Chemical Papers
et al. 2007). For the treatment of cognitive dysfunction and
AD-associated memory loss, there are a number of synthetic
drugs currently available, which are the AChE inhibitors
such as rivastigmine, tacrine, and donepezil (Mukherjee
et al. 2007; Oh et al. 2004). According to the literature
results, the commonly used the AChE synthetic inhibitors
have been shown to have side eꢀects such as gastrointesti-
nal disturbance and hepatotoxicity, while the sulfonamides
used have no side eꢀects (Köksal et al. 2019). Sulfonamides,
which are important bioactive compounds with many bio-
logical effects such as diuretic, antitumor, antithyroid,
antibacterial, anti-carbon anhydrase, antidiabetic, hypogly-
cemic, and protease inhibitor activity, have been found to
be beneꢁcial in AD. The sulfonamide derivatives used for
symptomatic treatment of AD has inhibited the formation of
amyloid-β which occurred by a β-amyloid precursor protein
the highest HOMO energy have the probability to strongly
inhibiting the receptor. In addition, the compounds with
smaller HOMO–LUMO energy gaps tend to be more active
(Sakkiah and Lee 2012). Based on their high HOMO values
and small energy gaps, S2 and S4 (−8.21 eV for S2 and S4)
were assumed to be of interest. The MW of all the 4-amin-
obenzenesulfonamide derivatives was determined to be less
than 500 and hence predicting their easy absorption, dis-
tribution, metabolism, and excretion (recommended value:
130–725). All these physicochemical and pharmacokinetic
properties, as displayed in Table 2, are the compatibility
with Lipinski’s rule of ꢁve and thus making all these com-
pounds as good orally potent AChE inhibitors. In addition,
computed toxicity analysis results of compounds indicated
that derivatives were relatively safe and it was displayed
that there was a similarity between these agents and some
known central nervous system drugs, such as galantamine,
rivastigmine, tacrine, and donepezil (Wager et al. 2010). The
results suggested that the derivatives had no risk as a poten-
tial drug temporarily.
(
APP) (Bag et al. 2015).
In the context of this information, we investigated the
eꢀects of synthesized sulfonamide derivatives (S1–S4 and
S1i–S4i) on AChE enzymes. The molecular docking studies
were performed to determine the probable binding mecha-
The analysis of interactions between all derivatives and
the binding site of 4M0E is shown in Table 3. All the deriva-
tives in the series were active. Three compounds S2, S4i,
and S4 showed the highest Glide Gscores (−8.24, −7.84,
and −7.83, respectively) among all the derivatives. Dock-
ing study of compounds S2, S4i, and S4 into the active site
of target indicated that several molecular interactions were
supposed to be accountable for the remarkable aꢃnity of
these compounds.
nism. In this study, the K parameters of the sulfonamide
i
derivatives (S1–S4 and S1i–S4i) were determined with
Lineweaver–Burk graphs (1/V−1/[S]).
In our results, 4-((3,5-dibromo-2-hydroxybenzylidene)
amino)benzenesulfonamide (S2) has a high inhibitory eꢀect
than other derivatives. Inhibition type was found for sulfona-
mides derivatives (S1–S4 and S1i–S4i). The S1, S1i, S3,
and S3i derivatives have shown competitive inhibition type,
and K values were found to be 299.60± 8.04, 116.25± 2.12,
Recently, new inhibition studies from newly synthesized
derivatives have been performed in large numbers. In a
study on Benzoxazole, substitution derivatives worked on
the replacement of the indanone ring of donepezil with a
benzisoxazole ring system. Some compounds synthesized
from N-benzylpiperidine benzisoxazole derivatives showed
a high eꢀect of AChE inhibitory with the IC value of
i
2
03.76± 4.97, and 298.94± 7.49 µM, respectively. Accord-
ing to the results, the sulfonamide derivatives (S1, S1i, S3,
and S3i) may be attached to the functional ends of the amino
acids in the active site of the AChE enzyme. The S2, S2i, S4,
and S4i have shown a mixed-type inhibition and K values
i
were found to be 2.54± 0.22, 5.12± 0.10, 5.19± 0.44, and
5
0
4
.50 ± 0.31 µM, respectively (Table 1). According to this
0.8–14 nM. Moreover, the obtained compound, 1,2,4-thi-
adiazolidinone-substituted derivatives showed more selec-
tivity to the AChE (IC : 0.14 µM) when the donepezil
result, the derivatives (S2, S2i, S4, and S4i) can bind to
the enzyme substrate complex or free enzyme and lead to
inhibition. In this study, the molecular docking studies were
performed to determine the probable binding mechanism
of S1–S4 and S1i–S4i derivatives into the active site of the
AChE.
5
0
indanone system is replaced with the 1,2,4-thiadiazolidone
ring (Martinez et al. 2000). Andreani et al. has been shown
that alternative benzylpiperidinone substitution derivatives
have AChE inhibitory potential (IC : 8 µM) when the done-
50
Drug-likeness is a shred of evidence which deꢁnes an
integrated equilibrium between many molecular properties
and structural features, such as Lipinski’s rule of ꢁve, IC
pezil indanone system is replaced with substitution indole or
pyrol ring (Andreani et al. 2001). Benzophenone derivatives
which contain the N,N-benzyl methylamine as tertiary amino
function and benzophenone nucleus as an aromatic func-
tion also have high AChE inhibitory potential (Belluti et al.
2009; Singh et al. 2013). In another study on the inhibitory
eꢀect of sulfonamide derivatives on AChE and butyrylcho-
linesterase (BuChE), a series of new biphenyl bis-sulfona-
mide derivatives showed in vitro inhibition eꢀect. The IC
5
0
+
value for blockage of HERG K channels, Caco-2 cell per-
meability, MDCK cell permeability, and number of likely
metabolic reactions, which describe whether a speciꢁc agent
is comparable to already recognized medicates. In addition,
HOMO (electron donor) and LUMO (electron acceptor)
orbitals are responsible for charge transfer during a chemi-
cal reaction (Eroglu and Türkmen 2007). The ligands with
5
0
values of new biphenyl bis-sulfonamide derivatives were
1
3
I??k, Mesut
