2. Academic Validation
  3. Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones

Effect of α-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3 H)-ones

  • J Med Chem. 2019 Jan 24;62(2):604-621. doi: 10.1021/acs.jmedchem.8b01238.
Maxim B Nawrozkij 1,  Mariantonietta Forgione 2,  Alexandre S Yablokov 1,  Alessia Lucidi 2,  Daniela Tomaselli 2,  Alexandros Patsilinakos 2,  Cristina Panella 3,  Gebremedhin S Hailu 2,  Ivan A Kirillov 1,  Roger Badia 4,  Eva Riveira-Muñoz 4,  Emmanuele Crespan 5,  Jorge I Armijos Rivera 5,  Roberto Cirilli 3,  Rino Ragno 2,  José A Esté 4,  Giovanni Maga 5,  Antonello Mai 2 6,  Dante Rotili 2
Affiliations

Affiliations

  • 1 Volgograd State Technical University , Lenina Avenue 28 , 400005 Volgograd , Russia.
  • 2 Dipartimento di Chimica e Tecnologie del Farmaco , Università degli Studi di Roma "La Sapienza" , P. le A. Moro 5 , 00185 Roma , Italy.
  • 3 Centro Nazionale per il Controllo e la Valutazione dei Farmaci , Istituto Superiore di Sanità , Viale Regina Elena 299 , 00161 Roma , Italy.
  • 4 IrsiCaixa-AIDS Research Institute, Hospital Universitari Germans Trias i Pujol , Universitat Autònoma de Barcelona , 08916 Badalona , Spain.
  • 5 Istituto di Genetica Molecolare IGM-CNR , via Abbiategrasso 207 , 27100 Pavia , Italy.
  • 6 Istituto Pasteur-Fondazione Cenci Bolognetti , Università degli Studi di Roma "La Sapienza" , P. le A. Moro 5 , 00185 Roma , Italy.
PMID: 30525601 DOI: 10.1021/acs.jmedchem.8b01238
Abstract

Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best Antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.

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