2-(Alkyl/Aryl)Amino-6-Benzylpyrimidin-4(3H)-ones as Inhibitors of Wild-Type and Mutant HIV-1: Enantioselectivity Studies

被引：29

作者：

Rotili, Dante ^{[2
]}

Samuele, Alberta ^{[3
]}

Tarantino, Domenico ^{[2
]}

Ragno, Rino ^{[2
]}

Musmuca, Ira ^{[2
]}

Ballante, Flavio ^{[2
]}

Botta, Giorgia ^{[2
]}

Morera, Ludovica ^{[2
]}

Pierini, Marco ^{[2
]}

Cirilli, Roberto ^{[4
]}

Nawrozkij, Maxim B. ^{[5
]}

Gonzalez, Emmanuel ^{[1
]}

Clotet, Bonaventura ^{[1
]}

Artico, Marino ^{[2
]}

Este, Jose A. ^{[1
]}

Maga, Giovanni ^{[3
]}

Mai, Antonello ^{[2
]}

机构：

[1] Univ Autonoma Barcelona, Retrovirol Lab IrsiCaixa, Hosp Univ Germans Trias & Pujol, Badalona 08916, Spain

[2] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, I-00185 Rome, Italy

[3] CNR, IGM, I-27100 Pavia, Italy

[4] Ist Super Sanita, Dipartimento Farmaco, I-00161 Rome, Italy

[5] Volgograd State Tech Univ, Volgograd 400131, Russia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 07期

关键词：

REVERSE-TRANSCRIPTASE; NONNUCLEOSIDE INHIBITORS; KINETIC CHARACTERIZATION; RESISTANCE; POTENT; ENTRY;

D O I：

10.1021/jm201308v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 (MC1501) and 2 (MC2082), were tested in both cellular and enzyme assays. In general, the R forms were more potent than their S counterparts and racemates and (R)-2 was more efficient than (R)-1 and the reference compounds, with some exceptions. Interestingly, (R)-2 displayed a faster binding to K103N RT with respect to WT RT, while (R)-1 showed the opposite behavior.

引用

页码：3558 / 3562

页数：5

共 13 条

[1] Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (1989-2009)
de Bethune, Marie-Pierre
[J]. ANTIVIRAL RESEARCH, 2010, 85 (01) : 75 - 90
[2] Interaction kinetic characterization of HIV-1 reverse transcriptase non-nucleoside inhibitor resistance
Geitmann, M
Unge, T
Danielson, UH
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (08) : 2375 - 2387
[3] Biosensor-based kinetic characterization of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors
Geitmann, M
Unge, T
Danielson, UH
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (08) : 2367 - 2374
[4] Development of resistance to VIR-353 with cross-resistance to the natural HIV-1 entry virus inhibitory peptide (VIRIP)
Gonzalez, Emmanuel
Ballana, Ester
Clotet, Bonaventura
Este, Jose A.
[J]. AIDS, 2011, 25 (13) : 1575 - 1583
[5] ADS-J1 Inhibits HIV-1 Entry by Interacting with gp120 and Does Not Block Fusion-Active gp41 Core Formation
Gonzalez-Ortega, Emmanuel
Mena, Maria-Pau
Permanyer, Marc
Ballana, Ester
Clotet, Bonaventura
Este, Jose A.
[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2010, 54 (10) : 4487 - 4492
[6] Etravirine, a Next-Generation Nonnucleoside Reverse-Transcriptase Inhbitor
Johnson, Leonard B.
Saravolatz, Louis D.
[J]. CLINICAL INFECTIOUS DISEASES, 2009, 48 (08) : 1123 - 1128
[7] Resistance to Nevirapine of HIV-1 reverse transcriptase mutants: Loss of stabilizing interactions and thermodynamic or steric barriers are induced by different single amino acid substitutions
Maga, G
Amacker, M
Ruel, N
Hubscher, U
Spadari, S
[J]. JOURNAL OF MOLECULAR BIOLOGY, 1997, 274 (05) : 738 - 747
[8] 5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family
Mai, A
Artico, M
Ragno, R
Sbardella, G
Massa, S
Musiu, C
Mura, M
Marturana, F
Cadeddu, A
Maga, G
La Colla, P
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (06) : 2065 - 2077
[9] Structure-based design, synthesis, and biological evaluation of conformationally restricted novel 2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones as non-nucleoside inhibitors of HIV-1 reverse transcriptase
Mai, A
Sbardella, G
Artico, M
Ragno, R
Massa, S
Novellino, E
Greco, G
Lavecchia, A
Musiu, C
La Colla, M
Murgioni, C
La Colla, P
Loddo, R
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (16) : 2544 - 2554
[10] Synthesis and biological properties of novel 2-Aminopyrimidin-4(3H)-ones highly potent against HIV-1 mutant strains
Mai, Antonello
Artico, Marino
Rotili, Dante
Tarantino, Domenico
Clotet-Codina, Imma
Armand-Ugon, Mercedes
Ragno, Rino
Simeoni, Silvia
Sbardella, Gianluca
Nawrozkij, Maxim B.
Samuele, Alberta
Maga, Giovanni
Este, Jose A.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (22) : 5412 - 5424

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