U. Das et al. / European Journal of Medicinal Chemistry 45 (2010) 4682e4686
4685
lacks an acidic group which is considered to be required for
5.4. Evaluation of 1h and 2 on respiration of rat liver mitochondria
uncoupling properties [29]. Hence it is likely that this compound
induces a mitochondrial permeability transition. On the other
hand, the same concentrations of 2 had no effect on respiration.
This result suggests that a contributing factor to the noteworthy
antitubercular properties of 1h is by interference with mitochon-
drial respiration and it may also explain, at least in part, its greater
potency than 2. Furthermore, while additional experimentation is
necessary, the possibility exists that a 3-aryl-2-propenoyl group is
required for an effect on mitochondrial respiration to be
demonstrated.
A rat was anesthetized with isoflurane and decapitated. The
mitochondria were isolated from the liver using a literature
methodology [34]. The consumption of oxygen by mitochondria
was determined by polarography using a previously reported
procedure [35]. Compounds 1h and 2 were dissolved in dime-
thylsulfoxide (4
mL) and the solvent control (dimethylsulfoxide,
4
m
L) caused a stimulation of respiration of 8.22 ꢁ 0.74%.
Acknowledgments
The authors thank the Canadian Institutes of Health Research for
an operating grant to J. R. Dimmock. The antitubercular data were
provided by the Tuberculosis Antimicrobial Acquisition and Coor-
dinating Facility (TAACF) through a research and development
contract with the U.S. National Institute of Allergy and Infectious
Diseases. Erin Watson is thanked for undertaking some of the
literature retrieval.
4. Conclusions
The importance of finding novel compounds which are struc-
turally divergent from contemporary antitubercular drugs is
axiomatic. This study revealed that in general a series of 2-(3-aryl-
1-oxo-2-propenyl)-3-methylquinoxaline-1,4-dioxides
1
display
excellent potencies towards M. tuberculosis. In particular, 1h
emerged as a potent lead compound for further studies. Quantita-
tive structureeactivity relationships revealed the importance of the
electronic and hydrophobic properties of the substituents in ring A
which afford guidelines for expanding the project. The observation
that some correlations were noted between antitubercular and
cytotoxic potencies afford some hope that dual action chemother-
apeutics may evolve from this study. The lead compound 1h
stimulated respiration in rat liver mitochondria which may indicate
that the compounds in series 1 exert their action in a different way
from available antimycobacterials thus revealing the possibility of
their use against drug-resistant bacteria.
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The
compounds in series 1 were culled from the literature [26] except
that the constant for the 3,4-methylenedioxy group was obtained
s, p and MR values of the aryl substituents in ring A of the
s
from a different reference [31]. The MR value of the hydrogen atom
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substituents, the figures of 1.03 and 2.06 were added to the
disubstituted and monosubstituted compounds, respectively. The
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semilogarithmic plots were made using a commercial software
package [32]. The Pearson’s coefficients obtained from the semi-
logarithmic plots between the IC50 values of 1aej,l against M.
tuberculosis and the
s and p figures of the aryl substituents are
0.892 and 0.609, respectively. The Pearson’s coefficients generated
when linear plots were constructed between the IC50 values of
1aej,l against M. tuberculosis and the IC50 figures against Molt 4/C8
and CEM cells are 0.758 and 0.704, respectively.
5.3. Antitubercular assay
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The compounds were evaluated against M. tuberculosis H37Rv
(ATCC 27294) in BACTEC 12B medium using the broth micro-
dilution Microplate Alamar Blue Assay [33].