
  • Docking analysis
  • Antiviral activity
  • Integrase-HIV
  • SITE
  • DNA

Synthesis of dihydropyrimidine alpha, gamma-diketobutanoic acid derivatives targeting HIV integrase


Journal Title:

European Journal of Medicinal Chemistry


Volume 104


, Pages 127-138

Type of Work:

Article | Post-print: After Peer Review


The synthesis and antiviral evaluation of a series of dihydropyrimidinone and thiopyrimidine derivatives bearing aryl α,γ-diketobutanoic acid moiety are described using the Biginelli multicomponent reaction as key step. The most active among 20 synthesized novel compounds were 4c, 4d and 5b, which possess nanomolar HIV-1 integrase (IN) stand transfer (ST) inhibition activities. In order to understand their mode of interactions within the IN active site, we docked all the compounds into the previously reported X-ray crystal structure of IN. We observed that compounds 4c, 4d and 5b occupied an area close to the two catalytic Mg2+ ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the β-diketo acid moiety of 4c, 4d and 5b chelating Mg2+. As those compounds lack anti-HIV activities in cell, their prodrugs were synthetized. The prodrug 4c′ exhibited an anti-HIV activity of 0.19 μM in primary human lymphocytes with some cytotoxicity. All together, these results indicate that the new analogs potentially interact within the catalytic site with highly conserved residues important for IN catalytic activity.

Copyright information:

© 2015 Elsevier Masson SAS.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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