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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

gHSQC and gHMQC experiment results of compound 56.
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fig03: gHSQC and gHMQC experiment results of compound 56.

Mentions: (E)-5-(2-(2-Oxo-2 H-[1,2,4]thiadiazolo[2,3-a]pyridin-8-yl)vinyl)-1,3,4-oxathiazol-2-one (56). According to Method E, 2-amino-3-bromopyridine (260 mg, 1.5 mmol) was used as starting bromide in the Mizoroki–Heck reaction. After 15 min of microwave irradiation (T=140 °C), the reaction mixture was irradiated for additional 15 min at 160 °C to afford full conversion. The resulting reaction mixture was cooled down to rt, and the formed Pd black was removed by filtration through Celite (EtOAc/MeOH 1:1). Evaporation of the solvent under reduced pressure gave a crude mixture containing DMF, which was taken in EtOAc (20 mL). The organic phase was washed with H2O (2×40 mL), the H2O phases were extracted with EtOAc (2×100 mL), and the collected organic phases were dried over Na2SO4. Evaporation of solvent gave 94 mg of a mixture containing the desired (E)-3-(2-aminopyridin-3-yl)acrylamide as a yellow solid. TLC: Mizoroki–Heck compound Rf=0.22 (EtOAc/MeOH 10:1); LC purity (254 nm)=90 %; ESI-MS m/z: 164 [M+H]+. According to Method B, the obtained Mizoroki–Heck reaction mixture (94 mg) was reacted with an excess of chlorocarbonyl sulfenyl chloride (0.50 mL), to give, after purification by trituration in CH3CN/H2O, 16 mg (4 % isolated yield after two steps) of the title compound as a pale yellow solid. LC purity (254 nm): 97 %; 1H NMR (400 MHz, [D6]DMSO): δ=8.02 (dd, J=7.0, 1.3 Hz, 1 H), 7.95 (dm, J=7.0 Hz, 1 H), 7.72 (d, J=16.0 Hz, 1 H), 7.62 (dd, J=16.2, 0.6 Hz, 1 H), 6.89 ppm (t, J=7.0 Hz, 1 H); 13C NMR (100 MHz, [D6]DMSO): δ=174.3, 173.3, 157.1, 148.0, 137.1, 134.8, 126.1, 125.0, 117.4, 111.6 ppm; ESI-MS m/z: 280 [M+H]+; HRMS m/z calcd for C10H5N3O3S2 [M+H]+ 279.9851, found 279.9843. gHSQC and gHMQC experiments showed no correlations between proton HE and carbon C10, suggesting the following structure (Figure 3) as the most probable one.


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)

gHSQC and gHMQC experiment results of compound 56.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: gHSQC and gHMQC experiment results of compound 56.
Mentions: (E)-5-(2-(2-Oxo-2 H-[1,2,4]thiadiazolo[2,3-a]pyridin-8-yl)vinyl)-1,3,4-oxathiazol-2-one (56). According to Method E, 2-amino-3-bromopyridine (260 mg, 1.5 mmol) was used as starting bromide in the Mizoroki–Heck reaction. After 15 min of microwave irradiation (T=140 °C), the reaction mixture was irradiated for additional 15 min at 160 °C to afford full conversion. The resulting reaction mixture was cooled down to rt, and the formed Pd black was removed by filtration through Celite (EtOAc/MeOH 1:1). Evaporation of the solvent under reduced pressure gave a crude mixture containing DMF, which was taken in EtOAc (20 mL). The organic phase was washed with H2O (2×40 mL), the H2O phases were extracted with EtOAc (2×100 mL), and the collected organic phases were dried over Na2SO4. Evaporation of solvent gave 94 mg of a mixture containing the desired (E)-3-(2-aminopyridin-3-yl)acrylamide as a yellow solid. TLC: Mizoroki–Heck compound Rf=0.22 (EtOAc/MeOH 10:1); LC purity (254 nm)=90 %; ESI-MS m/z: 164 [M+H]+. According to Method B, the obtained Mizoroki–Heck reaction mixture (94 mg) was reacted with an excess of chlorocarbonyl sulfenyl chloride (0.50 mL), to give, after purification by trituration in CH3CN/H2O, 16 mg (4 % isolated yield after two steps) of the title compound as a pale yellow solid. LC purity (254 nm): 97 %; 1H NMR (400 MHz, [D6]DMSO): δ=8.02 (dd, J=7.0, 1.3 Hz, 1 H), 7.95 (dm, J=7.0 Hz, 1 H), 7.72 (d, J=16.0 Hz, 1 H), 7.62 (dd, J=16.2, 0.6 Hz, 1 H), 6.89 ppm (t, J=7.0 Hz, 1 H); 13C NMR (100 MHz, [D6]DMSO): δ=174.3, 173.3, 157.1, 148.0, 137.1, 134.8, 126.1, 125.0, 117.4, 111.6 ppm; ESI-MS m/z: 280 [M+H]+; HRMS m/z calcd for C10H5N3O3S2 [M+H]+ 279.9851, found 279.9843. gHSQC and gHMQC experiments showed no correlations between proton HE and carbon C10, suggesting the following structure (Figure 3) as the most probable one.

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