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Antimycobacterial pyridine carboxamides: From design to in vivo activity

DE. Nawrot, G. Bouz, O. Janďourek, K. Konečná, P. Paterová, P. Bárta, M. Novák, R. Kučera, J. Zemanová, M. Forbak, J. Korduláková, O. Pavliš, P. Kubíčková, M. Doležal, J. Zitko

. 2023 ; 258 (-) : 115617. [pub] 20230630

Jazyk angličtina Země Francie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc23016086

Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).

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$a Nawrot, Daria Elżbieta $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: nawrotd@faf.cuni.cz
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$a Antimycobacterial pyridine carboxamides: From design to in vivo activity / $c DE. Nawrot, G. Bouz, O. Janďourek, K. Konečná, P. Paterová, P. Bárta, M. Novák, R. Kučera, J. Zemanová, M. Forbak, J. Korduláková, O. Pavliš, P. Kubíčková, M. Doležal, J. Zitko
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$a Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).
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$a myši $7 D051379
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$a isoniazid $x farmakologie $7 D007538
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$a kyselina aminosalicylová $x farmakologie $7 D010131
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$a antituberkulotika $x chemie $7 D000995
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$a Mycobacterium tuberculosis $7 D009169
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$a tuberkulóza $x farmakoterapie $x mikrobiologie $7 D014376
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$a methionin $7 D008715
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$a Bouz, Ghada $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: bouzg@faf.cuni.cz
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$a Janďourek, Ondřej $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: jando6aa@faf.cuni.cz
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$a Konečná, Klára $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: konecna@faf.cuni.cz
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$a Paterová, Pavla $u Department of Clinical Microbiology, University Hospital, Sokolská 581, 500 05, Hradec, Králové, Czech Republic. Electronic address: pavla.paterova@fnhk.cz
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$a Bárta, Pavel $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: bartp7aa@faf.cuni.cz
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$a Novák, Martin $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, Sokolská 581, 50005, Hradec Králové, Czech Republic. Electronic address: martin.novak@fnhk.cz
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$a Kučera, Radim $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: kucerar@faf.cuni.cz
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$a Zemanová, Júlia $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 84215, Bratislava, Slovakia. Electronic address: julia.zemanova@uniba.sk
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$a Forbak, Martin $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 84215, Bratislava, Slovakia. Electronic address: forbak1@uniba.sk
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$a Korduláková, Jana $u Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská Dolina, Ilkovičova 6, 84215, Bratislava, Slovakia. Electronic address: jana.kordulakova@uniba.sk
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$a Pavliš, Oto $u Military Health Institute, Military Medical Agency, Tychonova 1, 160 01, Prague 6, Czech Republic. Electronic address: oto.pavlis@email.cz
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$a Kubíčková, Pavla $u Military Health Institute, Military Medical Agency, Tychonova 1, 160 01, Prague 6, Czech Republic. Electronic address: pafcule@centrum.cz
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$a Doležal, Martin, $d 1961- $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: dolezalm@faf.cuni.cz $7 jn19981000714
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$a Zitko, Jan $u Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, 50005, Hradec Králové, Czech Republic. Electronic address: jan.zitko@faf.cuni.cz
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