A. Kamal et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6842–6846
6843
O2N
O
O
O
NH
O
O
N
N
N
N
N
N
N
H
O2N
O2N
NHAc
OH
O
O
O
F
(3)
(1)
(2)
Figure 1. Structures of some antimicrobial agents containing nitrofuran moiety.
antimicrobial agents26–29 and prompted by the diverse biological
profile of 1,2,3-triazole as well as nitrofuran heterocycle, we report
herein the design and synthesis of nitrofuramide linked triazole
hybrids, and evaluation for their anti-mycobacterial as well as anti-
bacterial activities.
and compounds 8e, 8f against B. subtilis MTCC 121. The bactericidal
activity was found to follow the similar trend as that of the inhib-
itory activity against the respective bacterial strains. The com-
pounds 8a, 8e, 8f, 8g have demonstrated good bactericidal
activity (2.34 lg/ml) against M. luteus MTCC 2470, compounds
The synthetic route to achieve the title compounds 8a–j is out-
lined in Scheme 1. As shown, 5-nitro-2-furoic acid was reacted
with propargyl amine in presence of EDC and HOBt in CH2Cl2.
The resultant amide (7) containing terminal alkyne functionality
was reacted with substituted benzyl azides 11a–j following click
chemistry protocol30 to obtain the final compounds 8a–j in good
yields (79–92%). The structure of the triazole was initially con-
firmed by NMR data and was supported by X-ray crystallographic
study performed on 8d to precisely determine the formation of 1,4-
isomer. The X-ray results31 shown in Figure 3 proved the exclusive
formation of the 1,4-isomer through the application of copper cat-
alyzed azide alkyne cycloaddition.
Substituted benzyl azides required as precursors were prepared
using a reported procedure32 as shown in Scheme 2. The corre-
sponding starting benzaldehydes were reduced to respective ben-
zyl alcohol 9a–j using sodium borohydride in methanol. The
respective alcohol obtained was brominated using PBr3 in dry
ether at 0 °C. Overnight stirring of respective benzyl bromide
10a–j with sodium azide in DMSO afforded the azide intermediates
11a–j in good yields.
8b, 8e, 8f against S. aureus MLS-16 MTCC 2940 and compound 8d
against B. subtilis MTCC 121. Compounds 8e and 8h have exhibited
excellent bactericidal effects with MBC value of 1.17 lg/ml against
B. subtilis MTCC 121 and M. luteus MTCC 2470, respectively. It is
remarkable that compound 8e was found to be equipotent to the
standard drug Ciprofloxacin in terms of bactericidal activity
against the bacterial strain B. subtilis MTCC 121. However, it was
observed that not even a single compound was active against the
Gram-negative bacterial strain, Pseudomonas aeruginosa MTCC
2453 and the fungal strain, Candida albicans, even at the maximum
concentration used (150 lg/ml).
The structure–activity relationship study reveals that the sub-
stituents with electron withdrawing nature like nitro, fluoro,
chloro, trifluoromethyl improved the activity. The compound with
nitro group at meta position possesses slightly better activity as
compared to its para counterpart. Substituents fluoro, trifluoro-
methyl and hydroxyl at para position conferred better activity
while the methoxy substituent did not have any significant effect
on the activity.
Further these triazole conjugates 8a–e were tested on two resis-
tant bacterial strains namely methicillin resistant Staphylococcus
aureus (MRSA) and vancomycin resistant Enterococcus (VRE) and
the results are listed in Table 3. The compounds have shown prom-
ising antimicrobial activity against MRSA strain whereas against
VRE these compounds were found to be inactive. Interestingly
the compounds 8b, 8c, 8d, 8e have shown equal potency to that
The newly synthesized nitrofuran–triazole derivatives (8a–j)
were tested for antimicrobial activity against both Gram-positive
and Gram-negative bacterial strains. The results (Tables 1 and 2)
illustrate that all the ten compounds show different level of inhib-
itory and bactericidal effects with Minimum Inhibitory Concentra-
tion (MIC) and Minimum Bactericidal Concentration (MBC) values
ranging from 1.17 to 75
lg/ml. Interestingly, these compounds
of Linezolid against MRSA strain with MIC value of 8 lg/ml, while
showed selectivity towards Gram-positive pathogenic strains like
8a was moderately active.
Micrococcus luteus, Staphylococcus aureus (MLS-16) and Bacillus sub-
These conjugates were also evaluated for anti-biofilm activity
against three bacterial strains, namely Staphylococcus aureus MTCC
96, Staphylococcus aureus MLS-16 MTCC 2940 and Klebsiella planti-
cola MTCC 530. The results tabulated in Table 4 show that all the
compounds exhibited excellent biofilm inhibition against the
tilis with MIC and MBC values of <10
lg/ml except for the com-
pound 8j (MBC value of 18.75 g/ml against S. aureus and B.
l
subtilis). Compounds 8b, 8d, 8e and 8j displayed broad spectrum
of activity exhibiting excellent inhibitory as well as bactericidal ef-
fects in Gram-positive bacterial strains and moderate activity
against Gram-negative bacterial strains. Compounds 8a, 8h
strain S. aureus MLS-16 MTCC 2940 (IC50 <10 lg/ml) and good to
moderate activity against other two strains. Complying with the
antimicrobial activity, compound 8b displayed significant anti-bio-
film activity among the series against S. aureus MLS-16 MTCC 2940
showed excellent inhibitory activity (1.17
lg/ml) against M. luteus
MTCC 2470, compound 8b against S. aureus MLS-16 MTCC 2940
Cl
O
HO
O
HN
N
O
S
H
O
Cl
Cl
NH2
N
N
O
N
N
S
N
O
N
OH
O
S
N
H
O
OH
N
N
O
H2N
NH2
N
(5)
(6)
(4)
Figure 2. Structures of some drugs containing triazole nucleus.