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Organic & Biomolecular Chemistry
Page 4 of 4
DOI: 10.1039/C7OB00897J
ARTICLE
Journal Name
each well for turbidity, indicating overnight growth. The MIC
was recorded as the lowest concentration with no visible
growth. Each compound was tested in triplicate.
Notes and references
§BAA-44 was clinically isolated in Portugal with multi-drug
resistance across broad spectrum including methicillin,
a
Racemic mixtures of 9b and 10 were prepared and
evaluated against a multi-drug resistant MRSA strain BAA-44.§
The introduction of the ester stereocenter in 9b nullified the
imipenem, cephalothin, erythromycin, rifampin, ciprofloxacin,
doxycycline, and clindamycin. BAA-1720 was clinically isolated in
the United Kingdom with resistance to methicillin (a.k.a.
MRSA252). ATCC-33592 was clinically isolated from human
blood in the United States with resistance to methicillin and
gentamicin. NRS-100 was isolated in the United Kingdom as a
community-acquired strain with resistance to methicillin (a.k.a.
strain COL, a.k.a. NR-45906).
re-sensitizing activity compared to the initial lead, 1 §§
.
However, we were pleased to discover that 10 was a potent
antibacterial agent with an MIC of 4 µg/mL, the same as the
lead compound, 2. The cytotoxicity of 10 in mammalian cells
§§RMA and HeLa assay protocols are available in the electronic
supplementary information (ESI).
was also evaluated using human cervical adenocarcinoma
(HeLa) cells.§§ The half-growth inhibitory concentration (GI50)
of the racemic mixture of 10 was found to be 14 µg/mL, a
1
2
3
4
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modest improvement over 2 (GI50 = 8 µg/mL).
Pure samples of each enantiomer of 10 were then
prepared to determine which were responsible for the
observed antibacterial activity. Four MRSA strains were
assayed including BAA-44, BAA-1720, ATCC-33592, and NRS-
100.§ Interestingly, both enantiomers of 10 inhibited the
growth of all four MRSA
1.htm. Accessed January 26, 2017.
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strains at 4 µg/mL (table 1), the same MIC as the initial lead
compound 2, suggesting the absolute stereochemistry of the
tricyclic indoline is not essential to the antibacterial activity.
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9
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The preparation of enantiopure tricyclic indolines was
successfully carried out from commercially available chiral
starting materials using highly diastereoselective gold-
catalyzed cyclization and reductive ring-opening reactions. We
demonstrated that the minor perturbation of the cyclization
precursor
induce a change in the pivotal cyclization, yielding an excess of
one diastereomer. Although the re-sensitizing activity of was
lost in the analogue 9a, the enantiopure analogues of were
7 with an added stereocenter was sufficient to
1
2
found to be active in MRSA with equal potency. The abolition
of activity of 9a was not surprising considering that the
addition of a new functional group to a bioactive compound
inherently risks altering the desired activity. However, the fact
,
861.
19 a) T. Wang, X. Duan, H. Zhao, S. Zhai, C. Tao, H. Wang, Y. Li,
that 10 and
2 had equal potency demonstrates that this
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strategy is valid as a proof of concept. We hope that this study
will pave the way for future research, such as the
determination of the biological target of 10 and other
compounds like it that have we have previously reported. The
relationship between stereochemistry and activity of such
compounds may also be elucidated. With the current demand
for new antibiotics with unique modes of action, the discovery
of structures from previously unexplored chemical space will
be of vital importance.
20 a) H. Shi, C. Tan, W. Zhang, Z. Zhang, R. Long, J. Gong, T. Luo
and Z. Yang, J. Org. Chem., 2016, 81, 751. b) Y. Wang, A. D.
Lackner and F. D. Toste, Acc. Chem. Res., 2014, 47, 889. c) C.
Shu, M. Liu, S. Wang, L. Li and L. Ye, J. Org. Chem., 2013, 78
,
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K. Sharma, V. S. Parmar, L. Van Meervelt, E. V. Van der
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,
Acknowledgements
22 E. Siddalingamurthy, K. M. Mahadevan, J. N. Masagalli and H.
N. Harishkumar, Tetrahedron Lett., 2013, 54, 5591.
23 Clinical and Laboratory Standards Institute (CLSI). Methods
for Dilution Amntimicrobial Susceptibility Tests for Bacteria
That Grow Aerobically; Approved Standard; CLSI: Wayne, PA,
2009.
We thank the National Institute of Health (Grant No. R21-
AI121581) for financial support.
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