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Design and synthesis of 2-(2-isonicotinoylhydrazineylidene)propanamides as InhA inhibitors with high antitubercular activity
V. Pflégr, L. Horváth, J. Stolaříková, A. Pál, J. Korduláková, S. Bősze, J. Vinšová, M. Krátký
Jazyk angličtina Země Francie
Typ dokumentu časopisecké články
- MeSH
- amidy chemie metabolismus farmakologie terapeutické užití MeSH
- aniliny chemie MeSH
- antituberkulotika chemická syntéza metabolismus farmakologie terapeutické užití MeSH
- bakteriální léková rezistence účinky léků MeSH
- bakteriální proteiny antagonisté a inhibitory metabolismus MeSH
- buňky Hep G2 MeSH
- kyselina pyrohroznová chemie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis účinky léků metabolismus MeSH
- oxidoreduktasy antagonisté a inhibitory metabolismus MeSH
- racionální návrh léčiv * MeSH
- tuberkulóza farmakoterapie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Based on successful antitubercular isoniazid scaffold we have designed its "mee-too" analogues by a combination of this drug linked with substituted anilines through pyruvic acid as a bridge. Lipophilicity important for passive diffusion through impenetrable mycobacterial cell wall was increased by halogen substitution on the aniline. We prepared twenty new 2-(2-isonicotinoylhydrazineylidene)propanamides that were assayed against susceptible Mycobacterium tuberculosis H37Rv, nontuberculous mycobacteria, and also multidrug-resistant tuberculous strains (MDR-TB). All the compounds showed excellent activity not only against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.03 μM), but also against M. kansasii (MIC ≥2 μM). The most active molecules have CF3 and OCF3 substituent in the position 4 on the aniline ring. MIC against MDR-TB were from 8 μM. The most effective derivatives were used for the mechanism of action investigation. The treatment of Mtb. H37Ra with tested compounds led to decreased production of mycolic acids and the strains overproducing InhA were more resistant to them. These results confirm that studied compounds inhibit the enoyl-acyl carrier protein reductase (InhA) in mycobacteria. The compounds did not show any cytotoxic and cytostatic activity for HepG2 cells. The amides can be considered as a promising scaffold for antitubercular drug discovery having better antimicrobial properties than original isoniazid together with a significantly improved pharmaco-toxicological profile.
Citace poskytuje Crossref.org
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- $a Pflégr, Václav $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
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- $a Design and synthesis of 2-(2-isonicotinoylhydrazineylidene)propanamides as InhA inhibitors with high antitubercular activity / $c V. Pflégr, L. Horváth, J. Stolaříková, A. Pál, J. Korduláková, S. Bősze, J. Vinšová, M. Krátký
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- $a Based on successful antitubercular isoniazid scaffold we have designed its "mee-too" analogues by a combination of this drug linked with substituted anilines through pyruvic acid as a bridge. Lipophilicity important for passive diffusion through impenetrable mycobacterial cell wall was increased by halogen substitution on the aniline. We prepared twenty new 2-(2-isonicotinoylhydrazineylidene)propanamides that were assayed against susceptible Mycobacterium tuberculosis H37Rv, nontuberculous mycobacteria, and also multidrug-resistant tuberculous strains (MDR-TB). All the compounds showed excellent activity not only against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.03 μM), but also against M. kansasii (MIC ≥2 μM). The most active molecules have CF3 and OCF3 substituent in the position 4 on the aniline ring. MIC against MDR-TB were from 8 μM. The most effective derivatives were used for the mechanism of action investigation. The treatment of Mtb. H37Ra with tested compounds led to decreased production of mycolic acids and the strains overproducing InhA were more resistant to them. These results confirm that studied compounds inhibit the enoyl-acyl carrier protein reductase (InhA) in mycobacteria. The compounds did not show any cytotoxic and cytostatic activity for HepG2 cells. The amides can be considered as a promising scaffold for antitubercular drug discovery having better antimicrobial properties than original isoniazid together with a significantly improved pharmaco-toxicological profile.
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- $a Korduláková, Jana $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina CH-1, Ilkovičova 6, 842 15, Bratislava, Slovakia
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- $a Vinšová, Jarmila $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic
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- $a Krátký, Martin $u Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic. Electronic address: martin.kratky@faf.cuni.cz
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