Effect of alpha-Methoxy Substitution on the Anti-HIV Activity of Dihydropyrimidin-4(3H)-ones
Por:
Nawrozkij, MB, Forgione, M, Yablokov, AS, Lucidi, A, Tomaselli, D, Patsilinakos, A, Panella, C, Hailu, GS, Kirillov, IA, Badia, R, Riveira-Munoz, E, Crespan, E, Rivera, JIA, Cirilli, R, Ragno, R, Este, JA, Maga, G, Mai, A and Rotili, D
Publicada:
24 ene 2019
Ahead of Print:
20 dic 2018
Resumen:
Conformational restriction applied to dihydrobenzylpyrimidin-4-(3H)-ones (DABOs) by the intoduction of a methyl group at the alpha-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 alpha-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 alpha-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 alpha-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 a-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 a-methoxy stereogenic center.
Filiaciones:
Nawrozkij, MB:
Volgograd State Tech Univ, Lenina Ave 28, Volgograd 400005, Russia
Forgione, M:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
Yablokov, AS:
Volgograd State Tech Univ, Lenina Ave 28, Volgograd 400005, Russia
Lucidi, A:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
Tomaselli, D:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
Patsilinakos, A:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
Panella, C:
Ctr Nazl Controllo & Valutaz Farmaci, Ist Super Sanity, Viale Regina Elena 299, I-00161 Rome, Italy
Hailu, GS:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
Kirillov, IA:
Volgograd State Tech Univ, Lenina Ave 28, Volgograd 400005, Russia
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, IrsiCaixa AIDS Res Inst, Badalona 08916, Spain
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, IrsiCaixa AIDS Res Inst, Badalona 08916, Spain
Crespan, E:
CNR, IGM, Via Abbiategrasso 207, I-27100 Pavia, Italy
Rivera, JIA:
CNR, IGM, Via Abbiategrasso 207, I-27100 Pavia, Italy
Cirilli, R:
Ctr Nazl Controllo & Valutaz Farmaci, Ist Super Sanity, Viale Regina Elena 299, I-00161 Rome, Italy
Ragno, R:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, IrsiCaixa AIDS Res Inst, Badalona 08916, Spain
Maga, G:
CNR, IGM, Via Abbiategrasso 207, I-27100 Pavia, Italy
Mai, A:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
Univ Roma La Sapienza, Ist Pasteur, Fdn Cenci Bolognetti, P A Moro 5, I-00185 Rome, Italy
Rotili, D:
Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, P A Moro 5, I-00185 Rome, Italy
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