Synthesis of methyl 5-S-alkyl-5-thio-d-arabinofuranosides and evaluation of their antimycobacterial activity

Antigen 85C-mediated acyl-transfer between synthetic acyl donors and fragments of the arabinan

“…Acyl donor 1 for enzymatic reaction was synthesized by literature procedure [21]. Synthesis of methyl α-D-arabinofuranoside 2 and its β-anomer 3 was accomplished in high yield employing a kinetically controlled glycosylation to produce products that were separated by flash column chromatography (Scheme 1) [20]. The terminal arabinan fragment 9 was synthesized from glycosyl acceptor 4 [25] and glycosyl donor 5 [26] using a stereoselective protocol developed by Boons et al [27].…”

“…To initiate a study on ag85C-mediated acyl-transfer we are required to synthesize an acyl donor 1, and three acceptors 2-3 [20,22,23] and 9 [24]. Acyl donor 1 for enzymatic reaction was synthesized by literature procedure [21].…”

“…The latter studies are further supported by crystallographic data indicating high similarity between the active sites of the three homologs [17][18][19]. In our ongoing efforts to identify inhibitors of ag85 we developed a synthetic acyl donor that can be used in lieu of TMM, isolated from M. tuberculosis, to study ag85-mediated acyl-transfer and to rapidly evaluate ag85 inhibitors [20]. In this communication we demonstrate p-nitrophenyl 6-O-octanoyl-β-D-glucopyranoside (1), Scheme 1, is capable of donating acyl groups in the presence of ag85C to synthetic arabinofuranosides modeling the terminal and penultimate residues of the AG with regiochemistry identical to that seen in the whole cell system.…”

Synthesis and antitubercular activity of novel 4-substituted imidazolyl-2,6-dimethyl-N3,N5-bisaryl-1,4-dihydropyridine-3,5-dicarboxamides

“…This obstacle in the treatment of tuberculosis and the statistical facts about its prevalence tell us about the necessity of searching and synthesizing new more potent and less prone to resistance compounds with less side-effects. The number of publications providing a better insight about M. tuberculosis, the process of the disease and numerous novel molecules as potential leads for TB drug discovery have increased since the mid-1990s [10][11][12][13][14][15][16][17][18]. Among them are reviews on drugs currently used in antituberculosis treatment, compounds undergoing clinical trials and new synthetic molecules with antimycobacterial activity [10,18].…”

The Cord Factor: Structure, Biosynthesis and Application in Drug Research – Achilles Heel of Mycobacterium tuberculosis?

“…Methyl -D-arabinofuranoside (Sanki et al, 2009b) Ag85C 5-S-alkyl-5-thioarabinofuranoside analogues (Sanki et al, 2008) Ag85 complex Trehalose analogues (Wang et al, 2004) Ag85 complex ADT (6-azido-6-deoxy-, ′-trehalose) (Belisle et al, 1997;Mizuguchi et al, 1983) Ag85 complex Phosphonate compounds (Gobec et al, 2004;Gobec et al, 2007) Ag85C DEP (Diethyl phosphate) (Ronning et al, 2000) The mycobacterial glycolipids and TMM levels in the cell wall might give an indirect indication of the fitness of the cell inside the host cells specially in macrophages. Thus the quantitation of the mycobacterial TMM status after drug treatment may allow the estimation of drug effectiveness.…”