title: Modular approach to triazole-linked 1,6-α-D-oligomannosides to the discovery of inhibitors of Mycobacterium tuberculosis cell wall synthetase.
abstract: 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.
authors.affiliation: Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Lo Conte
authors.forename: Alberto
authors.initials: A
authors.lastname: Marra
authors.forename: Angela
authors.initials: A
authors.lastname: Chambery
authors.forename: Sudagar S
authors.initials: SS
authors.lastname: Gurcha
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dondoni
mesh_terms: 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*
chemical_list: D004791:Enzyme Inhibitors; D009844:Oligosaccharides; D014230:Triazoles; C028569:oligomannoside; D008364:Mannosyltransferases
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