Synthesis of thio-derivatives conjugated to glycero-carbohydrates and their potential as anti-tuberculosis agents

Abstract

Tuberculosis is a disease that still brings risks to global health since resistance to existing drugs promotes the search for new treatments. The aim of this study was therefore to synthesize new glycero-carbohydrates conjugated to thio-heterocycles and evaluate its biological profile against tuberculosis. We first synthesized glycerol derivatives: glycerol carbonate 1 (96%), tosylated glycerol carbonate 2 (65%), glycerol iodo-carbonate 3 (80%) and glycerol thio-carbonate 4 (85%). The (R) azido-alcohol 7a was previously prepared by our research group, as was the mixture of diastereoisomers of the 2,3-unsaturated O-glycosides 6a/6b which was used to prepare the keto-azide 8, with a yield of 88%. In another synthetic strategy, we protected tri-O-acetyl-D-glucal 5 with (Z)-1,2-bis(phenylsulfonyl)ethylene (BPSE) 9 to obtain PSE-glucal 10 (77%). The double bond epoxidation reaction of PSE-glucal 10 with m-CPBA stereoselectively provided the unprecedented α-mannopyranoside 11 in 52% yield, and after acetylation under acidic conditions (K-10) we obtained α- mannopyranoside 12 (77%). The aglycone portion of α-mannopyranoside 12 was also replaced by the glycerol carbonate ring, and the unprecedented R/S mixture of β- mannopyranoside 13 was obtained in 64% yield. In the glycosylation reaction under Ferrier conditions between PSE-glucal 10 and glycerol carbonate 1, was observed the formation of a complex mixture 14a and the mixture R/S of the new α-2-deoxy-O- glucoside isomer 14b with yields of 33% and 42%, as a result of a Michael addition reaction. The new heterocycles 1,3-oxazolidine-2-thione 16a and 1,3-thiazolidine-2- thione 16b were synthesized from (R) azido-alcohol 7a using CS2 and PPh3, with yields of 22% and 39%, respectively. 2-mercapto-oxazole 17 (59%) was prepared from the reaction of keto-azide 8 in the presence of CS2 and PPh3 as well. Finally, in the biological study, thio-derivatives 16a, 16b and 17 didn’t show any activity against tuberculosis, however, they weren’t considered toxic to the cells tested.