title: N-substituted 2-isonicotinoylhydrazinecarboxamides--new antimycobacterial active molecules.
abstract: This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4-octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 μM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl)hydrazinecarboxamide (MIC=4 μM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria.
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. rychtarz@faf.cuni.cz.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Rychtarčíková
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. martin.kratky@faf.cuni.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Krátký
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia. martin.gazvoda@fkkt.uni-lj.si.
authors.forename: Martin
authors.initials: M
authors.lastname: Gazvoda
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. komlm3aa@faf.cuni.cz.
authors.forename: Markéta
authors.initials: M
authors.lastname: Komlóová
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia. Slovenko.Polanc@fkkt.uni-lj.si.
authors.forename: Slovenko
authors.initials: S
authors.lastname: Polanc
authors.affiliation: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia. marijan.kocevar@fkkt.uni-lj.si.
authors.forename: Marijan
authors.initials: M
authors.lastname: Kočevar
authors.affiliation: Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00 Ostrava, Czech Republic. Jirina.Stolarikova@zu.cz.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.affiliation: Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. jarmila.vinsova@faf.cuni.cz.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Vinšová
mesh_terms: D000588:Amines / Q000737:chemistry; D000814:Aniline Compounds / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001393:Azoles / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003500:Cyclization; D024881:Drug Resistance, Bacterial; D006801:Humans; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology; D009162:Mycobacterium avium / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D019909:Mycobacterium kansasii / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000302:isolation & purification; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000814:Aniline Compounds; D000995:Antitubercular Agents; D001393:Azoles; D001426:Bacterial Proteins; D011725:Pyridines; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; C023650:aniline; D007538:Isoniazid