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Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.

Russo F, Gising J, Åkerbladh L, Roos AK, Naworyta A, Mowbray SL, Sokolowski A, Henderson I, Alling T, Bailey MA, Files M, Parish T, Karlén A, Larhed M - ChemistryOpen (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

General synthetic route for the preparation of 5-styryl-oxathiazolones.
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sch01: General synthetic route for the preparation of 5-styryl-oxathiazolones.

Mentions: A series of 5-styryl-oxathiazol-2-ones was synthesized to further investigate the effect of the phenyl substitution on the structure–activity relationship of proteasome inhibitors. For this, we developed a synthetic route where aryl iodides or bromides were used as starting material in a microwave-assisted Mizoroki–Heck cross-coupling reaction with acrylamide to yield the corresponding 3-substituted acrylamides.20, 21 The final 5-substituted-oxathiazolones were obtained by treating the corresponding amides with chlorocarbonyl sulfenyl chloride (Scheme 1).


Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.

Russo F, Gising J, Åkerbladh L, Roos AK, Naworyta A, Mowbray SL, Sokolowski A, Henderson I, Alling T, Bailey MA, Files M, Parish T, Karlén A, Larhed M - ChemistryOpen (2015)

General synthetic route for the preparation of 5-styryl-oxathiazolones.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4522185&req=5

sch01: General synthetic route for the preparation of 5-styryl-oxathiazolones.
Mentions: A series of 5-styryl-oxathiazol-2-ones was synthesized to further investigate the effect of the phenyl substitution on the structure–activity relationship of proteasome inhibitors. For this, we developed a synthetic route where aryl iodides or bromides were used as starting material in a microwave-assisted Mizoroki–Heck cross-coupling reaction with acrylamide to yield the corresponding 3-substituted acrylamides.20, 21 The final 5-substituted-oxathiazolones were obtained by treating the corresponding amides with chlorocarbonyl sulfenyl chloride (Scheme 1).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University Box 574, 751 23, Uppsala, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus