Synthesis and comparative carbonic anhydrase inhibition of new Schiff's bases incorporating benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds

Article abstract of DOI:10.1016/j.bioorg.2019.103225

Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff's bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (K_I) in the range 93.5–428.1 nM (AAZ and SLC-0111: K_I, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with K_I ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: K_I, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with K_I in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (K_I, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with K_I values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: K_I, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.

Full text of DOI:10.1016/j.bioorg.2019.103225

BioorganicChemistry92(2019)103225
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis and comparative carbonic anhydrase inhibition of new Schiff’s
bases incorporating benzenesulfonamide, methanesulfonamide, and
methylsulfonylbenzene scaffolds
⁎
Adel S. El-Azaba, , Alaa A.-M. Abdel-Aziza, Silvia Buab, Alessio Nocentinib,
Mohammed M. Alanazia, Nawaf A. AlSaifa, Ibrahim A. Al-Suwaidana, Mohamed M. Hefnawya,
⁎
Claudiu T. Supuranb,
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
b Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly syn-
thesized Schiff’s bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaf-
folds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to
those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for
the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (KI) in
the range 93.5–428.1 nM (AAZ and SLC-0111: KI, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a
proved to be effective hCA II inhibitors, with KI ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: KI, 12.0 and
960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with KI in the range 8.5–24.9 nM; these
values are superior or equivalent to that of AAZ and SLC-0111 (KI, 25.0 and 45.0 nM, respectively). Compounds
4a–8a displayed effective hCA XII inhibitory activity with KI values ranging from 8.6 to 43.2 nM (AAZ and SLC-
0111: KI, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micro-
molar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.
Synthesis
Schiff’s base
Benzenesulfonamide
Carbonic anhydrase inhibition
Acetazolamide
Molecular docking
1. Introduction
with strong and selective CA II/XII inhibition is necessary [7].
Sulfonamides are the most effective compounds as CA inhibitors
The zinc enzyme, carbonic anhydrase (CA, EC 4.2.1.1), plays vital
physiological roles [1] by catalyzing the simple interconversion be-
tween carbon dioxide and bicarbonate. Inhibitors of this enzyme are
used to treat many diseases, including glaucoma [2], various neurolo-
gical disorders [3], gastroduodenal ulcers, and acid-base disequilibria
[4]. Although sulfonamides (i.e., CA inhibitors) such as acetazolamide
were developed several decades ago for clinical use, only few display
high selective human (h) CA isozyme inhibition; to date, 15 hCAs have
been described. Isoenzyme selectivity is a crucial factor for inhibitors
such as SLC-0111 (Fig. 1), a new antitumor/anti-metastatic sulfona-
mide in Phase II clinical trials for the management of advanced meta-
static solid tumors [5]. Synthesis of new CA inhibitors with high spe-
cificity toward certain hCA isozymes is thus a critical goal [6].
Compounds designed as antitumor treatments should efficiently inhibit
isoenzymes CA IX/XII and not the off-targets, CA I and II, to reduce the
side effects of the drug. Hence, the design of antiglaucoma compounds
[6]. However, some sulfonamides such as celecoxib, are cyclooxygenase
(COX) inhibitors, while others are antitumor and antibacterial agents
[6,8–13]. Sulfonamide-linked chalcone derivatives I (Fig. 1) display
strong hCA I and CA II inhibitory activities with KI values of 9.88–24.4
and 20.0–55.43 nM, respectively [14]. Interestingly, phenols containing
amines, such as dopamine II (Fig. 1), have interesting hCA I and CA II
with KI values of 13.5 and 9.2 μM, respectively [15]. Phenols containing
acrylic acid III (Fig. 1) showed hCA I, CA II, hCA IX, and CA XII in-
hibition with KI values of 1.07–2.89, 0.98–2.40 μM, 5.33–9.87, and
8.01–9.78 μM, respectively [16]. Furthermore, mono, di, or tri-bromo-
4-((methylsulfonyl)methyl)benzene-1,2-diol IV (Fig. 1) displayed good
hCA I and CA II inhibition with KI values of 58.16–83.04 and
45.04–58.34 nM, respectively, while 3-hydroxybenzoic acid and 3,5-
dihydroxybenzoic acid V (Fig. 1) inhibited hCA I and CA II with KI
values of 0.55–2.37 and 0.51–0.60 μM, respectively [17]. Recently, hCA
I was reported to be selectively inhibited by hydrazinecarbothioamide
⁎ Corresponding authors.
E-mail addresses: adelazab@ksu.edu.sa (A.S. El-Azab), claudiu.supuran@unifi.it (C.T. Supuran).
https://doi.org/10.1016/j.bioorg.2019.103225
Received 26 May 2019; Received in revised form 25 August 2019; Accepted 27 August 2019
Availableonline28August2019
0045-2068/©2019ElsevierInc.Allrightsreserved.

A.S. El-Azab, et al.
BioorganicChemistry92(2019)103225
Fig. 1. The reported carbonic anhydrase (CA) inhibitors (SLC-0111 and I–X) and the designed Schiff’s bases, 4–18.
derivatives VI (Fig. 1) with KI values of 43.9–86.4 nM [18]. The hCA II
was also selectively inhibited by Schiff’s bases containing benzoic acid
and benzenesulfonamide moieties VII (Fig. 1) and displayed KI values
between 79.9 and 236.0 nM [19]. The Schiff’s base derivatives of 4-(2-
aminoethyl)- benzenesulfonamide VIII (Fig. 1) showed versatile in-
hibition against CAs I, II, IX, and XII with KIs of 393.0–453.0,
374.0–474, 39.1–138.0, and 46.8–3115 nM, respectively [7]. Several
Schiff’s bases of isoindoline-1,3-dione-linked benzenesulfonamide IX
(Fig. 1) showed selective inhibition of the tumor-associated CA IX with
KIs ranging from 17.3 to 164.3 nM [6a]. Just recently, hCAs I, II, and IX
were demonstrated to be inhibited by 4-[(3-oxo-3-arylprop-1-en-1-yl)
amino]benzenesulfonamides X (Fig. 1) with KIs of 30.80–323.10 nM,
0.48–8.70 nM, and 0.22–0.31 nM, respectively [20].
Recently, we reported the CA inhibitory activities of isoindoline-1,3-
dione bearing benzenesulfonamides [6,8–10,11a]. In the present study,
we aimed to report: (i) the synthesis of new derivatives of phenolic
Schiff’s bases containing benzenesulfonamide, methanesulfonamide,
and methylsulfonylbenzene moieties (Fig. 1: 4–18), (ii) evaluation re-
sults for the CA inhibitory activity of these compounds on isoenzymes
hCAs I, II, IX, and XII; (iii) the structure-activity relationships of these
Schiff’s bases with various substituents; (iv) the effectiveness of ben-
zenesulfonamide relative to methanesulfonamide and methylsulfo-
nylbenzene for the inhibition of CA isoforms I, II, IX, and XII, and (v)
molecular docking results for the docking of the target molecules into
the putative binding site of CA isoforms I, II, IX, and XII.
2

A.S. El-Azab, et al.
BioorganicChemistry92(2019)103225
Scheme 1. Synthesis of new Schiff’s bases.
amount of acetic acid at room temperature (Scheme 1). Multiple spectral
analyses were performed to confirm the structures of the target com-
pounds. The newly synthesized compounds were confirmed by an amide
fragment from the benzylidene benzohydrazide moiety (ArCON-
HeN]CHAr) by 1H NMR with a peak for the amidic protons at
12.32–11.59 ppm and 13C NMR with characteristic peaks at 162.92–160-
23 ppm for the carbonyl groups. Additionally, the imine fragment of the
benzylidene benzohydrazide moiety (ArCONHeN]CHAr) was verified
by 1H NMR with a peak at 8.69–8.34 ppm and 13C NMR spectra with
characteristic peaks at 150.81–147.03 ppm. The phenolic OH group was
verified by a singlet peak at 11.37–9.63 ppm in the 1H NMR spectrum
while the amino group of the 4-aminosulfonyl moiety (-SO2NH2) for
compounds 4a-8a was verified by a peak at 7.57–7.53 ppm in the 1H
NMR spectrum. The amino and methyl groups of the 4-methanesulfo-
namide moiety (-NHSO2CH3) of compounds 9b-13b were verified by
respective peaks at 11.35–9.58 and 3.12–3.10 ppm in the 1H NMR
spectrum, while the methyl group of the 4-methanesulfonamide moiety
(-NHSO2CH3) was validated by peaks at 40.42–40.26 ppm in the 13C
NMR spectrum. The methyl group of the 4-methylsulfonyl moiety
Table 1
Inhibition data of human CA isoforms hCA I, II, IX and XII with compounds
reported here and the standard sulfonamide inhibitor acetazolamide (AAZ) and
SLC-0111 by a stopped flow CO2 hydrase assay [23].
Cmpd
KI (nM)a
hCA I
hCA II
hCA IX
hCA XII
4a
117.2
428.1
93.5
26.8
18.9
15.8
23.3
24.9
8.5
32.7
8.6
5a
65.5
6a
18.2
43.2
25.6
9.7
7a
130.8
234.4
> 100
> 100
55.0
58.5
8a
133.3
> 100
> 100
5.6
9bb
> 100
> 100
1.4
> 100
> 100
6.3
10bb
11bb
12bb
13bb
14cb
15cb
16cb
17cb
18cb
AAZ
SLC-0111
84.0
10.0
1.8
4.7
> 100
> 100
> 100
69.7
28.7
10.0
> 100
> 100
4.6
> 100
> 100
> 100
7.8
> 100
> 100
4.6
47.8
14.0
5.0
5.9
> 100
250.0
5080.0
42.0
45.0
25.0
45.0
> 100
5.7
(-SO2CH3) of compounds 14c-18c was verified by
a peak at
3.32–3.29 ppm and 43.77–43.71 ppm in the 1H NMR and 13C NMR
spectra, respectively.
12.0
960.0
4.5
a
Mean from three different assays, by a stopped flow technique (errors were
5–10% of the reported values).
Data are in μM.
2.2. CA inhibitory activity
in the range of
b
The CA inhibitory activity of the newly synthesized compounds (4a-
8a, 9b–13b, and 14c–18c) against hCA isoforms I, II, IX, and XII was
measured and compared to that of acetazolamide (AAZ) and SLC-0111,
which are standard sulfonamide inhibitors (Table 1) [23].
2. Results and discussion
2.1. Chemistry
For the inhibitory activity of CA toward single hCA isoforms, hCA I
was found to be potently inhibited by compounds 4a–8a with inhibition
constant (KI) values ranging from 93.5 to 428.1 nM (AAZ and SLC-
0111: KI, 250.0 and 5080 nM, respectively). Compounds 11b, 12b,
16c, and 17c showed weak hCA I inhibitory activity with KI values of
47.8–84.0 μM. In contrast, 9b, 10b, 13b, 14c, 15c, and 18c had no
inhibitory activity with KIs > 100 μM (Table 1). Compounds 4a–8a
proved to be effective hCA II inhibitors (KI, 18.2–133.3 nM) as they
almost displayed equal potency to AAZ (KI, 12.0 nM) but had better
The acid hydrazides (3a-c) were obtained by reacting esters 2a-c with
hydrazine hydrate according to a reported procedure [6a,21,22]. The 4-
[2-(2,3 and 4-hydroxybenzylidene)hydrazine-1-carbonyl]benzenesulfo-
namides (4a–8a), 4-(2-(2,3 and 4-hydroxybenzylidene)hydrazine-1-car-
bonyl)phenyl)methanesulfonamides (9b–13b), and 2,3 and 4-hydro-
xybenzylidene)-4-(methylsulfonyl)benzohydrazides
(14c–18c)
had
yields of 84–95% when the appropriate aldehyde was mixed with the 4-
substituted-benzohydrazides (3a–c) in methanol containing a catalytic
3

A.S. El-Azab, et al.
BioorganicChemistry92(2019)103225
values than SLC-0111 (KI, 960.0 nM). Compounds 11b–13b and
16c–18c showed weak hCA II inhibitory activity with KI values of
4.6–42.0 μM. In contrast, 9b–10b and 14c–15c had no inhibitory ac-
tivity with KIs > 100 μM (Table 1). For hCA IX inhibition, compounds
4a–8a proved to be potent inhibitors (KI values of 8.5–24.9 nM), with
values greater than or equal to those of AAZ and SLC-0111 (KI, 25.0
and 45.0 nM, respectively). Compounds 11b–13b and 16c–18c showed
weak inhibitory activity with KIs from 1.4 to 45.0 μM while 9b–10b and
14c–15c had no inhibitory activity with KIs > 100 μM (Table 1). For
hCA XII inhibitory activity, compounds 4a–8a displayed effective in-
hibition with KI values ranging from 8.6 to 43.2 nM; these values were
comparable to AAZ and SLC-0111 (KI, 5.7 and 4.5 nM, respectively).
Compounds 11b–12b and 16c–17c showed weak inhibitory activity
with KIs from 4.7 to 7.8 μM while compounds 9b, 10b, 13b, 14c, 15c,
and 18c had no inhibitory activity with KIs > 100 μM (Table 1).
corresponding 3-hydroxybenzylidene derivative 6a (KI, 24.9 nM)
and 4-hydroxybenzylidene derivative 7a (KI, 130.8 nM), while the
3-hydroxybenzylidene derivative 6a (KI, 24.9 nM) is more potent
than the 4-hydroxybenzylidene derivative 7a (KI, 130.8 nM); and
4) the 4-hydroxy-3-methoxybenzylidene derivative 8a (KI, 8.5 nM)
is more potent than the 4-diethylamino-2-hydroxybenzylidene
derivative 5a (KI, 15.8 nM).
(V) For hCA XII inhibition, analysis of the structure-activity relation-
ship of the 4-(2-(2-substituted-benzylidene)hydrazine-1-carbonyl)
benzenesulfonamide derivatives 4a–8a indicated that: 1) the 4-
diethylamino-2-hydroxybenzylidene derivative 5a (KI, 8.6 nM) is
more potent than the substituted-benzylidene derivatives 4a, 6a,
7a and 8a (KI, 9.7–43.2 nM); 2) the 4-hydroxybenzylidene deri-
vative 7a (KI, 25.6 nM) is more potent than the corresponding 2-
hydroxybenzylidene derivative 4a and 3-hydroxybenzylidene de-
rivative 6a (KI, 32.7 and 43.2 nM, respectively); 3) the 4-diethy-
lamino-2-hydroxybenzylidene derivative 5a (KI, 8.6 nM) is more
potent than the 4-hydroxy-3-methoxybenzylidene derivative 8a
(KI, 9.7 nM); and 4) 2-hydroxybenzylidene derivative 4a (KI,
32.7 nM) is more potent than the corresponding 3-hydro-
xybenzylidene derivative 6a (KI, 43.2 nM).
2.3. Structure-activity relationship analysis
(I) Based on the inhibition results for the hCA isoforms using com-
pounds 4a–8a, 9b–13b, and 14c–18c, the 4-(2-(2-substituted-
benzylidene)hydrazine-1-carbonyl)benzenesulfonamides (4a–8a)
were more active than the corresponding N-(4-(2-(substituted-
benzylidene)hydrazine-1-carbonyl)phenyl)methanesulfonamides
(9b–13b) and N′-(substituted-benzylidene)-4-(methylsulfonyl)
benzohydrazides (14c–18c) (Table 1).
2.4. Molecular docking studies
Molecular modeling techniques are important tools for theoretically
revealing the biological activities of target molecules and for gaining
structural insights for the design of novel therapeutic agents [24–27].
Molecular docking was therefore performed with MOE 2008.10 soft-
ware (Chemical Computing Group Inc.) according to the standard
protocol and the MOE’s pose viewer utility [28]. The crystal structures
of the CA isozymes with their co-crystallized inhibitors were obtained
from protein data bank (PDB).
(II) For hCA I inhibition, analysis of the structure–activity relationship
of the 4-(2-(2-substituted-benzylidene)hydrazine-1-carbonyl)ben-
zenesulfonamide derivatives 4a–8a indicated that: 1) 4-(2-(3-hy-
droxybenzylidene)hydrazine-1-carbonyl)benzenesulfonamide (6a)
with KI of 93.5 nM, is more active than the corresponding 2-hy-
droxybenzylidene derivative 4a (KI; 117.2 nM) and 4-hydro-
xybenzylidene derivative 7a (KI, 130.8 nM), while the 2-hydro-
xybenzylidene derivative 4a (KI, 117.2 nM) is more potent than
the 4-hydroxybenzylidene derivative 7a (KI, 130.8 nM); 2) in-
troducing an N,N-diethylamino or a 3-methoxy group in the hy-
droxybenzylidene moiety (e.g., 5a and 8a) decreases the potency
of hCA I inhibition (KIs, 428.1 and 234.4 nM, respectively); (4-(2-
(4-(diethylamino)-2-hydroxybenzylidene)hydrazine-1-carbonyl)
benzenesulfonamide (5a) (KI, 428.1 nM) is more active than 4-(2-
(4-hydroxy-3-methoxybenzylidene)hydrazine-1-carbonyl)benze-
nesulfonamide (8a) (KI , 234.4 nM).
2.4.1. Molecular docking with hCA I and hCA II
Molecular docking was used to study the interaction between
compound 6a (the most active) and hCA I, and hCA II as well as identify
the best binding (Fig. 2). The co-crystallized inhibitors 2,3,5,6-tetra-
fluoro-4-(propylthio)benzenesulfonamide and 4-{[(4- fluorophenyl)
carbamothioyl]amino}benzene-1-sulfonamide with the corresponding
hCA I and hCA II isozymes, respectively, were retrieved from Protein
Data Bank (pdb entries: 4WR7, and 5ULN, respectively) [29].
The results of the docking of compound 6a into the catalytic active
site of CA I (Fig. 2, upper panel) and CA II (Fig. 2, lower panel) showed
that the benzenesulfonamide scaffold traveled deep into the catalytic
site and the zinc ion was coordinated by the negatively charged
SO2NH– moiety. Moreover, the sulfonamide group formed two addi-
tional hydrogen bonds with Thr199 (2.97 Å and 3.01 Å with CA I and
2.86 Å and 3.06 Å with CA II). The benzenesulfonamide ring had a
hydrophobic interaction with Leu198, His200 (CA I), and Val121 (CA
II). The extended structure of N-benzylidene-3-hydroxybenzohydrazide
on the hydrophobic part of CA I interacts with Phe91, Leu131, Ala135,
and Ala132 from one side and Tyr204 and Pro202 from the other side.
On the other hand, the extended tail structure of compound 6a was
located on the hydrophobic part of CA II in a direction opposite to that
of the tail of the co-crystallized ligand that formed contacts with
Phe131, Ile91, Thr200, Pro201, and Pro202. The carbonyl group (C]
O) of N-benzylidene-3-hydroxybenzohydrazide forms a weak hydrogen
bond with CH-Aromatic group of Phe91 (3.04 Å) in CA I, while a hy-
drogen bond with Pro201 mediated by HOH601 was formed for CA II.
Finally, the 3-hydroxyl moiety formed a strong H-bond with Tyr204
(2.49 Å) for CA I, while the Gln92 in CA II interacted with the NH group
of the N-benzylidene-3-hydroxybenzohydrazide fragment by a H-bond
(3.12 Å).
(III) For hCA II inhibition, analysis of the structure–activity relation-
ship of the 4-(2-(2-substituted-benzylidene)hydrazine-1-carbonyl)
benzenesulfonamide derivatives 4a–8a indicated that: (1) the 3-
hydroxybenzylidene derivative 6a (KI, 18.2 nM) is more active
than the corresponding 2-hydroxybenzylidene derivative 4a (KI,
26.8 nM) and 4-hydroxybenzylidene derivative 7a (KI, 58.5 nM),
while the 2-hydroxybenzylidene derivative 4a (KI, 117.2 nM) is
more potent than the 4-hydroxybenzylidene derivative 7a (KI,
130.8 nM); (2) introducing the N,N-diethylamino or 3-methoxy
group in the hydroxybenzylidene moiety (e.g., 5a and 8a) leads to
a decrease in the potency of hCA II inhibition (KI, 65.5 and
133.3 nM, respectively), while (4-(2-(4-(diethylamino)-2-hydro-
xybenzylidene)hydrazine-1-carbonyl)benzenesulfonamide (5a) (KI
value, 65.5 nM) is less active than 4-(2-(4-hydroxy-3-methox-
ybenzylidene)hydrazine-1-carbonyl)benzenesulfonamide (8a) (KI
value, 133.3 nM).
(IV) For hCA IX inhibition, analysis of the structure–activity relation-
ship of the 4-(2-(2-substituted-benzylidene)hydrazine-1-carbonyl)
benzenesulfonamide derivatives 4a–8a indicated that: 1) the 4-
hydroxy-3-methoxybenzylidene derivative 8a (KI, 8.5 nM) is more
active than the substituted-benzylidene derivatives 4a–7a (KI,
15.8–24.9 nM); 2) the 4-diethylamino-2-hydroxybenzylidene de-
rivative 5a is more active than the substituted-benzylidene deri-
vatives 4a, 6a, and 7a (KI, 18.9–24.9 nM); 3) the 2-hydro-
xybenzylidene derivative 4a (KI, 18.9 nM) is more potent than the
2.4.2. Molecular docking with tumor-associated hCA IX and hCA XII
The docking interactions between compound 8a (the most active
4

A.S. El-Azab, et al.
BioorganicChemistry92(2019)103225
Fig. 2. Left: Three-dimensional binding interactions between compound 6a (red color) and both hCA I (upper panel) and hCA II (lower panel). Right: Compound 6a
(red color) superimposed on the co-crystallized inhibitors (magenta and blue colors) inside the pockets of the active site. Hydrogen bonds are represented as a blue
line.
derivative) and hCA IX, and compound 5a (the most active derivative)
and hCA XII were assessed in silico (Fig. 3). The putative binding sites
on hCA IX and hCA XII with the co-crystallized inhibitors 5-(1-naph-
while the 2-hydroxyphenyl fragment of compound 5a in CA XII formed
two additional H-bonds with Ser132 and Ser135 via HOH1646.
thalen-1-yl-1,2,3-triazol-4-yl)thiophene-2-sulfonamide
and
acet-
3. Conclusion
azolamide respectively, were retrieved from Protein Data Bank (pdb
entries: 5FL4, and 1JD0, respectively) [30].
A new series of substituted Schiff’s base 4a–8a, 9b–13b, and
14c–18c was synthesized and evaluated for their in vitro hCA inhibitory
activity relative to standard compounds, AAZ and SLC-0111 (Table 1).
Compounds 4a–8a showed strong inhibitory activity against hCA I (KIs,
93.5–428.1 nM) compared to AAZ and SLC-0111 (KIs, 250.0 and
5080 nM, respectively) while compounds 11b, 12b, 16c, and 17c
showed weak hCA I inhibitory activity (KIs, 47.8–84.0 μM). Compounds
4a–8a were also confirmed to be effective hCA II inhibitors (KI,
18.2–133.3 nM) compared to AAZ and SLC-0111 (KI, 12.0 and
960.0 nM, respectively). In contrast, a weak hCA II inhibitory activity
was displayed by compounds 11b–13b and 16c–18c as they had KI
values ranging from 4.6 to 42.0 μM (Table 1). Against hCA IX, com-
pounds 4a–8a exhibited effective inhibition (KI, 8.5–24.9 nM); hence,
they were found to be more potent than or equal to AAZ (KI, 25.0 nM)
and more active than SLC-0111 (KI, 45.0 nM). Conversely, a weak in-
hibitory activity was displayed by compounds 11b–13b and 16c–18c
(KIs, 1.4–45.0 μM). Compared to AAZ and SLC-0111 (KI, 5.7 and
4.5 nM, respectively), compounds 4a–8a demonstrated efficient hCA
XII inhibitory activity with KI values ranging from 8.6 to 43.2 nM. In-
terestingly, compound 5a showed selective tumor-associated isoenzyme
CA IX/XII inhibition with KIs of 15.8 and 8.6, respectively. In contrast,
compounds 11b–12b and 16c–17c displayed weak inhibitory activity
with KIs in the range, 4.7–7.8 μM. By docking compounds 5a, 6a, and
By molecular docking into the respective catalytic active sites of CA
IX (Fig. 3, upper panel) and CA XII (Fig. 3, lower panel), compounds 8a
and 5a displayed similar binding interactions with their co-crystallized
ligands. Furthermore, a binding orientation analogous to that of hCA II
was displayed by the benzenesulfonamide scaffold. Its aromatic portion
formed hydrophobic contacts with Leu199, Thr200, Pro202, and
Pro203 (CA IX) and Leu198, Thr200, and Pro201 (CA XII) on one side,
and Val121 and Val142 (CA IX) and Val121 and Val143 (CA XII) on the
other side. The N-benzylidenebenzohydrazide moiety of compound 8a
was accommodated on the hydrophobic side of CA IX’s active site and
interacted with Leu134, Val130, and Pro203. The analog portion of
compound 5a was located on the hydrophobic side of CA XII which
binds with Asn62, Lys67, Pro201, Ser135, Ser132, and Ala131. The
carbonyl (C]O) group of the N-benzylidenebenzohydrazide moiety of
compound 8a formed weak H-bonds with the CH2 group of Pro203
(3.43 Å) and C]O group of Pro202; this was mediated by HOH2199 in
CA IX’s active site. Through the HOH molecules, the tail of compound
5a formed three H-bonds with Thr200, Gln92, and Lys67 for CA XII
while the NH group of the N-benzylidenebenzohydrazide moiety of
compound 8a formed an H-bond with the conserved Gln92 (3.01 Å).
Finally, the 3-methoxy-4-hydroxyphenyl fragment of compound 8a
formed two strong H-bonds with Asp131 (2.9 and 3.09 Å) in CA IX,
5

A.S. El-Azab, et al.
BioorganicChemistry92(2019)103225
Fig. 3. Left: Three-dimensional binding interactions of compounds 8a (cyan color) and 5a (brown color) with hCA IX (upper panel) and hCA XII (lower panel),
respectively. Right: compounds 8a (cyan color) and 5a (brown color) superimposed on the co-crystallized inhibitors (green and yellow colors) inside the pockets of
the active site. Hydrogen bonds are indicated as blue lines.
8a into the binding sites of hCA I, II, IX, and XII, the binding mode
could be assessed and insights for further lead optimization could be
gained.
(KBr, cm−1) ν: 3411, 3341, 3255, 3232 (NH, NH2, and OH), 1654
(C]O), 1610 (C]N), 1354, 1150 (SO2); 1H NMR (700 MHz, DMSO‑d6):
δ 12.28 (s, 1H), 11.20 (s, 1H), 8.69 (s, 1H), 8.12 (d, 2H, J = 8.23 Hz),
8.06 (d, 2H, J = 8.24 Hz), 7.60 (d, 1H, J = 7.46 Hz), 7.57 (s, 2H), 7.32
(t, 1H, J = 7.62 Hz), 6.96 (d, 1H, J = 8.26 Hz), 6.94 (t, 1H,
4. Experimental
J = 7.45 Hz); 13C NMR (176 MHz, DMSO‑d6):
δ 162.31, 157.94,
4.1. Chemistry
149.15, 147.30, 136.23, 132.10, 129.82, 128.88, 126.31, 119.89,
119.14, 116.91;[m/z: 319 & M+1: 320].
Melting points (uncorrected) were recorded using a Barnstead 9100
electrothermal melting apparatus (APS Water Services Corporation,
Van Nuys, CA, USA). IR spectra were recorded with an FT-IR Perkin-
Elmer spectrometer (PerkinElmer Inc., Waltham, MA, USA). The NMR
spectra were measured in DMSO‑d6 using Bruker 700 MHz instrument
(Bruker, Billerica, MA, USA), with TMS as the internal standard.
Chemical shifts were reported in δ ppm. Mass spectra were recorded on
a Varian TQ 320 GC/MS/MS mass spectrometer (Varian, Palo Alto, CA).
C, H, and N were analyzed at the Research Centre, College of Pharmacy,
4.1.1.2. 4-(2-(4-(N,N-Diethylamino)-2-hydroxybenzylidene)hydrazine-1-
carbonyl)benzenesulfonamide (5a). M.P. 239–241 °C, 89% yield
(CH3CH2OH); IR (KBr, cm−1) ν: 3399, 3283, 3198 (NH, NH2, and
OH), 1650 (C]O), 1628 (C]N), 1348, 1162 (SO2); 1H NMR (700 MHz,
DMSO‑d6): δ 11.96 (s, 1H), 11.37 (s, 1H), 8.45 (s, 1H), 8.07 (s, 2H),
7.97 (s, 2H), 7.53 (s, 2H), 7.23 (d, 1H, J = 8.41 Hz), 6.28 (d, 1H,
J = 8.13 Hz), 6.14 (s, 1H), 3.36 (s, 4H), 1.11 (s, 6H); 13C NMR
(176 MHz, DMSO‑d6): δ 160.23, 150.92, 150.78, 147.03, 136.57,
132.09, 128.66, 126.24, 106.80, 104.21, 97.92, 44.28; [m/z: 390 &
M+1: 391].
King Saud University, Saudi Arabia. The results were within
0.4% of
the theoretical values. Acid hydrazides 3a-c were synthesized according
to the reported procedure [6a,21,22].
4.1.1.3. 4-(2-(3-Hydroxybenzylidene)hydrazine-1-carbonyl)
4.1.1. General method for the preparation of the Schiff’s bases 4–18
An appropriate phenolic aldehyde (10 mmol) was mixed with 4-
substituted-benzohydrazides 3a-c (10 mmol) in methanol (10 ml) con-
taining a catalytic amount of acetic acid (5 drops) at room temperature
for 24 h. The solid formed after cooling was filtered, washed with
water, and dried (Scheme 1).
benzenesulfonamide (6a). M.P. 297–299 °C, 86% yield (CH3OH); IR
(KBr, cm−1) ν: 3457, 3315, 3175, 3232 (NH, NH2, and OH), 1630
(C]O), 1605 (C]N), 1381, 1148 (SO2); 1H NMR (700 MHz, DMSO‑d6):
δ 11.97 (s, 1H), 9.67 (s, 1H), 8.38 (s, 1H), 8.09 (d, 2H, J = 8.38 Hz),
7.79 (d, 2H, J = 8.39 Hz), 7.55 (s, 2H), 7.26 (dd, 2H, J = 19.0 &
15.64), 7.13 (d, 1H, J = 7.60 Hz), 6.86 (dd, 1H, J = 8.04 & 1.88 Hz),
13C NMR (176 MHz, DMSO‑d6): δ 162.56, 158.17, 149.05, 147.12,
136.80, 135.87, 130.43, 128.83, 126.24, 119.45, 118.13, 113.12; [m/z:
319 & M+1: 320].
4.1.1.1. 4-(2-(2-Hydroxybenzylidene)hydrazine-1-carbonyl)
benzenesulfonamide (4a). M.P. 267–268 °C, 93% yield (CH3OH); IR
6

A.S. El-Azab, et al.
BioorganicChemistry92(2019)103225
4.1.1.4. 4-(2-(4-Hydroxybenzylidene)hydrazine-1-carbonyl)
(C]O), 1608 (C]N), 1338, 1151 (SO2); 1H NMR (700 MHz, DMSO‑d6):
δ 11.63 (s, 1H), 10.21 (s, 1H), 9.58 (s, 1H), 8.34 (s, 1H), 7.90 (d, 2H,
J = 8.18 Hz), 7.32 (s, 1H), 7.30 (d, 2H, J = 8.05 Hz), 7.09 (d, 1H,
J = 7.91 Hz), 6.85 (d, 2H, 7.92 Hz), 3.83 (s, 3H), 3.10 (s, 3H); 13C NMR
(176 MHz, DMSO‑d6): δ 162.76, 149.41, 148.57, 148.50, 142.01,
129.48, 128.62, 126.21, 122.61, 118.41, 115.88, 109.30, 55.98,
40.41; [m/z: 363 & M+1: 364].
benzenesulfonamide (7a). M.P. 340–341 °C, 91% yield (CH3OH); 1H
NMR (700 MHz, DMSO‑d6): δ 11.82 (s, 1H), 9.99 (s, 1H), 8.36 (s,
1H), 8.06 (d, 2H, J = 8.19 Hz), 7.96 (d, 2H J = 8.26 Hz), 7.59 (d, 2H,
J = 8.40 Hz), 7.53 (s, 2H), 6.86 (d, 2H, J = 8.33 Hz), 13C NMR
(176 MHz, DMSO‑d6): δ 162.30, 160.07, 149.30, 146.98, 137.01,
129.48, 128.72, 126.20, 125.58, 116.22.
4.1.1.5. 4-(2-(4-Hydroxy-3-methoxybenzylidene)hydrazine-1-carbonyl)
benzenesulfonamide (8a). M.P. 264–265 °C, 95% yield (CH3CH2OH); IR
(KBr, cm−1) ν: 3451, 3278, 3201 (NH, NH2, and OH), 1654 (C]O),
1621 (C]N), 1330, 1160 (SO2); 1H NMR (700 MHz, DMSO‑d6): δ 11.89
(s, 1H), 9.63 (s, 1H), 8.37 (s, 1H), 8.09 (d, 2H, J = 7.39 Hz), 7.98 (d,
2H, J = 7.35 Hz), 7.56 (s, 2H), 7.35 (s, 1H), 7.12 (d, 1H, J = 7.91 Hz),
6.88 (d, 1H, J = 7.70 Hz), 3.684 (s, 3H); 13C NMR (176 MHz,
4.1.1.11. N′-(2-Hydroxybenzylidene)-4-(methylsulfonyl)benzohydrazide
(14c). M.P. 248–249 °C, 93% yield (CH3OH); IR (KBr, cm−1) ν: 3443,
3348 (NH and OH), 1635 (C]O), 1605 (C]N), 1317, 1135 (SO2); 1H
NMR (700 MHz, DMSO‑d6): δ 12.32 (s, 1H), 11.14 (s, 1H), 8.69 (s, 1H),
8.18 (d, 2H, J = 7.77 Hz), 8.12 (d, 2H, J = 7.77 Hz), 7.61 (d, 1H,
J = 7.63 Hz), 7.33 (t, 1H, J = 7.70), 7.95 (t, 2H, J = 15.75 Hz), 3.31 (s,
3H); 13C NMR (176 MHz, DMSO‑d6): δ 162.06, 157.92, 149.19, 143.93,
137.83, 132.15, 129.71, 129.16, 127.70, 119.90, 119.17, 116.91,
43.72; [m/z: 318 & M+1: 319].
DMSO‑d6):
δ 162.44, 149.66, 149.61, 148.54, 147.01, 137.00,
128.77, 126.24, 125.97, 122.92, 115.93, 109.37, 56.00; [m/z: 349 &
M+1: 350].
4.1.1.12. N′-(4-(N,N-Diethylamino)-2-hydroxybenzylidene)-4-
(methylsulfonyl)benzohydrazide (15c). M.P. 237–239 °C, 86% yield
(CH3CH2OH); IR (KBr, cm−1) ν: 3447, 3295 (NH and OH), 1654 (C]
O), 1611 (C]N), 1310, 1151 (SO2); 1H NMR (700 MHz, DMSO‑d6): δ
12.04 (s, 1H), 11.36 (s, 1H), 8.45 (s, 1H), 8.15 (d, 2H, J = 8.05 Hz),
8.10 (d, 2H, J = 8.12 Hz), 7.24 (d, 1H, J = 8.68 Hz), 6.28 (d, 1H,
J = 8.82 Hz), 6.14 (s, 1H), 3.35 (q, 4H, J = 6.93 & 6.95 Hz), 3.29 (s,
3H), 1.10 (t, 6H, J = 7.03 Hz); 13C NMR (176 MHz, DMSO‑d6): δ
161.39, 160.24, 151.09, 150.81, 143.63, 138.17, 132.11, 128.98,
127.65, 106.74, 104.21, 97.85, 44.28, 43.74, 12.99; [m/z: 398 & M
+1: 399].
4.1.1.6. N-(4-(2-(2-Hydroxybenzylidene)hydrazine-1-carbonyl)phenyl)
methanesulfonamide (9b). M.P. 253–255 °C, 90% yield (CH3OH); IR
(KBr, cm−1) ν: 3401, 3335, 3181 (NH and OH), 1671 (C]O), 1616
(C]N), 1324, 1154 (SO2); 1H NMR (700 MHz, DMSO‑d6): δ 12.07 (s,
1H), 11.35 (s, 1H), 10.27 (s, 1H), 8.64 (s, 1H), 7.95 (d, 2H,
J = 8.10 Hz), 7.54 (d, 1H, J = 7.51 Hz), 7.33 (d, 2H, J = 8.19 Hz),
7.30 (t, 1H, J = 7.63 & 8.19 Hz), 6.95 (d, 1H, J = 8.19 Hz), 6.92 (t, 1H,
J = 14.98 Hz), 3.12 (s, 3H); 13C NMR (176 MHz, DMSO‑d6): δ 162.67,
157.92, 148.50, 142.40, 131.80, 130.00, 129.64, 127.69, 119.81,
119.14, 118.36, 116.89, 40.27; [m/z: 333 & M+1: 334].
4.1.1.7. N-(4-(2-(4-(N,N-Diethylamino)-2-hydroxybenzylidene)hydrazine-
1-carbonyl)phenyl)methanesulfonamide (10b). M.P. 261–263 °C, 84%
yield (CH3CH2OH); IR (KBr, cm−1) ν: 3448, 3398, 3199 (NH and OH),
1647 (C]O), 1610 (C]N), 1334, 1157 (SO2); 1H NMR (700 MHz,
DMSO‑d6): δ 11.75 (s, 1H), 11.50 (s, 1H), 10.22 (s, 1H), 8.41 (s, 1H),
7.90 (d, 1H, J = 0.85 Hz), 7.89 (s, 1H), 7.31 (d, 2H, J = 8.19 Hz), 7.19
(d, 1H, J = 8.68 Hz), 8.26 (d, 1H, J = 8.68 Hz), 6.13 (s, 1H), 3.35 (q, 4H,
J = 6.84 Hz), 3.10 (s, 3H), 1.10 (t, 6H, J = 7.0 Hz); 13C NMR (176 MHz,
DMSO‑d6): δ 162.07, 160.15, 150.56, 150.17, 142.07, 132.06, 129.40,
128.13, 118.41, 106.89, 104.07, 97.93, 44.26, 40.26; [m/z: 404 & M+1:
405].
4.1.1.13. N′-(3-Hydroxybenzylidene)-4-(methylsulfonyl)benzohydrazide
(16c). M.P. 245–246 °C, 91% yield (CH3OH); IR (KBr, cm−1) ν: 3482,
3299 (NH and OH), 1636 (C]O), 1605 (C]N), 1311, 1157 (SO2); 1H
NMR (700 MHz, DMSO‑d6): δ 12.04 (s, 1H), 9.69 (s, 1H), 8.39 (s, 1H),
8.16 (d, 2H, J = 8.12 Hz), 8.10 (d, 2H, J = 13.16 Hz), 7.28 (t, 1H,
J = 7.78 Hz), 7.24 (s, 1H), 7.13 (d, 1H, J = 7.49 Hz), 6.86 (d, 1H,
J = 7.94 Hz), 3.30 (s, 3H); 13C NMR (176 MHz, DMSO‑d6): δ 162.34,
158.17, 149.28, 143.76, 138.39, 135.81, 130.43, 129.13, 127.65,
119.47, 118.18, 113.15, 43.74; [m/z: 318 & M+1: 319].
4.1.1.14. N′-(4-Hydroxybenzylidene)-4-(methylsulfonyl)benzohydrazide
(17c). M.P. 287–289 °C, 88% yield (CH3OH); IR (KBr, cm−1) ν: 3482,
3299 (NH and OH), 1647 (C]O), 1612 (C]N), 1313, 1139 (SO2); 1H
NMR (700 MHz, DMSO‑d6): δ 11.89 (s, 1H), 10.01 (s, 1H), 8.37 (s, 1H),
8.14 (d, 2H, J = 7.63 Hz), 8.09 (d, 2H, J = 7.84 Hz), 7.59 (d, 2H,
J = 7.84 Hz), 6.86 (d, 2H, J = 7.77 Hz), 3.30 (s, 3H); 13C NMR
(176 MHz, DMSO‑d6): δ 162.07, 160.12, 149.50, 143.62, 138.61,
130.73, 129.53, 129.05, 127.62, 126.83, 125.52, 116.23, 43.75; [m/
z: 318 & M+1: 319].
4.1.1.8. N-(4-(2-(3-Hydroxybenzylidene)hydrazine-1-carbonyl)phenyl)
methanesulfonamide (11b). M.P. 255–257 °C, 92% yield (CH3OH); IR
(KBr, cm−1) ν: 3410, 3306, 3213 (NH and OH), 1688 (C]O), 1609
(C]N), 1341, 1149 (SO2); 1H NMR (700 MHz, DMSO‑d6): δ 11.74 (s,
1H), 10.23 (s, 1H), 9.66 (s, 1H), 8.36 (s, 1H), 7.91 (d, 2H, J = 8.02 Hz),
7.31 (d, 2H, J = 8.22 Hz), 7.26 (t, 1H, J = 7.70 & 7.67 Hz), 7.21 (s,
1H), 7.10 (d, 1H, J = 7.28 Hz), 7.84 (d, 1H, J = 7.70 Hz), 3.11 (s, 3H);
13C NMR (176 MHz, DMSO‑d6): δ 162.92, 158.13, 148.04, 142.16,
136.09, 130.37, 129.57, 128.38, 119.28, 118.37, 117.87, 113.02,
40.28; [m/z: 333 & M+1: 334].
4.1.1.15. N′-(4-Hydroxy-3-methoxybenzylidene)-4-(methylsulfonyl)
benzohydrazide (18c). M.P. 216–217 °C, 92% yield (CH3CH2OH); IR
(KBr, cm−1) ν: 3498, 3291 (NH and OH), 1661 (C]O), 1620 (C]N),
1280, 1156 (SO2); 1H NMR (700 MHz, DMSO‑d6): δ 11.92 (s, 1H), 9.63
(s, 1H), 8.36 (s, 1H), 8.14 (d, 2H, J = 8.05 Hz), 8.10 (d, 2H,
J = 8.05 Hz),7.34 (s, 1H), 7.12 (d, 1H, J = 8.05 Hz), 6.86 (d, 1H,
J = 7.98 Hz), 3.84 (s, 3H), 3.30 (s, 3H); 13C NMR (176 MHz, DMSO‑d6):
δ 162.12, 149.74, 149.70, 148.53, 143.62, 138.61, 129.05, 127.63,
125.92, 122.89, 115.92, 109.42, 56.00, 43.76; [m/z: 348 & M+1: 349].
4.1.1.9. N-(4-(2-(4-Hydroxybenzylidene)hydrazine-1-carbonyl)phenyl)
methanesulfonamide (12b). M.P. 317–319 °C, 94% yield (CH3OH); IR
(KBr, cm−1) ν: 3490, 3310, 3296 (NH and OH), 1653 (C]O), 1611
(C]N), 1293, 1151 (SO2); 1H NMR (700 MHz, DMSO‑d6): δ 11.59 (s,
1H), 10.20 (s, 1H), 9.95 (s, 1H), 8.34 (s, 1H), 7.89 (d, 2H, J = 7.89 Hz),
7.56 (d, 2H, J = 7.82 Hz), 7.30 (d, 2H, J = 7.90 Hz), 6.84 (d, 2H,
J = 7.81 Hz), 3.10 (s, 3H); 13C NMR (176 MHz, DMSO‑d6): δ 162.70,
159.84, 148.30, 141.99, 129.47, 129.30, 128.63, 125.79, 118.40,
116.17, 40.42; [m/z: 333 & M+1: 334].
4.2. CA inhibition
The inhibition assay for the hCA I, II, IX, and XII isozymes was
carried out with the SX.18MV-R stopped-flow instrument (Applied
Photophysics, Oxford, UK) according to the method reported previously
[23].
4.1.1.10. N-(4-(2-(4-Hydroxy-3-methoxybenzylidene)hydrazine-1-
carbonyl)phenyl)methanesulfonamide (13b). M.P. 242–244 °C, 91% yield
(CH3CH2OH); IR (KBr, cm−1) ν: 3421, 3330, 3123 (NH and OH), 1636
7

A.S. El-Azab, et al.
BioorganicChemistry92(2019)103225
4.3. Docking methodology
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Molecular docking was conducted with MOE 2008.10 from the
Chemical Computing Group Inc. [28] according to the reported
methods [24–27].
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Acknowledgments
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(b) S.B.Ö. Sarikaya, F. Topal, M. Şentürk, İ. Gülçin, C.T. Supuran, Bioorg. Med.
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The authors extend their appreciation to the Deanship of Scientific
Research at King Saud University for funding the work through the
research group project No. RGP-163.
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Appendix A. Supplementary material
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