-
Je něco špatně v tomto záznamu ?
Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid
G. Bouz, P. Šlechta, O. Jand'ourek, K. Konečná, P. Paterová, P. Bárta, M. Novák, R. Kučera, NK. Dal, F. Fenaroli, J. Zemanová, M. Forbak, J. Korduláková, O. Pavliš, P. Kubíčková, M. Doležal, J. Zitko
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Odkazy
PubMed
36577009
DOI
10.1021/acsinfecdis.2c00433
Knihovny.cz E-zdroje
- MeSH
- antituberkulotika chemie MeSH
- COVID-19 * MeSH
- dánio pruhované MeSH
- kyselina aminosalicylová * farmakologie MeSH
- laktony MeSH
- lidé MeSH
- Mycobacterium tuberculosis * MeSH
- myši MeSH
- pyrazinamid farmakologie MeSH
- SARS-CoV-2 MeSH
- tuberkulóza * farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11') had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11' opens in human plasma to its parent compound 11 (t1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t1/2 of compound 11 overcomes the main drawback of PAS (short t1/2 necessitating frequent administration of high doses of PAS).
Department of Biosciences University of Oslo Blindernveien 31 Oslo 0371 Norway
Military Health Institute Military Medical Agency Tychonova 1 Prague 6 160 01 Czech Republic
- 000
- 00000naa a2200000 a 4500
- 001
- bmc23004608
- 003
- CZ-PrNML
- 005
- 20240522135315.0
- 007
- ta
- 008
- 230418s2023 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1021/acsinfecdis.2c00433 $2 doi
- 035 __
- $a (PubMed)36577009
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Bouz, Ghada $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic $1 https://orcid.org/0000000320245788
- 245 10
- $a Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid / $c G. Bouz, P. Šlechta, O. Jand'ourek, K. Konečná, P. Paterová, P. Bárta, M. Novák, R. Kučera, NK. Dal, F. Fenaroli, J. Zemanová, M. Forbak, J. Korduláková, O. Pavliš, P. Kubíčková, M. Doležal, J. Zitko
- 520 9_
- $a Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11') had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11' opens in human plasma to its parent compound 11 (t1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t1/2 of compound 11 overcomes the main drawback of PAS (short t1/2 necessitating frequent administration of high doses of PAS).
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a pyrazinamid $x farmakologie $7 D011718
- 650 12
- $a kyselina aminosalicylová $x farmakologie $7 D010131
- 650 _2
- $a dánio pruhované $7 D015027
- 650 12
- $a COVID-19 $7 D000086382
- 650 _2
- $a SARS-CoV-2 $7 D000086402
- 650 _2
- $a antituberkulotika $x chemie $7 D000995
- 650 12
- $a Mycobacterium tuberculosis $7 D009169
- 650 12
- $a tuberkulóza $x farmakoterapie $7 D014376
- 650 _2
- $a laktony $7 D007783
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Šlechta, Petr $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic
- 700 1_
- $a Jand'ourek, Ondřej $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic
- 700 1_
- $a Konečná, Klára $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic
- 700 1_
- $a Paterová, Pavla $u Department of Clinical Microbiology, University Hospital, Sokolská 581, Hradec Králové 500 05, Czech Republic
- 700 1_
- $a Bárta, Pavel $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic
- 700 1_
- $a Novák, Martin $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic $u Biomedical Research Center, University Hospital Hradec Kralove, Sokolská 581, Hradec Králové 500 05, Czech Republic
- 700 1_
- $a Kučera, Radim $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic
- 700 1_
- $a Dal, Nils-Jørgen Knudsen $u Department of Biosciences, University of Oslo, Blindernveien 31, Oslo 0371, Norway
- 700 1_
- $a Fenaroli, Federico $u Department of Biosciences, University of Oslo, Blindernveien 31, Oslo 0371, Norway $1 https://orcid.org/0000000290608786
- 700 1_
- $a Zemanová, Júlia $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, Bratislava 84215, Slovakia
- 700 1_
- $a Forbak, Martin $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, Bratislava 84215, Slovakia
- 700 1_
- $a Korduláková, Jana $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, Bratislava 84215, Slovakia
- 700 1_
- $a Pavliš, Oto $u Military Health Institute, Military Medical Agency, Tychonova 1, Prague 6 160 01, Czech Republic
- 700 1_
- $a Kubíčková, Pavla $u Military Health Institute, Military Medical Agency, Tychonova 1, Prague 6 160 01, Czech Republic
- 700 1_
- $a Doležal, Martin, $d 1961- $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic $7 jn19981000714
- 700 1_
- $a Zitko, Jan $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic $1 https://orcid.org/0000000301049925 $7 xx0230408
- 773 0_
- $w MED00205751 $t ACS infectious diseases $x 2373-8227 $g Roč. 9, č. 1 (2023), s. 79-96
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/36577009 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y p $z 0
- 990 __
- $a 20230418 $b ABA008
- 991 __
- $a 20240522135311 $b ABA008
- 999 __
- $a ok $b bmc $g 1924979 $s 1190817
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2023 $b 9 $c 1 $d 79-96 $e 20221228 $i 2373-8227 $m ACS infectious diseases $n ACS infect. dis. $x MED00205751
- LZP __
- $a Pubmed-20230418