-
Something wrong with this record ?
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
Language English Country France
Document type Journal Article
- MeSH
- Amides chemistry metabolism pharmacology therapeutic use MeSH
- Aniline Compounds chemistry MeSH
- Antitubercular Agents chemical synthesis metabolism pharmacology therapeutic use MeSH
- Drug Resistance, Bacterial drug effects MeSH
- Bacterial Proteins antagonists & inhibitors metabolism MeSH
- Hep G2 Cells MeSH
- Pyruvic Acid chemistry MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Mycobacterium tuberculosis drug effects metabolism MeSH
- Oxidoreductases antagonists & inhibitors metabolism MeSH
- Drug Design * MeSH
- Tuberculosis drug therapy MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article 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.
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc22003234
- 003
- CZ-PrNML
- 005
- 20220127150542.0
- 007
- ta
- 008
- 220113s2021 fr f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.ejmech.2021.113668 $2 doi
- 035 __
- $a (PubMed)34198149
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a fr
- 100 1_
- $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
- 245 10
- $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
- 520 9_
- $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.
- 650 _2
- $a amidy $x chemie $x metabolismus $x farmakologie $x terapeutické užití $7 D000577
- 650 _2
- $a aniliny $x chemie $7 D000814
- 650 _2
- $a antituberkulotika $x chemická syntéza $x metabolismus $x farmakologie $x terapeutické užití $7 D000995
- 650 _2
- $a bakteriální proteiny $x antagonisté a inhibitory $x metabolismus $7 D001426
- 650 _2
- $a viabilita buněk $x účinky léků $7 D002470
- 650 12
- $a racionální návrh léčiv $7 D015195
- 650 _2
- $a bakteriální léková rezistence $x účinky léků $7 D024881
- 650 _2
- $a buňky Hep G2 $7 D056945
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a mikrobiální testy citlivosti $7 D008826
- 650 _2
- $a Mycobacterium tuberculosis $x účinky léků $x metabolismus $7 D009169
- 650 _2
- $a oxidoreduktasy $x antagonisté a inhibitory $x metabolismus $7 D010088
- 650 _2
- $a kyselina pyrohroznová $x chemie $7 D019289
- 650 _2
- $a vztahy mezi strukturou a aktivitou $7 D013329
- 650 _2
- $a tuberkulóza $x farmakoterapie $7 D014376
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Horváth, Lilla $u MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), Institute of Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518, Budapest 112, Hungary
- 700 1_
- $a Stolaříková, Jiřina $u Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00, Ostrava, Czech Republic
- 700 1_
- $a Pál, Adrián $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina CH-1, Ilkovičova 6, 842 15, Bratislava, Slovakia
- 700 1_
- $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
- 700 1_
- $a Bősze, Szilvia $u MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), Institute of Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518, Budapest 112, Hungary
- 700 1_
- $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
- 700 1_
- $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
- 773 0_
- $w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 223, č. - (2021), s. 113668
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/34198149 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y p $z 0
- 990 __
- $a 20220113 $b ABA008
- 991 __
- $a 20220127150538 $b ABA008
- 999 __
- $a ok $b bmc $g 1750863 $s 1154383
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2021 $b 223 $c - $d 113668 $e 20210623 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628
- LZP __
- $a Pubmed-20220113
