N-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity

Article abstract of DOI:10.1021/acsmedchemlett.9b00285

Herein we demonstrate the expanded utility of a recently described N-trifluoromethylthiolation protocol to sulfonimidamide containing substances. The novel N-trifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for antibacterial activity against Mycobacterium tuberculosis (M. tb.) and Mycobacterium abscessus and Gram + Ve (Streptococcus aureus, Bacillus subtilis), and Gram - Ve (Escherichia coli, Pseudomonas aeruginosa) bacteria. Two compounds, 13 and 15 showed high antimycobacterial activity with MIC value of 4-8 μg/mL; i.e. comparable to WHO recommended first line antibiotic for TB infection ethambutol. The same compounds were also found to be cytotoxic in HepG2 cells (compound 13 IC₅₀ = 15 μg/mL; compound 15 IC₅₀ = 65 μg/mL). A structure activity relationship, using matched pair analysis, gave the unexpected conclusion that the trifluoromethylthio moiety was responsible for the cellular and bacterial toxicity. Given the increasing use of the trifluoromethylthio group in contemporary medicinal chemistry, this observation calls for considerations before implementation of the functionality in drug design.

Full text of DOI:10.1021/acsmedchemlett.9b00285

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Letter
N-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines:
Anti-microbial, anti-mycobacterial, and cytotoxic activity
Niranjan Thota, Parameshwar Makam, Kamal Krishna Rajbongshi, Savania Nagiah, Naeem
Sheik Abdul, Anil A. Chuturgoon, Amit Kaushik, Gyanu Lamichhane, Anou M. Somboro,
Hendrik Gerhardus Kruger, Thavendran Govender, Tricia Naicker, and Per I Arvidsson
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00285 • Publication Date (Web): 11 Sep 2019
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ACS Medicinal Chemistry Letters
N-Trifluoromethylthiolated
foximines: Anti-microbial, anti-mycobacterial, and cytotoxic
activity
Niranjan Thota,a,† Parameshwar Makam,a,‡ Kamal K. Rajbongshi,a Savania Nagiah,b Naeem Sheik Ab-
dul,b Anil A Chuturgoon,b Amit Kaushik,c Gyanu Lamichhane,c Anou M. Somboro,d Hendrik G. Kru-
ger,a Thavendran Govender,e Tricia Naicker;a Per I Arvidssona,f*
Sulfonimidamides
and
Sul-
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a Catalysis and Peptide Research Unit University of KwaZulu Natal Durban, 4001 (South Africa)
b Discipline of Medical Biochemistry, University of KwaZulu-Natal, Durban, 4001 (South Africa)
c Division of Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, Maryland (USA)
d Biomedical Resource Unit, College of Health Science, University of KwaZulu-Natal, Durban, 4001 (South Africa)
e Ansynth Pty Ltd., 498 Grove End Drive, Phoenix, Durban, 4068 (South Africa)
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f Science for Life Laboratory Drug Discovery and Development Platform and Division of Translational Medicine and Chem-
ical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 171 77 (Sweden).
KEYWORDS: Trifluoromethylthio; Sulfonimidamide, Mycobacterium tuberculosis; Mycobacterium abscessus; Cytotoxici-
ty; Medicinal chemistry; Drug discovery
ABSTRACT: Herein we demonstrate the expanded utility of a recently described N-trifluoromethylthiolation protocol to sulfonim-
idamide containing substances. The novel N-trifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for
antibacterial activity against Mycobacterium tuberculosis (M. tb.) and Mycobacterium abscessus and Gram +Ve (Streptococcus
aureus, Bacillus subtilis) and Gram – Ve (Escherichia coli, Pseudomonas aeruginosa) bacteria. Two compounds, 13 and 15
showed high antimycobacterial activity with MIC value of 4-8 μg/mL; i.e. comparable to WHO recommended first line antibiotic
for TB infection ethambutol. The same compounds were also found to be cytotoxic in HepG2 cells (compound 13 IC50 = 15 µg/mL;
compound 15 IC50 = 65 µg/mL). A structure activity relationship, using matched pair analysis, gave the unexpected conclusion that
the trifluoromethylthio moiety was responsible for the cellular and bacterial toxicity. Given the increasing use of the trifluorome-
thylthio group in contemporary medicinal chemistry, this observation calls for considerations before implementation of the func-
tionality in drug design.
Drug resistant microorganisms are becoming a major threat
to human health and civilization. If we fail to overcome this
menace, we will re-enter an era where minor infections again
become lethal.1,2 Furthermore, the limited arsenal of new
antibiotics, and the declining global efforts in identification of
new chemical entities (NCEs) with antibiotic activity, enhance
the alarming spread of strains that are resistant to known
drugs.3,4 Mycobacterium tuberculosis (M. tb.) is the causative
agent of tuberculosis (TB), one of the world’s leading airborne
contagious diseases. According to the WHO report, it is esti-
mated that TB remained as one of the top infectious disease in
2017 with 10 million new infections and 1.6 million deaths!
Drug resistant strains of M. tb. threaten the health of millions
of people. Hence, urgent efforts are required to identify NCEs
with novel mechanism of actions and significant therapeutic
activities against both Gram-positive and Gram-negative bac-
teria as well as M. tb..
Analogously, contemporary medicinal- and agro-
chemistry make extensive use of fluorine and fluorinated
functional groups to optimize the pharmacological activity, not
least the metabolic stability, of small molecule drugs.8-12 The
trifluoromethylthio (-SCF3) functional group has rapidly
emerged as a potential substitute for the more common trifluo-
romethyl (-CF3) group. Some representative examples of bio-
logically active molecules containing a -SCF3 group are de-
picted in Figure 1.
NH2
O
N
O
N
O
O
F3CS
N
N
N
SCF3
N
F3CS
OH
NH2
O
N
H
O
HO
Adenosine analogue
OH
Methionine anlogue
Toltrazuril
(Coccidiostatics)
F3CS
O
OH
N
N
N
N
N
N
N
N
H
N
NK
N
SCF3
O
N
S
O
Sulfur containing molecules have historically played
S
N
H
SCF3
H
Tiflorex
(nervous anorexia treatment)
a vital role in pharmaceutical and agrochemical applications.5
Among these, the sulfonamide scaffold has been a central
functional group in molecules with a wide spectrum of biolog-
ical activities over a long time.6 Analogs of the sulfonamide
functional group, e.g. their mono aza-analogue sulfonimidam-
ides (SIAs), have recently gained attention as a sulfonamide
bioisostere.7
Cefazaflur
(cephalosporin antibiotic)
Losartan analogue
O
O
NR3
S
R1
R2
SCF3
Cyclic sulfenamide with SCF3
Figure 1: Active pharmaceutical ingredients containing a SCF3
group.
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ACS Medicinal Chemistry Letters
Notably, all compounds in Figure 1 contains C-SCF3 linkages;
Page 2 of 6
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to the best of our knowledge no biological activity of any
molecule with an N-SCF3 bond has been reported until
now.12,13 Although the electron-withdrawing properties of -CF3
(σm: 0.44) and -SCF3 (σm: 0.40) are similar, the lipophilicity of
the SCF3 moiety (clogP = 1.95 for Me-SCF3) is much higher
than that of the -CF3 group (clogP = 1.11 for Me-CF3). The
increased lipophilicity has been shown to increase membrane
permeability, and in some cases, improve the metabolic stabil-
ity of the final molecules.14 In this manuscript, we explore the
interesting combination of the SIA and the -SCF3 functional
groups, and report the unexpected anti-mycobacterial and
cytotoxic activity that was linked to the trifluoromethylthio
functional group.
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Methods for selective introduction of -CF3 or -SCF3
groups typically make use of toxic reagents and harsh experi-
mental conditions; still contemporary advances such as fluo-
rine exchange reactions and gaseous trifluoromethylthiolating
agents are noteworthy.15-17 Recently, much research has fo-
cused on using advanced electrophilic reagents such as N-
trifluoromethylthio phthalimide, N-trifluoromethylthio saccha-
rin, and trifluoromethanesulfanylanilides for introducing -CF3
and -SCF3 groups under mild conditions.18-22 To date there is
only one example of N-trifluoromethylthiolation of a S=N
functional group; Bolm and co-workers reported the prepara-
tion of N-trifluoromethylthio-sulfoximines through a two-step
“umpolung” protocol in which the sulfoximine (SI) was first
brominated to the corresponding N-bromo sulfoximine, which
Scheme 1. Synthesis of N-SCF3 substituted SIAs. The normal-
ly nucleophilic imine-N of SIA is subjected to “umpolung”
through bromination, and undergoes nucleophilic replacement
with the CF3S- anion.
In order to compare structure activity (SAR) relationships, we
also prepared a set of known -SCF3 and -CF3 functionalized
sulfoximines. N-Trifluoromethylthio analogs 21 and 2223 and
the N-trifluoromethyl derivatives 23 and 2428 were prepared
using Bolm’s procedure as shown in Scheme 2.
-
underwent nucleophilic attack by the SCF3 anion from silver
trifluoromethanethiolate (AgSCF3).23 We decided to explore
this methodology for trifluoromethylation of the related SIA
functionality.
The starting materials for these studies, i.e. SIAs 6a-e,24,25 11a-
d26 and SIs 21a & 22a were prepared according to published
procedures. Detailed descriptions of the synthetic sequences
are reported in the supporting information, Scheme S1 & S2.
Next, we employed Bolm´s procedure for trifluoromethylthio-
lation of SIs to these SIAs. First, silver trifluoromethanethio-
late (AgSCF3) was prepared by refluxing a suspension of AgF
in CS2.27 Initially, we used substrate 6a as a model for optimiz-
ing the protocol. SIA 6a was treated with N-bromosuccinimide
(NBS) to get its corresponding bromo derivative, which was
treated with AgSCF3 reagent (1.2 eq.) at room temperature.
Indeed product 12 was formed but the reaction was incom-
Scheme 2. Synthesis of known N-trifluoromethylthio- and N-
trifluoromethyl- sulfoximines for SAR analysis.
Up to now, N-trifluoromethylthiolated SIAs have
never been synthesized; consequently, any possible biological
activities of these compounds are yet to be explored. In this
direction, we subjected several of the novel SIAs (Schemes S1
& S2 SI) and SCF3-SIAs prepared in Scheme 1 & 2 for our
routine screen of antibacterial activity vs. the gram-positive
bacteria S. aureus and B. subtilis and the gram-negative bacte-
ria E. coli and P. aeruginosa. None of the SIAs with free
imine-NH (e.g. 6 or 11) displayed antibacterial activities.
Among the tested SCF3-SIAs, only compound 13 had note-
worthy activity vs. B. subtilis.
1
plete. Compound 12 was identified by 19F, H, 13C-NMR and
HRMS spectroscopy. The signals for CF3 group in SIA 6a
were found at δ -50.36 in the 19F, which is very similar to δ -
50.69 and δ -50.39 observed for the similar N-SCF3 sul-
foximines 21 and 22. In contrast, the 19F chemical shifts of
CF3 substituted sulfoximines 23 and 24 have been observed at
δ -41.83 and δ -40.97, respectively. Our efforts to expand
Bolm´s N-trifluoromethylthiolation protocol to SIA deriva-
tives proved successful without much additional optimization,
see SI information for our attempt to optimize the reaction
time. Using this methodology, we could prepare the novel N-
trifluoromethylthio SIAs 12-20 in Scheme 1.
Despite the poor antibacterial activity observed, a
few compounds were evaluated for efficacy against M. tb. and
M. abscessus (which are neither gram-positive nor gram-
negative). To our surprise, SCF3-SIAs 13 and 15 showed
potent activity vs. M. tb. with MIC as low as 4 µg/mL, which
is comparable to WHO recommended drugs for TB such as
ethambutol (1-4 µg/mL)29 or the carbapenem class of antibiot-
ics (meropenem 5-10 µg/mL).30 This promising discovery
made us prepare and evaluate related SCF3-SIs 21 and 22.
Indeed, these N-SCF3 functionalized analogs also proved to be
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potent inhibitors of M. tb. with MICs 4-8 µg/mL and with
vanced stage drug substances without known toxicity, e.g.
Figure 1. Notably, in all these advanced molecules, the -SCF3
group is situated on an aromatic ring, or in some cases on an
aliphatic carbon, i.e. with a C-SCF3 bond.
1
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selectivity over gram-positive and gram-negative bacteria,
Table 1. In addition to activity against M. tb., moderate activi-
ty against M. abscessus suggests that these compounds likely
exhibit selectivity towards mycobacteria.
Although a full understanding of the toxicity induced
by the -SCF3 functionality is beyond the scope of this article, it
is tempting to speculate that the N-SCF3 bond in SIAs and SIs
are labile and generate trifluoromercaptomethanol, or some
other derivative, that is responsible for the cell killing effect.
We observed no chemical instability of the N-SCF3 bond in
SIAs or SIs. Similarly, we could not detect a difference in
Cystein-adduct formation for the SCF3 SI 22 or the matched
CF3 SI 24, since no adducts were found for any of the com-
pounds (only attempted in the absence of metabolic activation,
see SI for details). We therefore hypothesize that a cellular
metabolic process is involved in the liberation of toxic species.
This assumption could also rationalize the difference in toxici-
ty seen for the gram-positive and gram-negative bacterial
strains tested and the M. tb and human cells. The compounds
found to be active on M. tb. and HEPG2, i.e. 13, 15, 21, and
22, also displayed the highest antibacterial activity vs. the
investigated strains, although far less potent than their activity
on M. tb. The difference in cellular toxicity can be rationalized
by a difference in metabolizing enzymes or susceptibility to
toxicity by the liberated toxicophore. Yet another observation
supporting the involvement of N-SCF3 bond stability in the
liberation of the toxicophore relates to the electronic nature of
the molecules. The M. tb. activity of the matched SIA pairs 14
vs. 17, 15 vs. 18, and 13 vs. 19 demonstrate that the strongly
electron withdrawing nitro-substituent always decrease the
compound´s antibacterial effect.
The activity of N-SCF3 functionalized SIAs 13 & 15
and SIs 21 & 22 versus M. tb., but not vs. gram-positive or
gram-negative bacteria, suggested that we had identified a
novel class of selective anti-tubercular agents. We therefore
profiled the substance´s cytotoxic effects on a human-derived
liver carcinoma cell line (HepG2). The MTT assay, a colori-
metric measure of cellular metabolic activity, measured cell
viability and extracellular lactate dehydrogenase (LDH) was
used as an indicator of necrotic cell death. Both compounds 13
(15 µg/mL; 20 µM) and 15 (65 µg/mL; 50 µM) reduced cell
viability in HEPG2 cells as evidenced by the MTT assay,
Table 1. Similarly, the SCF3 SIs 21 and 22 showed cytotoxici-
ty versus HepG2 cells, although at higher concentration for
compound 22 (90 µg/mL; 300 µM) than 21 (14 µg/mL; 50
µM). Interestingly, the SI analog 21a, which lacks the SCF3
group, only displayed toxicity above 650 µM.
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It appears from the above results, that the SCF3
group impose toxicity to both M. tb. and cells of human origin
when linked to the imine Nitrogen atom of sulfonimidamides
and sulfoximines. In order to better understand the SAR, we
prepared two known N-trifluoromethyl (CF3) sulfoximines, i.e.
23 & 24, and evaluated their activity on M. tb.. Intriguingly,
none of these compounds demonstrated any anti-M. tb. activi-
ty. Likewise, 23 and 24 lacked cytotoxicity vs. HepG2 cells.
This matched-pair analysis further supports the hypothesis that
the SCF3 functional group is responsible for the observed cell
toxicity. However, the -SCF3 moiety is present in many ad-
Table 1. Summary of Biological activities measured for -SCF3 Sulfonimidamide and Sulfoximines and -CF3 Sulfoximines
derivatives.
Entry
ATCC Strains (µg/mL)
MIC (µg/mL)
Cytotoxicity
Gram +Ve Gram –Ve
S. aureus
B. subtilis
E.coli
P. aerugino-
M. tb H37Rv
M. abscessus HEPG2
LDHa
sa
(µg/mL) (µg/mL)
6a
11c
12
13
14
15
16
17
-
-
-
-
-
>64
>64
-
>64
>64
-
-
-
-
-
-
-
-
32
32
32
8
128
128
256
512
-
-
4-8
>64
15
0.1
-
-
-
-
-
-
-
-
8-16
4-8
16-32
>64
-
-
65
0.1
64
32
>512
>512
256
-
-
-
-
128/256
128/256
128/256
16-32
32-64
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Page 4 of 6
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19
32
32
64
64
-
-
>64
32-64
16-32
-
-
-
1
2
3
4
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6
7
8
>512
>512
16-32
-
-
20
32/64
>512
16
16/32
>512
-
>512
>512
16-32
16-32
-
-
-
>512
21a
>100
15
100
0.1
16
16
16
128
256
21
22
23
4-8
>64
32
256
90
1
-
9
4-8
>64
-
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>512
>512
>512
>512
>512
>512
>512
>512
>64
>200
200
>64
-
200
24
-
= Not analyzed; aLowest concentration where LDH
release was observed
Author contributions
NT, PM, KKR and TN performed synthesis and compounds
characterization; SN, NSA and AAC performed and super-
vised cytotoxicity measurements, AK and GL performed TB
testing, AMS, HGK, and TG performed and supervised anti-
bacterial testing, PIA initiated the project and wrote the manu-
script together with NT, PM, and TN. All authors contributed
to the final version.
In summary, we have demonstrated that the trifluoromethyl-
thiolation protocol initially developed for sulfoximines can be
expanded to sulfonimidamide substrates. We also report an
unexpectedly high activity of N-trifluoromethylthiolated sul-
fonimidamides (SIAs) and sulfoximines (SIs) versus M. tb. –
the causative pathogen of TB – the most widespread infectious
disease that is responsible for millions of deaths every year.
Further exploration of this finding demonstrated that both N-
SCF3 substituted SIAs and SIs display cytotoxicity versus cells
of human origin, but more modestly vs. gram-positive and
gram-negative bacteria. Comparison with the corresponding
N-CF3 substituted SIs suggests that the SCF3 functionality is
responsible for the toxicity. As far as we know, the present
study is the first report of biological activity of N-SCF3 deriva-
tives and the results obtained are of particular importance
given the high utilization of the -SCF3 group in contemporary
drug design!
Acknowledgements & Funding sources
This work is based on the research supported in part by the
National Research Foundation of South Africa for the Grant
87706. The Medicinal Research Council and the UKZN-
School of Health Sciences is gratefully acknowledged for
assistance with HRMS and postdoctoral fellowships to N. T
and P. M., respectively. Activity evaluation against mycobac-
teria spp was supported by National Institutes of Health, USA
award R33AI111739 to G.L.
Conflict of Interest
The authors have no conflict of interest to disclose.
ASSOCIATED CONTENT
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mation is available free of charge on the ACS Publications
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AUTHOR INFORMATION
Corresponding Author
*E-mail: per.arvidsson@scilifelab.se.
Present Addresses
†Department of Drug Design and Pharmacology Faculty of
Health and Medical Sciences University of Copenhagen, Uni-
versitetsparken 2, 2100 Copenhagen, Denmark.
‡Chemical Science Research Group, Division of Research and
Development, Lovely Professional University, Phagwara,
Punjab, 144411. India.
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