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6847
fluorescent protein reporter assay.18 Briefly, the compound was
initially dissolved in dimethylsulfoxide (DMSO), and two-fold dilu-
tions were made in 7H9 broth in microplates. The initial inoculum
of 2 Â 105 CFU/mL of Mtb H37Rv-GFP, which was grown in Middle-
brook 7H9 media, was exposed to the compounds for 7 days. The
fluorescence was measured in a Fluostar Optima microplate fluo-
rometer (BMG Labtech, Germany), and the MIC was defined as
the lowest concentration of compounds that inhibited fluorescence
by 90%, compared with the fluorescence of bacteria only wells.
We investigated the antitubercular activity of triazole 7a and 7b
32 lg/mL, and investigated the selective indexes (SI). The SI values
were ranged from 1 to 3, indicating that cytotoxicity profile should
be improved further to develop this triazole series as antitubercu-
lar agents.
In summary, replacing the imidazole on econazole with
1H-1,2,3-triazole could be tolerable to maintain antitubercular
activities, based on the activity profiles of the hydroxy-triazoles
(10) prepared. Overall, hydroxy-triazoles (10) tend to be more
active than ether-triazoles (11). While 10d was as active as econa-
zole, 10a was two-fold more active than econazole. Moreover, the
triazole series compounds prepared were not active at all against
C. albicans, suggesting that the mode of action of the triazoles
prepared might be quite different from that of econazole.4,19 Thus,
this 1H-1,2,3-triazole scaffold could be further optimized to
develop Mtb specific agents.
as controls. Triazole 7a gave the MIC value of 64 lg/mL. Although
7a is 4 times less active than econazole, it still maintains the anti-
tubercular activity, indicating that replacing the imidazole on
econazole with 1H-1,2,3-triazole could be tolerated in terms of
the activity (Table 1). However, in case of 7b, the activity was abol-
ished, compared with econazole. While we have tried several dif-
ferent alkynes to prepare ether-triazoles 11, most of them were
not active against Mtb. Moreover, when the benzyl group was re-
placed with 4-trifluoromethoxybenzyl or 2,4-difluorobenzyl sub-
stituents, the activity was not improved. This led us to
investigate the activity of hydroxy-triazoles 10. It turned out that
hydroxy-triazoles 10 appeared to be far more active, compared
with ether-triazoles 11. Some of the hydroxy-triazoles such as
10e, 10f, 10g, and 10h were two-fold less active than econazole.
While 10d (R1 = cyclohexyl) was as active as econazole, 10a
(R1 = n-Bu) was two-fold more active than econazole. However,
their corresponding ether-triazoles 11h and 11a, respectively,
were not active, confirming that hydroxy-triazoles 10 are more ac-
tive than ether-triazoles 11. This trend appears to be applicable in
the case of amine containing triazoles. While the MIC values of
Acknowledgments
This work was supported by Korea Research Institute of
Chemical Technology (KRICT) and by the International Research
& Development Program of the National Research Foundation of
Korea (NRF) funded by the Ministry of Education, Science and
Technology (MEST) of Korea (Grant number: K20501000001-
09E0100-00110, FY 2009)
Supplementary data
Supplementary data associated with this article can be found, in
hydroxy-triazoles such as 10f, 10g, and 10h were 32 lg/mL, their
corresponding ether-triazoles (11j, 11k, and 11l, respectively)
were inactive.
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