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S. K. SAMANTA ET AL.
Toxicity and hence lethal effect of H2S are attributed
as it is a colourless, highly water-soluble, and flam-
mable gas with an unpleasant rotten egg smell (13).
So, the irregular levels of H2S are strictly related to
many diseases, for example, slow growth, Alzheimer’s
disease, cardiovascular disease, Down’s syndrome, dia-
betes, osteoporosis, leucocyte loss, cancer, and liver
Therefore, to better comprehend the role of H2S in
pathological and physiological processes, the recognition
of H2S has become a vital topic of scientific research,
especially in biological systems (21). A number of analy-
tical techniques have been reported for the detection of
H2S, like gas chromatography and electrochemical (22)
and colorimetric (23) methods. But, due to the short life-
time of H2S in live cells, these approaches experience
complications in preserving precision and real-time
imaging.
Recently, fluorescent chemodosimeters have fascinated
a considerable devotion due to the benefit of high sensi-
tivity, selectivity, and real-time detection (24–26). To date,
lots of fluorescent sensors for H2S have been reported so
far. Mostly, reduction of azide and nitro functionality,
nucleophilic addition, and coppersulfide precipitation-
based fluorescent probes have been reported for H2
S detection (27–41). These sensors are highly efficient at
the task they are designed to perform. However, there is
still room for new ideas in this field. Cleavage of dinitro-
phenyl ether group has become an interesting approach
for H2S detection. Some design strategies relied on intra-
molecular cyclisation followed by regeneration fluorescent
moiety. In a few cases, S2- were recognised in terms of
secondary analyte detection from a metal-bound ensem-
ble. Recently, dinitrophenyl ether group incorporated into
a lysosome-targeted 1,8-naphthalimide fluorophore for
live cell imaging of H2S has been reported by Tang et al.
(42). A mitochondria-targeted fluorescent sensor for detec-
tion of H2S has been explored by Yoon et al., where the
response time is 40 min (43). Merocyanine-based fluores-
cent chemodosimeters for the detection of H2S over other
interfering biothiols have been synthesised by three inde-
pendent groups of authors, namely, Guo, Zhao and
Goswami et al. (44–46). In their strategy, an electrophilic
indolium part of merocyanine unit is responsible for the
facile nucleophilic reaction of S2-/SH− which is accompa-
nied by a change in optical properties. Recently our group
reported a merocyanine-based dual-reactive centre for H2
S, wherein the low the H2S concentration, the more reac-
tive indolium moiety was reacted and then the dinitrophe-
nyl-ether part was cleaved upon increasing the analyte
concentration (47). As manifested by Holmes et al. that at
a physiological pH, simple thiols can react readily with
some Michael acceptors. But, due to fast equilibrium, the
products could not be obtained or recognised from the
reaction mixture (48). Anchored in Holmes’ fallout, we
proposed that, due to the high reactivity of H2S over the
biothiols, certain Michael acceptors might be helpful to
distinguish H2S from biological thiols by stimulating the
intramolecular cyclisation reaction at physiological pH. For
instance, biothiols have a nucleophilic sulfhydryl group (–
SH) and the pKa of H2S (6.9) is lower than that of Hcy (8.9),
Cys (8.3), or GSH (9.2), demonstrating that H2S has a higher
nucleophilicity than other biothiols under physiological
conditions. Therefore, it is effortless to discriminate Hcy/
Cys/GSH from H2S simply via nucleophilic reaction-based
strategies in physiological media. In this respect, Xian
group has successfully developed this type of fluorescent
chemosensors for the selective detection and bioimaging
of H2S (49). Nevertheless, in Table S7, (50-57) we have
compared some recent H2S probes with our probe in
different aspects.
Detection of H2S through the formation of S-
heterocycle, coupled with indole in a ratiometric manner.
Herein, we have designed a 3-indolylacrylate deriva-
tive, 3-IA, by connecting an ethyl acrylate in 3-position of
indole as Michael acceptor and an ester group ortho to
ethyl acrylate was employed as a specific function for
cyclisation via intramolecular nucleophilic attack. In parti-
cular, ratiometric fluorescent probes are always favoured
to ‘on-off’ or ‘off-on’ response as they are able to evade
fake detection and improved signal-to-noise ratio as the
detection occurs by using the intensity ratio of two differ-
ent wavelengths. The philosophy of the design lies in that
the methylene malonate will trap H2S through Michael
reaction to yield an intermediate 3-IASH moiety, which
can undergo tandem intramolecular nucleophilic attack
on the reactive ester carbonyl group, present in suitable
position, through a five-membered cyclic transition state,
illuminating blue to green emission. Thus, the design
strategy revealed a route for the synthesis of the indole–
thiophene-coupled new heterocyclic compound. In
adddition to this no ratiometric fluorescent response
was observed when probe 3-IA reacts with other biothiols.
Based on the above reaction strategy, highly discrimina-
tive detection of H2S over other biothiols can be succes-
sively employed. However, the detection limit is not as
impressive as that of some other reported H2S probe (58).
The sensing mechanism involving nucleophilic attack at
electrophilic centre leading to cyclisation that ultimately
leads to ratiometric fluorescent spectral changes is an
important aspect of this work. Most importantly, our
design strategy is completely different from those