2-Alkyl-1,2-benzisoselenazol-3(2H)-ones, represented by ebselen (1a), are being studied intensively for a range of medicinal applications. We describe both a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (KSeCN) and N-substituted ortho-halobenzamides to form 2-alkyl-1,2-benzisoselenazol-3(2H)-ones containing a C–Se–N bond. The copper ligand (1,10-phenanthroline) facilitates C–Se bond formation during heating via a mechanism that likely involves atom transfer (AT), whereas, in the absence of ligand, photoinduced activation likely proceeds through a single electron transfer (SET) mechanism. A library of 15 2-alkyl-1,2-benzisoselenazol-3(2H)-ones was prepared. One member of the library was azide-containing derivative 1j that was competent to undergo a strain-promoted azide–alkyne cycloaddition. The library was evaluated for inhibition of Mycobacterium tuberculosis (Mtb) growth and Mtb Antigen 85C (Mtb Ag85C) activity. Compound 1f was most potent with a minimal inhibitory concentration (MIC) of 12.5 μg/mL and an Mtb Ag85C apparent IC50 of 8.8 μM.

Tuberculosis (TB) is an epidemic disease and the growing burden of multidrug-resistant (MDR) TB world wide underlines the need to discover new drugs to treat the disease. Mycobacterium tuberculosis (Mtb) is the etiological agent of most cases of TB. Mtb is difficult to treat, in part, due to the presence of a sturdy hydrophobic barrier that prevents penetration of drugs through the cell wall. Mtb can also survive in a non-replicative state for long periods of time avoiding the action of common antibiotics. Trehalose is an essential metabolite in mycobacteria since it plays key roles in cell wall synthesis, transport of cell wall glycolipids, and energy storage. It is also known for its stress protective roles such as: protection from desiccation, freezing, starvation and osmotic stress in bacteria. In this review we discuss the drug discovery efforts against enzymes involved in the trehalose utilization pathways (TUPs) and their likelihood of becoming drug targets.

Streptomyces coelicolor (Sco) GlgEI is a glycoside hydrolase involved in α-glucan biosynthesis and can be used as a model enzyme for structure-based inhibitor design targeting Mycobacterium tuberculosis (Mtb) GlgE. The latter is a genetically validated drug target for the development of anti-Tuberculosis (TB) treatments. Inhibition of Mtb GlgE results in a lethal buildup of the GlgE substrate maltose-1-phosphate (M1P). However, Mtb GlgE is difficult to crystallize and affords lower resolution X-ray structures. Sco GlgEI-V279S on the other hand crystallizes readily, produces high resolution X-ray data, and has active site topology identical to Mtb GlgE. We report the X-ray structure of Sco GlgEI-V279S in complex with 2-deoxy-2,2-difluoro-α-maltosyl fluoride (α-MTF, 5) at 2.3Å resolution. α-MTF was designed as a non-hydrolysable mimic of M1P to probe the active site of GlgE1 prior to covalent bond formation without disruption of catalytic residues. The α-MTF complex revealed hydrogen bonding between Glu423 and the C1′F which provides evidence that Glu423 functions as proton donor during catalysis. Further, hydrogen bonding between Arg392 and the axial C2′ difluoromethylene moiety of α-MTF was observed suggesting that the C2′ position tolerates substitution with hydrogen bond acceptors. The key step in the synthesis of α-MDF was transformation of peracetylated 2-fluoro-maltal 1 into peracetylated 2,2-difluoro-α-maltosyl fluoride 2 in a single step via the use of Selectfluor®

Long treatment times, poor drug compliance, and natural selection during treatment of Mycobacterium tuberculosis (Mtb) have given rise to extensively drug-resistant tuberculosis (XDR-TB). As a result, there is a need to identify new antituberculosis drug targets. Mtb GlgE is a maltosyl transferase involved in α-glucan biosynthesis. Mutation of GlgE in Mtb increases the concentration of maltose-1-phosphate (M1P), one substrate for GlgE, causing rapid cell death. We have designed 2,5-dideoxy-3-O-α-d-glucopyranosyl-2,5-imino-d-mannitol (9) to act as an inhibitor of GlgE. Compound 9 was synthesized using a convergent synthesis by coupling thioglycosyl donor 14 and 5-azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (23) to form disaccharide 24. A reduction and intramolecular reductive amination transformed the intermediate disaccharide 24 to the desired pyrolidine 9. Compound 9 inhibited both Mtb GlgE and a variant of Streptomyces coelicolor (Sco) GlgEI with Ki = 237 ± 27 μM and Ki = 102 ± 7.52 μM, respectively. The results confirm that a Sco GlgE-V279S variant can be used as a model for Mtb GlgE. In conclusion, we designed a lead transition state inhibitor of GlgE, which will be instrumental in further elucidation of the enzymatic mechanism of Mtb GlgE.