Targeting -Acetylglucosaminidase in with Iminosugar Inhibitors.

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant , which has unfortunately also spread outside hospitals. Therefore, the development of new effective antibacterial agents is extremely important to solve the increasing problem of bacterial resistance.

Orthoester functionalized -guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol as pH-responsive inhibitors of β-glucocerebrosidase.

Alkylated guanidino derivatives of 1,5-dideoxy-1,5-imino-d-xylitol bearing an orthoester moiety were prepared using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that one of the compounds prepared displays potent inhibition against human β-glucocerebrosidase (GBA) at pH 7.0 with IC values in the low nanomolar range.

Probing the Inhibitor versus Chaperone Properties of sp²-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease.

A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d- or l-), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an -octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM).

N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol are Potent, Selective, and Stable Inhibitors of β-Glucocerebrosidase.

A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β-glucocerebrosidase with IC values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for β-galactosidase from bovine liver.

Bicyclic isoureas derived from 1-deoxynojirimycin are potent inhibitors of β-glucocerebrosidase.

A series of bicyclic isourea derivatives were prepared from 1-deoxynojirimycin using a concise synthetic protocol proceeding via a guanidino intermediate. Inhibition assays with a panel of glycosidases revealed that these deoxynojirimycin-derived bicyclic isoureas display very potent inhibition against human recombinant β-glucocerebrosidase with IC50 values in the low nanomolar range.

Synthesis and structural characterization of novel camphor-derived amines.

Two novel 4-substituted camphidine derivatives 10a,b have been prepared from (+)-camphor (1) in five steps, the Beckmann rearrangement being the bottleneck of the synthesis. Isoborneol derivative 5b, formed as a side product during the hydrogenation of arylidene ketone 3b, under Beckmann rearrangement conditions yielded interesting novel rearrangement products 11 and 12. (1S)-(+)-Camphorquinone (13) was transformed into diamines 15 and 16 in two steps, the former being cyclized into an imidazoline salt 17, an N-heterocyclic carbene precursor.