Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants. (Articolo in rivista)

Type
Label
  • Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants. (Articolo in rivista) (literal)
Anno
  • 2009-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1021/jm801330n (literal)
Alternative label
  • Radi M, Maga G, Alongi M, Angeli L, Samuele A, Zanoli S, Bellucci L, Tafi A, Casaluce G, Giorgi G, Armand-Ugon M, Gonzalez E, Esté JA, Baltzinger M, Bec G, Dumas P, Ennifar E, Botta M. (2009)
    Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants.
    in Journal of medicinal chemistry
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Radi M, Maga G, Alongi M, Angeli L, Samuele A, Zanoli S, Bellucci L, Tafi A, Casaluce G, Giorgi G, Armand-Ugon M, Gonzalez E, Esté JA, Baltzinger M, Bec G, Dumas P, Ennifar E, Botta M. (literal)
Pagina inizio
  • 840 (literal)
Pagina fine
  • 851 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 52 (literal)
Rivista
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Dipartimento Farmaco Chimico Tecnologico, University of Siena,Via Alcide de Gasperi 2, I-53100 Siena, Italy, Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, I-27100 Pavia, Italy, Dipartimento di Chimica, University of Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy, Retrovirology Laboratory irsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Auto?noma de Barcelona, E-08916 Badalona, Spain, Architecture et Re?activite? de l'ARN, UPR 9002 CNRS/Universite? Louis Pasteur, 15 rue Rene? Descartes, 67084 Strasbourg, France, UMR 7175 CNRS/Universite? Louis Pasteur, Ecole Supe?rieure de Biotechnologie Strasbourg, Boulevard Se?bastien Brandt, F-67400 Illkirch, France (literal)
Titolo
  • Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants. (literal)
Abstract
  • The role played by stereochemistry in the C2-substituent (left part) on the S-DABO scaffold for anti-HIV-1 activity has been investigated for the first time. A series of S-DABO analogues, where the double bond in the C2-substituent is replaced by an enantiopure isosteric cyclopropyl moiety, has been synthesized, leading to the identification of a potent lead compound endowed with picomolar activity against RT (wt) and nanomolar activity against selected drug-resistant mutants. Molecular modeling calculation, enzymatic studies, and surface plasmon resonance experiments allowed us to rationalize the biological behavior of the synthesized compounds, which act as mixed-type inhibitors of HIV-1 RT K103N, with a preferential association to the enzyme-substrate complex. Taken together, our data show that the right combination of stereochemistry on the left and right parts (C6-substituent) of the S-DABO scaffold plays a key role in the inhibition of both wild-type and drug-resistant enzymes, especially the K103N mutant. (literal)
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