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

被引：39

作者：

Radi, Marco ^{[1
]}

Maga, Giovanni ^{[2
]}

Alongi, Maddalena ^{[1
]}

Angeli, Lucilla ^{[1
]}

Samuele, Alberta ^{[2
]}

Zanoli, Samantha ^{[2
]}

Bellucci, Luca ^{[1
]}

Tafi, Andrea ^{[1
]}

Casaluce, Gianni ^{[1
]}

Giorgi, Gianluca ^{[3
]}

Armand-Ugon, Mercedes ^{[4
]}

Gonzalez, Emmanuel ^{[4
]}

Este, Jose A. ^{[2
]}

Baltzinger, Mireille ^{[6
]}

Bec, Guillaume ^{[5
]}

Dumas, Philippe ^{[5
]}

Ennifar, Eric ^{[5
]}

Botta, Maurizio ^{[1
]}

机构：

[1] Univ Siena, Dipartimento Farmaco Chim Tecnol, I-53100 Siena, Italy

[2] IGM CNR, Ist Genet Mol, I-27100 Pavia, Italy

[3] Univ Siena, Dipartimento Chim, I-53100 Siena, Italy

[4] Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Retrovirol Lab irsiCaixa, E-08916 Badalona, Spain

[5] Univ Strasbourg, CNRS, UPR 9002, Architecture & Reactivite ARN, F-67084 Strasbourg, France

[6] Univ Strasbourg 1, CNRS, UMR 7175, Ecole Super Biotechnol Strasbourg, F-67400 Illkirch Graffenstaden, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 03期

关键词：

STRUCTURE-BASED DESIGN; NONNUCLEOSIDE INHIBITORS; STRUCTURAL BASIS; WILD-TYPE; ENANTIOSELECTIVE CYCLOPROPANATION; KINETIC CHARACTERIZATION; ALLYLIC ALCOHOLS; RESISTANT; SERIES; COMPLEXES;

D O I：

10.1021/jm801330n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：840 / 851

页数：12

共 51 条

[11] Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants [J].