Synthesis of methyl 5-S-alkyl-5-thio-D-arabinofuranosides and evaluation of their antimycobacterial activity.
The emergence of drug resistant tuberculosis necessitates a search for new antimycobacterial compounds. The antigen 85 (ag85) complex is a family of mycolyl transferases involved in the synthesis of trehalose-6,6'-dimycolate and the mycolated hexasaccharide motif found at the terminus of the arabinogalactan in mycobacterium. Enzymes involved in the synthesis of cell wall structures like these are potential targets for the development of new antiinfectives. To potentially inhibit the ag85 complex, methyl 5-S-alkyl-5-thio-arabinofuranoside analogues were designed based on docking studies with ag85C derived from Mycobacterium tuberculosis. The target arabinofuranosides were then synthesized and the antibacterial activity evaluated against Mycobacterium smegmatis ATCC 14468. Two of the compounds, 5-S-octyl-5-thio-alpha-d-arabinofuranoside (8) and 5-S-octyl-5-thio-beta-d-arabinofuranoside (11), showed MICs of 256 and 512microg/mL, respectively. Attempts to directly evaluate acyltransferase inhibitory activity of the arabinofuranosides against ag85C are also described. In conclusion, a new class of antimycobacterial arabinofuranosides has been discovered.
Sanki
Aditya K
AK
Department of Chemistry, The University of Toledo, 2801 W. Bancroft Street, MS602, Toledo, OH 43606, United States.
Boucau
Julie
J
Srivastava
Parijat
P
Adams
Samuel S
SS
Ronning
Donald R
DR
Sucheck
Steven J
SJ
D000595:Amino Acid Sequence; D001089:Arabinose / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D013438:Sulfhydryl Compounds; D001089:Arabinose