Innovation Major Project of China [2018ZX09711001-007-002]
for financial support.
pneumonia producing NDM-1. Compound 8a contains a methyl
substituent on the amidine group while 8i has a dimethyl
substituent on the amidine group. This indicates that different
substituents on the amidine group exert different influences on
the activities of compounds containing different substitutes on
the phenyl ring.
Supplementary data Supplementary data to this article can be
found online at https://.
References and notes
to a pyridine ring to investigate the effect on anti-bacterial
activity. The antibacterial potency of 8j-8o against Gram-positive
bacteria was very similar to the lead parent compound 1.
Surprisingly, however, these compounds had better activity
against several gram-negative strains. Compound 8l was 4-fold
more potent against E. coli., K. pneumonia, P. aeruginosa, and C.
freundii than compound 1. In addition, it displayed an MIC of 2
μg/mL against K. pneumonia secreting NDM-1 enzyme, with
VCM and Lfox also displaying resistance (MIC > 128 μg/mL). In
general, for Gram-negative bacteria, compounds 8j-8l, which
contain a meta-N pyridine ring, displayed better anti-bacteria
activity than 8m-8o, which contain an ortho-N pyridine ring.
This two series of compounds had a similar trend, with dimethyl
substitution as the best and methyl substitution as the worst.
Modifying one benzene ring in diphenyl ether was
recognized to display greatly influence on its antibacterial
activity. Herein, we synthesized 8p-8r, with one pyridine ring
and a trifluoromethyl substitutent on a benzene ring, to
investigate the effect on anti-bacterial activity. As a result, we
found that the activity of 8p-8r was slightly lower than that of 8j-
8l against either the Gram-positive or Gram-negative bacteria. In
addition, changing the middle portion of the compound was
found to greatly influence its activity. Further research on the
SAR is still in progress.
Biol. 2012, 7, 1281-1291.
3. Martens, E.; Demain, A. L. J. Antibiot. (Tokyo). 2017, 70,
520-526.
4. Lam, S. J.; O'Brien-Simpson, N. M.; Pantarat, N.; Sulistio,
A.; Wong, E. H.; Chen, Y. Y.; Lenzo, J. C.; Holden, J. A.;
Blencowe, A.; Reynolds, E. C.; Qiao, G. G. Nat. Microbiol.
2016, 1, 16162-16177.
5. Nguyen, S. T.; Williams, J. D.; Butler, M. M.; Ding, X.;
Mills, D. M.; Tashjian, T. F.; Panchal, R. G.; Weir, S. K.;
Moon, C.; Kim, H. O.; Marsden, J. A.; Peet, N. P.; Bowlin,
T. L. Bioorg. Med. Chem. Lett. 2014, 24, 3366–3372.
6. Hu, L. X.; Kully, M. L.; Boykin, D. W.; Abood, N. Bioorg.
Med. Chem. Lett. 2009, 19, 1292-1295.
7. Hu, L. X.; Kully, M. L.; Boykin, D. W.; Abood, N. Bioorg.
Med. Chem. Lett. 2009, 19, 3374-3377.
8. Hu, L. X.; Kully, M. L.; Boykin, D. W.; Abood, N. Bioorg.
Med. Chem. Lett. 2009, 19, 4626-4629.
9. Nguyen, S. T.; Kwasny, S. M.; Ding, X.; Williams, J. D.;
Peet, N. P.; Bowlin, T. L.; Opperman, T. J. Bioorg. Med.
Chem. Lett. 2015, 23, 5789-5798.
10. Farahat, A. A.; Ismail, M. A.; Kumar, A.; Wenzler, T.;
Brun, R.; Paul, A.; Wilson, W. D.; Boykin, D. W. Eur. J.
Med. Chem. 2018, 143, 1590-1596.
11. Plaza, D. F.; Marino, A.; Delgado, G. J. Immunotoxicol.
2007, 4, 279-285.
12. Stokes, J. M.; MacNair, C. R.; Ilyas, B.; French, S.; Côté, J.
P.; Bouwman, C.; Farha, M. A.; Sieron, A. O.; Whitfield,
C.; Coombes, B. K.; Brown, E. D. Nat. Microbiol. 2017, 2,
17028-17038.
13. Williams, J. D.; Nguyen, S. T.; Gu, S.; Ding, X.; Butler, M.
M.; Tashjian, T. F.; Opperman, T. J.; Panchal, R. G.;
Bavari, S.; Peet, N. P.; Moir, D. T.; Bowlin, T. L. Bioorg.
Med. Chem. 2013, 21, 7790-7806.
14. Chen, X. F.; Hu, X. X.; Wu, Y. B.; Liu, Y. H.; Bian, C.;
Nie, T.; You, X. F.; Hu, L. X. Bioorg. Med. Chem. Lett.
2017, 27, 841-844.
Generally, disrupting the symmetry of the lead compound’s
(1) structure had a great influence on its activity and allowed us
to derive compounds with better activity against Gram-positive
and Gram-negative bacteria. Compound 8l was found to display
the best activity with MIC = 0.125 μg/mL against MRSA and
MIC = 2 μg/mL against K. pneumonia secreting NDM-1 enzyme.
A further evaluation of this compound is pending and will be
reported in the future. The structure-activity relationship
research revealed that the middle portion of the structures and the
amidine chains on bisamidine greatly affected its antibacterial
activity. Bisamidine compounds represent a new type of
antibiotic which are worthy of further research in the antibacterial
field.
15. Lazo, J. S.; Nunes, R.; Skoko, J. J.; Queiroz de Oliveira, P.
5650.
16. CLSI. In Methods for dilution antimicrobial susceptibility
tests for bacteria that grow aerobically; approved
standard-ninth edition. CLSI document M07-A9; Wayne, P.
A., Ed.; Clinical and Laboratory Standards Institute, 2012.
Acknowledgments:
The authors thank the National Natural Science Foundation of
China (Grants 81573298, 81621064), the CAMS Innovation
Fund for Medical Sciences [2017-I2M-1-012] and the Drug
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compounds against Gram-positive and
Gram-negative pathogens
Synthesis and in vitro activity of
asymmetric indole-based bisamidine
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