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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

Structures of the proteasome inhibitors Bortezomib and oxathiazol-2-one compounds HT1171 and GL5.
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fig01: Structures of the proteasome inhibitors Bortezomib and oxathiazol-2-one compounds HT1171 and GL5.

Mentions: In many diseases, such as cancer, auto-immune diseases, and neurodegenerative diseases, cells accumulate various proteins, and the human proteasome has thus emerged as a promising therapeutic target.6a,7a The first human proteasome inhibitor, Bortezomib (Velcade), was approved for clinical use in the USA in 2003 and in Europe in 2004 for the treatment of multiple myeloma (Figure 1). The X-ray structure of the yeast proteasome in complex with the compound was reported in 2006, giving valuable insights into its binding interactions.10 Serious toxicity associated with peptidyl boronates, such as Bortezomib, is mainly due to the inhibition of the β5 subunit of the human proteasome,11 precluding the use for treatment of, for example, infectious diseases. Therefore, the search for alternative classes of inhibitors with greater selectivity towards prokaryotic proteasomes is ongoing.


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)

Structures of the proteasome inhibitors Bortezomib and oxathiazol-2-one compounds HT1171 and GL5.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Structures of the proteasome inhibitors Bortezomib and oxathiazol-2-one compounds HT1171 and GL5.
Mentions: In many diseases, such as cancer, auto-immune diseases, and neurodegenerative diseases, cells accumulate various proteins, and the human proteasome has thus emerged as a promising therapeutic target.6a,7a The first human proteasome inhibitor, Bortezomib (Velcade), was approved for clinical use in the USA in 2003 and in Europe in 2004 for the treatment of multiple myeloma (Figure 1). The X-ray structure of the yeast proteasome in complex with the compound was reported in 2006, giving valuable insights into its binding interactions.10 Serious toxicity associated with peptidyl boronates, such as Bortezomib, is mainly due to the inhibition of the β5 subunit of the human proteasome,11 precluding the use for treatment of, for example, infectious diseases. Therefore, the search for alternative classes of inhibitors with greater selectivity towards prokaryotic proteasomes is ongoing.

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