Synthesis, antiviral, and anti-HIV-1 integrase activities of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines

被引：36

作者：

Brzozowski, Z

Saczewski, F

Sanchez, T

Kuo, CL

Gdaniec, M

Neamati, N

机构：

[1] Med Univ Gdansk, Dept Chem Technol Drugs, PL-80416 Gdansk, Poland

[2] Univ So Calif, Sch Pharm, Dept Pharmaceut Sci, Los Angeles, CA 90089 USA

[3] Adam Mickiewicz Univ Poznan, Fac Chem, PL-60780 Poznan, Poland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2004年 / 12卷 / 13期

关键词：

HIV-1 integrase inhibitors;

D O I：

10.1016/j.bmc.2004.04.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

HIV-1 integrase (IN) is an essential enzyme for effective viral replication and is an attractive target for selective blockade of viral infection. Previously, we identified a series of sulfones, sulfonamides, and mercaptosalicylhydrazides (MBSAs) as IN inhibitors with antiviral activities in cell-based assays. In an effort to optimize a series of our active site directed lead compounds, we designed and synthesized novel benzodithiazines starting from MBSAs. In contrast to all reported IN inhibitors benzodithiazines are essentially nontoxic. Significant antiviral potency was only observed at concentration exceedingly higher than that required to inhibit purified IN. (C) 2004 Elsevier Ltd. All rights reserved.

引用

收藏

页码：3663 / 3672

页数：10

相关论文

共 18 条

[1] HIV-1 integrase: Structural organization, conformational changes, and catalysis [J].

Asante-Appiah, E ;

Skalka, AM .

ADVANCES IN VIRUS RESEARCH, VOL 52, 1999, 52 :351-369

[2] Purification of untagged retroviral integrases by immobilized metal ion affinity chromatography [J].

Asante-Appiah, E ;

Merkel, G ;

Skalka, AM .

PROTEIN EXPRESSION AND PURIFICATION, 1998, 12 (01) :105-110

[3] Thermal fragmentation reactions of 1,4,2-dithiazines and 1,4,2,5-dithiadiazines in the presence of dienophiles: Synthesis of 1,4-dithiine derivatives. X-Ray crystal structures of a 1,4,2-dithiazine 1,1-dioxide and a 1,4,2,5-dithiadiazine derivative [J].

Bryce, MR ;

Yoshida, S ;

Batsanov, AS ;

Howard, JAK .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1997, (08) :1157-1161

[4] Small-molecule HIV-1 integrase inhibitors: the 2001-2002 update [J].

Dayam, R ;

Neamati, N .

CURRENT PHARMACEUTICAL DESIGN, 2003, 9 (22) :1789-1802

[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] Application of CoMFA and CoMSIA 3D-QSAR and docking studies in optimization of mercaptobenzenesulfonamides as HIV-1 integrase inhibitors [J].

Kuo, CL ;

Assefa, H ;

Kamath, S ;

Brzozowski, Z ;

Slawinski, J ;

Saczewski, F ;

Buolamwini, JK ;

Neamati, N .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (02) :385-399

[7] 2-mercaptobenzenesulphonamides as novel inhibitors of human immunodeficiency virus type 1 integrase and replication [J].

Neamati, N ;

Mazumder, A ;

Sunder, S ;

Owen, JM ;

Schultz, RJ ;

Pommier, Y .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1997, 8 (06) :485-495

[8] Metal-dependent inhibition of HIV-1 integrase [J].

Neamati, N ;

Lin, ZW ;

Karki, RG ;

Orr, A ;

Cowansage, M ;

Strumberg, D ;

Pais, GCG ;

Voigt, JH ;

Nicklaus, MC ;

Winslow, HE ;

Zhao, H ;

Turpin, JA ;

Yi, JZ ;

Skalka, AM ;

Burke, TR ;

Pommier, Y .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (26) :5661-5670

[9] Patented small molecule inhibitors of HIV-1 integrase: a 10-year saga [J].

Neamati, N .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2002, 12 (05) :709-724

[10] Design and discovery of HIV-1 integrase inhibitors [J].

Neamati, N ;

Sunder, S ;

Pommier, Y .

DRUG DISCOVERY TODAY, 1997, 2 (11) :487-498