than the 4-methoxyl and 4-methyl analog (1i and 1j, MICs of 8-
64 mg/L). Obviously, compound 1k showed an excellent activity
of anti MDR-MTB and XDR-MTB (MIC = 2 and 1 mg/L,
Table 2
compounds do not have MICs up to 128 mg/L, indicating
specificity to Mtb (Table 2).
In conclusion, we have designed and synthesized 25
compounds of disubstituted azole analogues. All the compounds
1a-y were tested for their anti-Mtb activities, including
replicating H37Rv, MDR-Mtb and XDR-Mtb strains, and also
assessed their cytotoxicity. The result reflected that 22
compounds (1a-n, 1r-y) of the disubstituted azole analogues have
potent activities and low cytotoxicity. The broad spectrum panel
of compounds 1b, 1k and 1r indicated these compounds have a
good selectivity for anti-Mtb. In addition, compared with the
current clinical drugs, this series appears to work through a novel
mechanism of action. Therefore, for future study and research,
this class can be further optimized through analog synthesis and
systematic medicinal chemistry evaluation.
Studies on Broad Spectrum Panel
MIC (mg/L)
species
1b
1k
1r
> 128*
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
> 128
S. aureus
E. coli
K. pneumoniae
P. aeruginosa
P. vulgaris
P. mirabilis
S. marcescens
A. calcoacetious
Acknowledgments
This work was supported by State Mega Programs
(2012ZX09301002-003/006), and grants from the National
Natural Science Foundation of China (81302816, 81001461,
81072672, 81321004).
* >, end points not determined
respectively). It is 4 and 8-fold than the lead compound 1a (MICs
= 8 mg/L). It seemed to be a good preference for higher ClogP
(ClogP = 5.19 for 1k vs 3.39 and 3.87 for 1i and 1j) and larger
area place in potency. Comparing thiazoles (1o, 1p, MICs >128
mg/L) and isoxazole (1q, MICs >128 mg/L) with the
corresponding oxazole analogs (1a, 1b, and 1k) indicates that the
oxazole ring is crucial for cellular potency. Investigating
substitution on the right phenyl ring (R2 and R3) (1r–x) gave
MICs ranging from 1 to 16 mg/L. A 2 to 8-fold improvement in
potency could be achieved by replacing the 1,4-Benzodioxan of
compound 1a with 1,2,3,4-tetrahydronaphthalene (1r).As the
compound 1k and 1r both perform a excellent anti-TB activity,
the hybrid compound 1y was synthesized and also showed a
potent anti-TB activity (MICs of 4-8 mg/L). However, the
compound 1y did not show a higher anti-TB activity than the
compound 1k or 1r. This may be caused by its high ClogP
(ClogP = 6.60).
More importantly, all the compounds, except 1o, 1p and 1q,
showed excellent potency against the MDR strain (FJ05120, a
strain that is resistant to isoniazid and rifmpin) and XDR strain
(FJ05195, a strain that is resistant to isoniazid, rifmpin,
streptomycin, capreomycin, and ofloxacin) with MICs of 1-64
mg/L (16 compounds have MICs of 1-16 mg/L and 5 compounds
of 32-64 mg/L)), which were much lower than the reference drug
rifmpin (MICs > 256 mg/L). Compound 1k (MICs of 1-2 mg/L)
was comparable to or slightly lower than the reference drugs,
isoniazid (MICs of 1-4 mg/L) and ethambutol (MICs of 1-8
mg/L). The exciting anti-Mtb result of the compounds encourage
us to believe that this class of molecules is likely to be effective
against a wide range of clinical isolates and is likely to act
through a novel mechanism.
Supplementary Date
Supplementary data associated with this article can be found, in
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