Mendeleev Commun., 2019, 29, 523–525
Table 2 Selectivity indices (SI) of hit compounds on HEK-293 and RBC.
SI on HEK-293 (CC50/MIC)// on RBC (HC50/MIC)
Compound
(alkyl, Hal)
MRSA
E. coli
K. pneumoniae
A. baumannii
P. aeruginosa
C. albicans
C. neoformans
3b (C8, Br)
3'b (C8, I)
3c (C9, Br)
3d (C10, Br)
3'd (C10, I)
3''d (C10, Cl)
BAC
1.0 // 11.8
0.54 // >4.0
2.85 // 6.3
0.8 // 1.08
0.68 // 0.78
2.03 // 1.13
<0.08 // <0.11
>1 // >1
0.06 // 0.74
0.27 // >2.0
0.71 // 1.58
1.6 // 2.15
1.35 // 1.55
4.05 // 2.25
0.08 // 0.11
>4 // >4
0.13 // 1.48
0.13 // >1.0
1.43 // 3.15
0.8 // 1.08
1.0 // 11.8
³8.0 // ³94.4
³17.2 // ³128
³22.8 // ³50.4
³12.8 // ³17.2
³21.6 // ³24.8
³32.4 // ³18
5.6 // 6.8
³8 // ³94.4
8.6 // >64
³8.0 // ³94.4
³17.2 // ³128
³22.8 // ³50.4
³12.8 // ³17.2
³21.6 // ³24.8
³32.4 // ³18
5.6 // 6.8
2.15 // >16
22.8 // 50.4
³12.8 // ³17.2
³21.6 // ³24.8
³32.4 // ³18
2.8 // 3.4
11.4 // 25.2
3.2 // 4.3
2.7 // 3.1
0.68 // 0.78
2.03 // 1.13
<0.08 // <0.11
>4 // >4
4.05 // 2.25
0.18 // 0.21
>32 // >32
0.85 // 1.03
CHG
>128 // >128
³13.6 // ³16.4
>1 // >1
– // –
4 (C12, Br)
0.21 // 0.23
0.85 // 1.03
0.43 // 0.51
³13.6 // ³16.4
³13.6 // ³16.4
(MIC £0.25 μg ml–1), on par with the comparators CHG and
analogue 4. The majority of the bispyridinium amphiphiles also
displayed potent anti-fungal activity (MIC £0.25 μg ml–1 both
against C. albicans and C. neoformans).
The nature of the counter-anion did not influence bioactivity.
For example, the MIC values for decyl-containing bromide 3d,
iodide 3'd and chloride 3''d agreed within a single-fold dilution
between some strains. A similar trend was observed for the
amphiphile pairs 3b/3'b and 3f/3'f equipped with C8 and C12
alkyls, respectively.
This work was supported by the Russian Science Foundation
(grant no. 17-73-20260). The antimicrobial screening performed
by CO-ADD (The Community for Antimicrobial Drug
Discovery) was funded by the Wellcome Trust (UK) and The
University of Queensland (Australia).
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.09.015.
Counter-screening was performed by assessing the cell
viability of human embryonic kidney cells (HEK-293, ATCC
CRL-1573) and human red blood cells (RBC, haemolytic
activity) upon exposure to the compounds. Compounds 3a and
3'a with shorter C7 alkyl did not exhibit appreciable cytotoxicity
or haemolysis at the highest concentration tested (32 μg ml–1). In
contrast, no clear relationship between alkyl chain length and
cytotoxicity and haemolysis was observed for the rest of
compounds. Nonetheless, some correlation is tracked in the
bromide–iodide series. In general, new bis-QACs with iodide
counter-anion have comparable or lower cytotoxicity vs.
HEK-293 and RBC compared to bromine analogues.
It should be noted that the selectivity indices (SI) of hit
compounds 3a–d (including 3'a,b,d and 3''d) on HEK-293
(i.e. CC50/MIC) and RBC (HC50/MIC) against some strains are
better than those of comparators (Table 2). For instance, SI for
salt 3b on RBC is the best against E. coli and K. pneumoniae
(³94.4 and 11.8, respectively). This also holds true for
compounds 3c and 3''d on HEK-293 against K. pneumoniae and
A. baumanni (SI is 2.85 and 4.05). All of novel bis-QACs possess
high selectivity both on HEK-293 and RBC against C. albicans
and C. neoformans.
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Received: 15th March 2019; Com. 19/5852
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