Optimization and Evaluation of 5-Styryl-Oxathiazol-2-oneMycobacterium tuberculosisProteasome Inhibitors as Potential Antitubercular Agents

Abstract

This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure–activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.

Targeting Phenotypically TolerantMycobacterium tuberculosis

“…Small molecule inhibitors targeting the proteasome, such as GL-5 ( compound 50 , an irreversible inhibitor) (106) and DPLG-2 ( compound 52, a reversible inhibitor) (229), killed M. tuberculosis rendered nonreplicating with acidified nitrite. Compound 51 , an analogue of GL-5, had bactericidal activity against a 2-week nutrient starved culture of M. tuberculosis (230). These studies indicate that targeting the ClpP1P2 and PrcAB proteolysis pathways are good strategies to kill nonreplicating persisters.…”

Kunkel Lecture: Fundamental immunodeficiency and its correction

“…An early example was a thioxothiazolidine that killed Mtb only when the Mtb was nonreplicating, without regard to diverse conditions tested that imposed nonreplication ( Bryk et al, 2008 ). Another target-based screen led to two chemically distinct classes of Mtb -selective proteasome inhibitors ( Lin et al, 2009 , 2013 ) that killed Mtb that was rendered nonreplicating by nitrosative stress ( Lin et al, 2009 , 2013 ) or by starvation ( Russo et al, 2015 ). A whole-cell screen designed to identify compounds that kill nonreplicating Mtb identified oxyphenbutazone ( Gold et al, 2012 ) and other compounds ( Warrier et al, 2015 ).…”

Crystal structure determination as part of an ongoing undergraduate organic laboratory project: 5-[(E)-styryl]-1,3,4-oxathiazol-2-one

“…Until recently, the predominant chemistry of the heterocycle was the thermal cycloreversion to the short-lived nitrile sulfide, a propargyl allenyl 1,3-dipole which could be trapped by electron-deficientbonds in reasonable yield to give families of new heterocycles (Paton, 1989). Industrially, various derivatives of the oxathiazolone heterocycle have been reported as potential fungicides (Klaus et al, 1965), pesticides (Hö lzl & Schnyder, 2004), polymer additives (Crosby 1978) and pharmaceuticals (Russo et al, 2015). In 2009, interest was renewed in the ring system with the report of the use of oxathiazolone derivatives as selective inhibitors for mycobacterial proteasomes (Lin et al, 2009).…”

“…In 2009, interest was renewed in the ring system with the report of the use of oxathiazolone derivatives as selective inhibitors for mycobacterial proteasomes (Lin et al, 2009). Subsequent research has uncovered potential use of styryl-substituted oxathiazolone derivatives as antitubercular 'warheads' (Russo et al, 2015). The significance of the structure and chemistry of styryl-substituted oxathiazolone molecules, especially with respect to their intermolecular interactions with the proteasome, has therefore placed some significance on the structure of the title compound.…”