Novel inhibitors of an emerging target in Mycobacterium tuberculosis;: Substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis

被引:183
作者
Babaoglu, K
Page, MA
Jones, VC
McNeil, MR
Dong, CJ
Naismith, JH
Lee, RE [1 ]
机构
[1] Univ Tennessee, Ctr Hlth Sci, Dept Pharmaceut Sci, Memphis, TN 38163 USA
[2] Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA
[3] Univ St Andrews, Ctr Biomol Sci, St Andrews KY16 9ST, Fife, Scotland
关键词
D O I
10.1016/S0960-894X(03)00673-5
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The emergence of multi-drug resistant tuberculosis, coupled with the increasing overlap of the AIDS and tuberculosis pandemics has brought tuberculosis 1 0 the forefront as a major worldwide health concern. In an attempt to find new inhibitors of the enzymes in the essential rhamnose biosynthetic pathway, a virtual library of 2,3,5 trisubstituted-4-thiazolidinones was created. These compounds were then docked into the active site cavity of 6'hydroxyl; dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase (RmlC) from Mycobacterium tuberculosis. The resulting docked conformations were consensus scored and the top 5% were slated for synthesis. Thus far, 94 compounds have been successfully synthesized and initially tested. Of those, 30 (32%) have greater than or equal to50% inhibitory activity (at 20 muM) in the coupled rhamnose synthetic assay with seven of the 30 also having modest activity against whole-cell M. tuberculosis. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3227 / 3230
页数:4
相关论文
共 15 条
[1]   4-thiazolidinones: Novel inhibitors of the bacterial enzyme MurB [J].
Andres, CJ ;
Bronson, JJ ;
D'Andrea, SV ;
Deshpande, MS ;
Falk, PJ ;
Grant-Young, KA ;
Harte, WE ;
Ho, HT ;
Misco, PF ;
Robertson, JG ;
Stock, D ;
Sun, YX ;
Walsh, AW .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (08) :715-717
[2]  
[Anonymous], J ORG CHEM
[3]   INHA, A GENE ENCODING A TARGET FOR ISONIAZID AND ETHIONAMIDE IN MYCOBACTERIUM-TUBERCULOSIS [J].
BANERJEE, A ;
DUBNAU, E ;
QUEMARD, A ;
BALASUBRAMANIAN, V ;
UM, KS ;
WILSON, T ;
COLLINS, D ;
DELISLE, G ;
JACOBS, WR .
SCIENCE, 1994, 263 (5144) :227-230
[4]   The Protein Data Bank [J].
Berman, HM ;
Battistuz, T ;
Bhat, TN ;
Bluhm, WF ;
Bourne, PE ;
Burkhardt, K ;
Iype, L ;
Jain, S ;
Fagan, P ;
Marvin, J ;
Padilla, D ;
Ravichandran, V ;
Schneider, B ;
Thanki, N ;
Weissig, H ;
Westbrook, JD ;
Zardecki, C .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2002, 58 :899-907
[5]   VALIDATION OF THE GENERAL-PURPOSE TRIPOS 5.2 FORCE-FIELD [J].
CLARK, M ;
CRAMER, RD ;
VANOPDENBOSCH, N .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1989, 10 (08) :982-1012
[6]   Global burden of tuberculosis - Estimated incidence, prevalence, and mortality by country [J].
Dye, C ;
Scheele, S ;
Dolin, P ;
Pathania, V ;
Raviglione, RC .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1999, 282 (07) :677-686
[7]   The rhamnose pathway [J].
Giraud, MF ;
Naismith, JH .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2000, 10 (06) :687-696
[8]   SYNTHESIS OF THE MYCOBACTERIAL ARABINOSE DONOR BETA-D-ARABINOFURANOSYL-1-MONOPHOSPHORYLDECAPRENOL, DEVELOPMENT OF A BASIC ARABINOSYL-TRANSFERASE ASSAY, AND IDENTIFICATION OF ETHAMBUTOL AS AN ARABINOSYL TRANSFERASE INHIBITOR [J].
LEE, RE ;
MIKUSOVA, K ;
BRENNAN, PJ ;
BESRA, GS .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1995, 117 (48) :11829-11832
[9]   Formation of dTDP-rhamnose is essential for growth of mycobacteria [J].
Ma, YF ;
Pan, F ;
McNeil, M .
JOURNAL OF BACTERIOLOGY, 2002, 184 (12) :3392-3395
[10]   Drug targeting Mycobacterium tuberculosis cell wall synthesis:: Genetics of dTDP-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP-glucose to dTDP-rhamnose [J].
Ma, YF ;
Stern, RJ ;
Scherman, MS ;
Vissa, VD ;
Yan, WX ;
Jones, VC ;
Zhang, FQ ;
Franzblau, SG ;
Lewis, WH ;
McNeil, MR .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2001, 45 (05) :1407-1416