R.R.Y. Bheemanaboina et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128198
ring in presence of base, two kinds of isomer products could be possibly
produced when the reaction of intermediate 4 with imidazoles occurred.
The single crystal of derivative 5k (Fig. 2) was cultivated and X-ray
diffraction analysis showed that sulfanilamide derivative was reacted
with imidazole nucleus at the 3-N position instead of the 1-N position,
which indicated that isomer 5k should be the main product.
The prepared compounds 5a-k and 6a-k were evaluated for their
antibacterial activities against the tested microorganisms as depicted in
Table 1. The significant effects of substituents of imidazole ring on the
biological activity were observed. Methyl-modified compound 5b
showed the same anti-MRSA activity as norfloxacin. Moreover, 2-ethyl-
4-methyl imidazole derivative 5f could effectively inhibit the growth of
the MRSA and E. faecalis strains with low MIC values of 4 and 16
respectively, which were 2-fold and 16-fold more potent than the posi-
tive control drug sulfathiazole (8 and 256 g/mL). Bromine-bearing
molecule 5h was active towards MRSA and E. faecalis, both MIC
values were 8 g/mL. However, the bioactivities of iodine-containing
μg/mL,
μ
μ
Fig. 2. Crystal structure of compound 5k (CCDC: 2075577).
compounds 5i–k against the same strains decreased. Notably, a few of
the deprotected sulfonamide imidazole derivatives exerted better ac-
tivity than the corresponding protected ones to some extent in inhibiting
the growth of the tested bacteria. Data analysis revealed that derivative
5f had great potential to become potent MRSA inhibitor.
bicarbonate to afford sodium 4-acetamidobenzenesulfinate 3 with a
high yield, following by the substitution reaction with 2-(chloromethyl)
oxirane at 80 ◦C using tetrabutylammonium iodide as catalyst to give N-
(4-((oxiran-2-ylmethyl)sulfonyl)phenyl)acetamide 4 with the yield of
53%. The intermediate 4 was then reacted with imidazole and its de-
rivatives to provide target compounds 5a–k with yield ranging from
57% to 72% through ring-opening reaction. Finally, compounds 5a–k
were further transformed into the deacetylate sulfonamide analogues
6a–k in ethanol in the presence of 40% hydrochloric acid under reflux.
Generally, secondary alcohol sulfanilamide derivatives were expected
from the ring-opened reaction of oxiranes by azole ring according to our
previous same condition, surprisingly, the sulfonyl-hybridized imida-
zolyl ethanols were primary alcohol structures, not second alcohol de-
rivative 7, which was not consistent with our previous researches.15 This
unique discovery was worthy of further exploration.
The resistance development of stubborn strains to clinical drugs has
aroused special attention to human.16,17 Therefore, we studied the
resistance of MRSA to the highly active molecule 5f. The research
findings (Fig. 3) showed that compound 5f was sensitive to MRSA even
after 13 passages. On the contrary, the MIC values of norfloxacin and
sulfathiazole towards MRSA increased significantly. This result
confirmed that less resistance tendency was pronounced for imidazole
derivative 5f. in comparison with clinical drug norfloxacin and
sulfathiazole.
Deoxyribonucleic acid is a significant genetic material and already
regarded as an important drug target to design and develop new efficient
antibacterial drugs. The interaction of MRSA DNA with compound 5f
was investigated by UV–vis spectroscopy to further explore the
There are two equivalent tautomeric interconversions for imidazole
Table 1
In vitro antibacterial MICs (µg/mL) for compounds 5a–k and 6a–ka, b.
Compdsc
Gram-positive bacteria
Gram-negative bacteria
MRSA
E. f
S. a
S. a 25,923
S. a 29,213
K. p
P. a. 27,853
P. a
A. b
E. c
E.c 25,922
5a
32
8
32
64
32
16
32
16
64
8
64
64
64
64
64
64
128
64
64
64
64
64
64
64
64
64
32
64
32
64
64
64
64
512
1
32
32
16
32
16
32
32
32
64
64
64
64
64
64
128
64
128
64
64
64
64
64
512
1
128
128
128
128
64
64
64
64
32
64
32
32
32
32
32
32
64
64
32
32
64
32
32
32
32
32
32
512
16
128
128
256
256
256
128
128
256
32
64
16
16
32
32
64
64
64
32
64
64
128
16
64
32
32
64
16
64
64
32
64
64
8
64
64
32
32
64
64
32
64
32
32
32
32
64
32
32
64
64
32
64
32
32
32
32
128
512
5b
64
64
5c
32
32
16
4
64
64
5d
32
64
5e
128
64
64
5f
128
32
64
5g
16
8
128
64
64
5h
256
64
64
5i
32
64
128
16
16
16
8
64
256
64
32
8
64
128
64
5j
64
256
64
256
256
256
128
256
256
256
128
128
256
256
128
256
128
256
5k
64
64
6a
32
128
128
128
128
64
128
128
64
6b
128
64
6c
16
32
8
6d
128
128
64
64
6e
16
16
8
128
64
6f
16
16
64
256
64
64
512
256
128
32
6g
64
64
6h
16
64
32
16
64
8
64
256
256
64
64
6i
64
64
6j
64
128
64
6k
64
256
128
256
Sulfathiazole
Norfloxacin
512
8
256
512
a Minimal inhibitory concentrations (MIC,
μg/mL) were determined by micro broth dilution method for microdilution plates.
b MRSA, methicillin-resistant Staphylococcus aureus; S. A., Staphylococcus aureus; S. A. 25923, Staphylococcus aureus ATCC 25923; S. A. 29213, Staphylococcus aureus
ATCC 29213; E. F., Enterococcus faecalis; K. P., Klebsiella pneumonia; E. C., Escherichia coli; E. C. 25922, Escherichia coli ATCC 25922; P. A., Pseudomonas aeruginosa; P. A.
27853, Pseudomonas aeruginosa ATCC 27853; A. B., Acinetobacter baumanii.
c
Compds = Compounds
3