Modular approach to triazole-linked 1,6-α-D-oligomannosides to the discovery of inhibitors of Mycobacterium tuberculosis cell wall synthetase.
Aiming at developing inhibitors of mannosyltransferases, the enzymes that participate in the biosynthesis of the cell envelope of Mycobacterium tuberculosis, the synthesis of a range of designed triazole-linked 1,6-oligomannosides up to a hexadecamer has been accomplished by a modular approach centered on the Cu(I)-catalyzed azide-alkyne cycloaddition as key process. The efficiency and fidelity of the cycloaddition are substantiated by high yields (76-96%) and exclusive formation of the expected 1,4-disubstituted triazole ring in all oligomer assembling reactions. Key features of oligomers thus prepared are the anomeric carbon-carbon bond of all mannoside residues and the 6-deoxymannoside capping residue. Suitable bioassays with dimer, tetramer, hexamer, octamer, decamer, and hexadecamer showed variable inhibitor activity against mycobacterial α-(1,6)-mannosyltransferases, the highest activity (IC(50) = 0.14-0.22 mM) being registered with the hexamannoside and octamannoside.
Lo Conte
Mauro
M
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy.
Marra
Alberto
A
Chambery
Angela
A
Gurcha
Sudagar S
SS
Besra
Gurdyal S
GS
Dondoni
Alessandro
A
D002473:Cell Wall / Q000201:enzymology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry*
D004791:Enzyme Inhibitors; D009844:Oligosaccharides; D014230:Triazoles; C028569:oligomannoside; D008364:Mannosyltransferases
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