Synthesis and in vitro antimycobacterial activity of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-4,5-dihydro-1H-1-(isonicotinoyl) pyrazoles.
A series of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-1H-1-isonicotinoyl-4,5-dihydropyrazoles (2a-i) were synthesised by the cyclocondensation reaction of 4-methoxy-1,1,1-trifluoro[chloro]-4-(substituted)-alk-3-en-2-ones (1a-i) and isoniazid (INH). Their in vitro antimicrobial activity was tested against INH-susceptible Mycobacterium tuberculosis H37Rv, INH-resistant clinical M. tuberculosis isolates and non-tuberculous mycobacteria. Amongst the synthesised compounds, 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)-pyrazole (2a) and 5-hydroxy-3-(4-methylphenyl)-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl) pyrazole (2d) were found to be the two most active agents against susceptible M. tuberculosis and several INH-resistant strains. The compound 3-(2-furyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)pyrazole (2f) was active against all the INH-resistant strains regardless of the genetic background at concentrations two- to four-fold its minimum inhibitory concentration against M. tuberculosis H37Rv. These compounds were inhibitors of mycolic acid biosynthesis, in agreement with the utilisation of the INH scaffold for their design. Interestingly, the most active compound against M. tuberculosis, 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-(isonicotinoyl)-pyrazole (2a), was even more potent than INH against non-tuberculous mycobacteria.
Departamento de Patologia, Fundação Universidade Federal do Rio Grande, Rio Grande do Sul, RS, Brazil. pedre@furg.br
Pedro E
PE
Almeida da Silva
Daniela F
DF
Ramos
Helio G
HG
Bonacorso
Agustina I
AI
de la Iglesia
Marli R
MR
Oliveira
Tatiane
T
Coelho
Jussara
J
Navarini
Hector R
HR
Morbidoni
Nilo
N
Zanatta
Marcos A P
MA
Martins
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D006801:Humans; D007538:Isoniazid / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology
D000995:Antitubercular Agents; D011720:Pyrazoles; D007538:Isoniazid