Studies on (beta,1-->5) and (beta,1-->6) linked octyl Gal(f) disaccharides as substrates for mycobacterial galactosyltransferase activity.
The emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis (MTB) and the continuing pandemic of tuberculosis emphasizes the urgent need for the development of new anti-tubercular agents with novel drug targets. The recent structural elucidation of the mycobacterial cell wall highlights a large variety of structurally unique components that may be a basis for new drug development. This publication describes the synthesis, characterization, and screening of several octyl Galf(beta,1-->5)Galf and octyl Galf(beta,1-->6)Galf derivatives. A cell-free assay system has been utilized for galactosyltransferase activity using UDP[14C]Galf as the glycosyl donor, and in vitro inhibitory activity has been determined in a colorimetric broth microdilution assay system against MTB H37Ra and three clinical isolates of Mycobacterium avium complex (MAC). Certain derivatives showed moderate activities against MTB and MAC. The biological evaluation of these disaccharides suggests that more hydrophobic analogues with a blocked reducing end showed better activity as compared to totally deprotected disaccharides that more closely resemble the natural substrates in cell wall biosynthesis.
Pathak
A K
AK
Department of Organic Chemistry, Southern Research Institute, PO Box 55305, Birmingham, AL 35255-5305, USA.
Pathak
V
V
Seitz
L
L
Maddry
J A
JA
Gurcha
S S
SS
Besra
G S
GS
Suling
W J
WJ
Reynolds
R C
RC
D000995:Antitubercular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001671:Biochemistry / Q000379:methods; D002236:Carbohydrate Conformation; D004187:Disaccharides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005700:Galactosyltransferases / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D009161:Mycobacterium / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D004187:Disaccharides; D005700:Galactosyltransferases