Synthesis and in vitro antimycobacterial activity of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-4,5-dihydro-1H-1-(isonicotinoyl) pyrazoles

被引:42
作者
Almeida da Silva, Pedro E. [1 ]
Ramos, Damela F. [1 ]
Bonacorso, Helio G. [2 ]
de la Iglesia, Agustina I. [3 ]
Oliveira, Marli R. [2 ]
Coelho, Tatiane [1 ]
Navarini, Jussara [2 ]
Morbidoni, Hector R. [3 ]
Zanatta, Nilo [2 ]
Martins, Marcos A. P. [2 ]
机构
[1] Fundacao Univ Fed Rio Grande, Dept Patol, Rio Grande Do Sul, Brazil
[2] Univ Fed Santa Maria, Dept Quim, Nucl Quim Heterociclos NUQUIMHE, BR-97119900 Santa Maria, RS, Brazil
[3] Univ Nacl Rosario, Fac Ciencias Med, Catedra Microbiol, RA-2000 Rosario, Santa Fe, Argentina
关键词
pyrazoles; pyrazolines; Mycobacterium tuberculosis; antimycobacterial activity;
D O I
10.1016/j.ijantimicag.2008.03.019
中图分类号
R51 [传染病];
学科分类号
100401 [流行病与卫生统计学];
摘要
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. (C) 2008 Published by Elsevier B.V. and the International Society of Chemotherapy.
引用
收藏
页码:139 / 144
页数:6
相关论文
共 41 条
[1]
Mycobacterium tuberculosis dihydrofolate reductase is a target for isoniazid [J].
Argyrou, A ;
Vetting, MW ;
Aladegbami, B ;
Blanchard, JS .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2006, 13 (05) :408-413
[2]
INHA, A GENE ENCODING A TARGET FOR ISONIAZID AND ETHIONAMIDE IN MYCOBACTERIUM-TUBERCULOSIS [J].
BANERJEE, A ;
DUBNAU, E ;
QUEMARD, A ;
BALASUBRAMANIAN, V ;
UM, KS ;
WILSON, T ;
COLLINS, D ;
DELISLE, G ;
JACOBS, WR .
SCIENCE, 1994, 263 (5144) :227-230
[3]
BERNSTEIN J, 1952, AM REV TUBERC PULM, V65, P357
[4]
One-pot synthesis of aryl and heteroaroyl-substituted hydroxypyrazolines from the reactions of β-alkoxyvinyl trichloromethyl ketones with heteroarylhydrazides [J].
Bonacorso, Helio G. ;
Oliveira, Marli R. ;
Costa, Michelle B. ;
Drekener, Roberta L. ;
da Silva, Leticia B. ;
Zanatta, Nilo ;
Martins, Marcos A. P. .
HETEROATOM CHEMISTRY, 2006, 17 (07) :685-691
[5]
Regiospecific synthesis of new non-condensed heteropolycyclic systems from β-heteroaryl-β-methoxyvinyl trihalomethyl ketones [J].
Bonacorso, HG ;
Oliveira, MR ;
Costa, MB ;
da Silva, LB ;
Zanatta, N ;
Martins, MAP ;
Flores, AFC .
JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY, 2005, 16 (04) :868-873
[6]
Regiospecific one-pot synthesis of new trifluoromethyl substituted heteroaryl pyrazolyl ketones [J].
Bonacorso, HG ;
Oliveira, MR ;
Costa, MB ;
da Silva, LB ;
Wastowski, AD ;
Zanatta, N ;
Martins, MAP .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 2005, 42 (04) :631-637
[7]
Trifluoroacetylation of unsymmetrical ketone acetals. A convenient route to obtain alkyl side chain trifluoromethylated heterocycles [J].
Bonacorso, HG ;
Martins, MAP ;
Bittencourt, SRT ;
Lourega, RV ;
Zanatta, N ;
Flores, AFC .
JOURNAL OF FLUORINE CHEMISTRY, 1999, 99 (02) :177-182
[8]
Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials [J].
Burman, WJ ;
Gallicano, K ;
Peloquin, C .
CLINICAL PHARMACOKINETICS, 2001, 40 (05) :327-341
[9]
Synergistic interactions of SQ109, a new ethylene diamine, with front-line antitubercular drugs in vitro [J].
Chen, Ping ;
Gearhart, Jackie ;
Protopopova, Marina ;
Einck, Leo ;
Nacy, Carol A. .
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2006, 58 (02) :332-337
[10]
Synthesis and antimycobacterial activity of some isonicotinoylhydrazones [J].
Cocco, MT ;
Congiu, C ;
Onnis, V ;
Pusceddu, MC ;
Schivo, ML ;
De Logu, A .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1999, 34 (12) :1071-1076