A refined pharmacophore model for HIV-1 integrase inhibitors: Optimization of potency in the 1H-benzylindole series

被引：33

作者：

De Luca, Laura ^{[1
]}

Barreca, Maria Letizia ^{[2
]}

Ferro, Stefania ^{[1
]}

Iraci, Nunzio ^{[1
]}

Michiels, Martine ^{[3
,4
]}

Christ, Frauke ^{[3
,4
]}

Debyser, Zeger ^{[3
,4
]}

Witvrouw, Myriam ^{[3
,4
]}

Chimirri, Alba ^{[1
]}

机构：

[1] Univ Messina, Dipartimento Farmaco Chim, I-98168 Messina, Italy

[2] Dipartiment Chim & Technol Farmaco, I-06123 Perugia, Italy

[3] Katholieke Univ Leuven, B-3000 Louvain, Belgium

[4] IRC KULAK, B-3000 Louvain, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 09期

关键词：

integrase; HIV; DKAs; pharmacophore model; synthesis of indole derivatives;

D O I：

10.1016/j.bmcl.2008.03.089

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integrase inhibitors which led to the discovery of some 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acids that are able to specifically inhibit the strand transfer step of integration at nanomolar concentration. The synthesis of the new designed molecules is also described. (c) 2008 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2891 / 2895

页数：5

相关论文

共 12 条

[1] Pharmacophore-based design of HIV-1 integrase strand-transfer inhibitors [J].

Barreca, ML ;

Ferro, S ;

Rao, A ;

De Luca, L ;

Zappalà, M ;

Monforte, AM ;

Debyser, Z ;

Witvrouw, M ;

Chimirri, A .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (22) :7084-7088

[2]

Billich Andreas, 2003, Curr Opin Investig Drugs, V4, P206

[3] New 4-[(1-benzyl-1H-indol-3-yl)carbonyl]-3-hydroxyfuran-2(5H)-ones, β-diketo acid analogs as HIV-1 integrase inhibitors [J].

Ferro, Stefania ;

Barreca, Maria Letizia ;

De Luca, Laura ;

Rao, Angela ;

Monforte, Anna Maria ;

Debyser, Zeger ;

Witvrouw, Myriam ;

Chimirri, Alba .

ARCHIV DER PHARMAZIE, 2007, 340 (06) :292-298

[4] Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes [J].

Grobler, JA ;

Stillmock, K ;

Hu, BH ;

Witmer, M ;

Felock, P ;

Espeseth, AS ;

Wolfe, A ;

Egbertson, M ;

Bourgeois, M ;

Melamed, J ;

Wai, JS ;

Young, S ;

Vacca, J ;

Hazuda, DJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (10) :6661-6666

[5] Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells [J].

Hazuda, DJ ;

Felock, P ;

Witmer, M ;

Wolfe, A ;

Stillmock, K ;

Grobler, JA ;

Espeseth, A ;

Gabryelski, L ;

Schleif, W ;

Blau, C ;

Miller, MD .

SCIENCE, 2000, 287 (5453) :646-650

[6] HIV-1 integrase inhibitors: A decade of research and two drugs in clinical trial [J].

Johnson, AA ;

Marchand, C ;

Pommier, Y .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2004, 4 (10) :1059-1077

[7] Metal-dependent inhibition of HIV-1 integrase by β-diketo acids and resistance of the soluble double-mutant (F185K/C280S) [J].

Marchand, C ;

Johnson, AA ;

Karki, RG ;

Pais, GCG ;

Zhang, XC ;

Cowansage, K ;

Patel, TA ;

Nicklaus, MC ;

Burke, TR ;

Pommier, Y .

MOLECULAR PHARMACOLOGY, 2003, 64 (03) :600-609

[8] RAPID AND AUTOMATED TETRAZOLIUM-BASED COLORIMETRIC ASSAY FOR THE DETECTION OF ANTI-HIV COMPOUNDS [J].

PAUWELS, R ;

BALZARINI, J ;

BABA, M ;

SNOECK, R ;

SCHOLS, D ;

HERDEWIJN, P ;

DESMYTER, J ;

DECLERCQ, E .

JOURNAL OF VIROLOGICAL METHODS, 1988, 20 (04) :309-321

[9] Integrase inhibitors to treat HIV/AIDS [J].

Pommier, Y ;

Johnson, AA ;

Marchand, C .

NATURE REVIEWS DRUG DISCOVERY, 2005, 4 (03) :236-248

[10] Strategies for identification of HIV-1 integrase inhibitors [J].

Ramcharan, Joseph ;

Skalka, Anna Marie .

FUTURE VIROLOGY, 2006, 1 (06) :717-731