In vitro antimycobacterial activity of 5-chloropyrazinamide. Antimicrob Agents Chemother 42: 462-463
Veterans Affairs Medical Center, Syracuse, New York 13210, USA.Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 02/1998; 42(2):462-3.
5-Chloropyrazinamide and 5-chloropyrazinoic acid were evaluated for in vitro activity against Mycobacterium tuberculosis, Mycobacterium bovis, and several nontuberculous mycobacteria by a broth dilution method. 5-Chloropyrazinamide was more active than pyrazinamide against all organisms tested. It is likely that this agent has a different mechanism of action than pyrazinamide.
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- "Isoniazid (INH) and rifampicin (RIF) were purchased from Sigma. 5-Cl-PZA was synthesized by one of the authors (JTW)14. For in vitro studies, 5-Cl-PZA was solubilised in DMSO and diluted with distilled water. "
ABSTRACT: Background & objectives: Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such analogue is 5-chloro-pyrazinamide (5-Cl-PZA) that has been tested under in vitro conditions against M. tuberculosis. The present study was designed with an aim to assess the activity of 5-Cl-PZA, alone and in combination with first-line drugs, against murine tuberculosis. Methods: The minimum inhibitory concentration (MIC) of 5-Cl-PZA in Middlebrook 7H9 broth (neutral pH) and the inhibitory titre of serum from mice that received a 300 mg/kg oral dose of 5-Cl-PZA 30 min before cardiac puncture were determined. To test the tolerability of orally administered 5-Cl-PZA, uninfected mice received doses up to 300 mg/kg for 2 wk. Four weeks after low-dose aerosol infection either with M. tuberculosis or M. bovis, mice were treated 5 days/wk with 5-Cl-PZA, at doses ranging from 37.5 to 150 mg/kg, either alone or in combination with isoniazid and rifampicin. Antimicrobial activity was assessed by colony-forming unit counts in lungs after 4 and 8 wk of treatment. Results: The MIC of 5-Cl-PZA against M. tuberculosis was between 12.5 and 25 μg/ml and the serum inhibitory titre was 1:4. Under the same experimental conditions, the MIC of pyrazinamide was >100 μg/ml and mouse serum had no inhibitory activity after a 300 mg/kg dose; 5-Cl-PZA was well tolerated in uninfected and infected mice up to 300 and 150 mg/kg, respectively. While PZA alone and in combination exhibited its usual antimicrobial activity in mice infected with M. tuberculosis and no activity in mice infected with M. bovis, 5-Cl-PZA exhibited antimicrobial activity neither in mice infected with M. tuberculosis nor in mice infected with M. bovis. Interpretation & conclusion: Our findings showed that 5-Cl-PZA at doses up to 150 mg/kg was not active in chronic murine TB model. Further studies need to be done to understand the mechanism and mode of inactivation in murine model of tuberculosis.
- "These compounds, namely, pyrazinoic acid pivaloyloxymethyl ester, pyrazinoic acid n-octyl ester, pyrazinethiocarboxamide and N-hydroxymethylpyrazinethiocarboxamide, may warrant further examinations. 5-Chloropyrazine-2-carboxamide (see Fig. 6, structure IX) showed excellent in vitro activity against PZA-resistant strains of M. tuberculosis (Cynamon et al., 1998). Therefore FAS I and/or FAS II were proposed as a target of this compound, i.e. this compound possesses a different mechanism of action (Boshoff et al., 2002). "
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ABSTRACT: A number of known antifungal pyrrole derivatives and some newly synthesized compounds (5–33) were tested in vitro against Mycobacterium tuberculosis CIP 103471. The majority of tested compounds were efficient antimycobacterial agents showing MIC values ranging from 0.5 to 32 μg/mL. A 3-D-QSAR study has been performed on these pyrrole derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. Due to the absence of information on a putative receptor responsible for this activity, classical quantitative structure–activity relationships (QSAR) and comparative molecular field analysis (CoMFA) have been applied. A model able to well correlate the antimycobacterial activity with the chemical structures of pyrrole derivatives 5–33 has been developed which is potentially helpful in the design of novel and more potent antituberculosis agents. The combination of CoMFA with classical QSAR descriptors led to a better hybrid 3-D-QSAR model, that successfully explains the structure–activity relationships (r2=0.86) of the training set. A comparison between the QSAR, CoMFA and mixed QSAR–CoMFA models is also presented. The hybrid model is to be preferred, however, because of its lowest values of the average absolute error of prediction toward a limited external test set.