title: Synthesis of dihydropyrimidine α,γ-diketobutanoic acid derivatives targeting HIV integrase.
abstract: 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 Mg(2+) ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the β-diketo acid moiety of 4c, 4d and 5b chelating Mg(2+). 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.
authors.affiliation: Univ. Orléans et CNRS, ICOA, UMR 7311, F-45067, Orléans, France.
authors.forename: Ozkan
authors.initials: O
authors.lastname: Sari
authors.affiliation: Univ. Orléans et CNRS, ICOA, UMR 7311, F-45067, Orléans, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Roy
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Univ. Orléans et CNRS, ICOA, UMR 7311, F-45067, Orléans, France; CNRS, CBM, UPR 4301, Univ. Orléans, F-45071, Orléans, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bourg
authors.affiliation: Univ. Orléans et CNRS, ICOA, UMR 7311, F-45067, Orléans, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, GA, 30322, USA.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.affiliation: Univ. Orléans et CNRS, ICOA, UMR 7311, F-45067, Orléans, France. Electronic address: luigi.agrofoglio@univ-orleans.fr.
authors.forename: Luigi A
authors.initials: LA
authors.lastname: Agrofoglio
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020148:Butyric Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011743:Pyrimidines; C000609858:dihydropyrimidine alpha,gamma-diketobutanoic acid; D020148:Butyric Acid; D019427:HIV Integrase
keywords: Antiviral activity; Dihydropyrimidine α,γ-diketobutanoic acid; Docking analysis; Integrase-HIV; Synthesis