Synthesis and biological evaluation of novel 3-(quinolin-4-ylamino)benzenesulfonamidesAQ3 as carbonic anhydrase isoforms I and II inhibitors

Article abstract of DOI:10.1080/14756366.2019.1652282

Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses. We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were in vitro evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with K_Is in the range of 0.966–9.091 μM, whereas hCA II in the range of 0.083–3.594 μM. The primary 7-chloro-6-flouro substituted sulphfonamide derivative 6e (K_I = 0.083 μM) proved to be the most active quinoline in inhibiting hCA II, whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 μM, confirming the crucial role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.

Full text of DOI:10.1080/14756366.2019.1652282

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: https://www.tandfonline.com/loi/ienz20
Synthesis and biological evaluation of novel 3-
(quinolin-4-ylamino)benzenesulfonamidesAQ3 as
carbonic anhydrase isoforms I and II inhibitors
Mohammad M. Al-Sanea, Ahmed Elkamhawy, Sora Paik, Silvia Bua, So Ha
Lee, Mohamed A. Abdelgawad, Eun Joo Roh, Wagdy M. Eldehna & Claudiu T.
Supuran
To cite this article: Mohammad M. Al-Sanea, Ahmed Elkamhawy, Sora Paik, Silvia Bua, So Ha
Lee, Mohamed A. Abdelgawad, Eun Joo Roh, Wagdy M. Eldehna & Claudiu T. Supuran (2019)
Synthesis and biological evaluation of novel 3-(quinolin-4-ylamino)benzenesulfonamidesAQ3
as carbonic anhydrase isoforms I and II inhibitors, Journal of Enzyme Inhibition and Medicinal
Chemistry, 34:1, 1457-1464, DOI: 10.1080/14756366.2019.1652282
To link to this article: https://doi.org/10.1080/14756366.2019.1652282
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
2019, VOL. 34, NO. 01, 1457–1464
https://doi.org/10.1080/14756366.2019.1652282
RESEARCH PAPER
Synthesis and biological evaluation of novel 3-(quinolin-4-
ylamino)benzenesulfonamidesAQ3 as carbonic anhydrase isoforms I and
II inhibitors
a
b,c
d
b
, Sora Paikb , Silvia Bua , So Ha Lee ,
ꢀ
ꢀ
ꢀ
Mohammad M. Al-Sanea , Ahmed Elkamhawy
Mohamed A. Abdelgawada,e, Eun Joo Rohb,f, Wagdy M. Eldehnag and Claudiu T. Supurand
b
aDepartment of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia; Chemical Kinomics Research Center,
c
Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of
d
Pharmacy, Mansoura University, Mansoura, Egypt; Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences,
e
f
University of Florence, Firenze, Italy; Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef, Egypt; Division of Bio-
g
Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea; Department of
Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
ABSTRACT
ARTICLE HISTORY
Received 4 July 2019
Revised 29 July 2019
Accepted 31 July 2019
Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses.
We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating
un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were in vitro
evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were
inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with KIs in the range of
0.966–9.091 lM, whereas hCA II in the range of 0.083–3.594 lM. The primary 7-chloro-6-flouro substituted
sulphfonamide derivative 6e (KI ¼ 0.083 lM) proved to be the most active quinoline in inhibiting hCA II,
whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 lM, confirming the crucial
role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.
KEYWORDS
Benzenesulfonamides; car-
bonic anhydrase; quinolines;
synthesis; cytosolic isoforms
hCA I and II
Introduction
aqueous humour is secreted within the eye, with the subsequent
increase in the intraocular pressure (IOP)9–11. CA inhibitors (CAIs)
are able to diminish IOP by decreasing the rate of bicarbonate for-
mation and thus secretion of the aqueous humour. For more than
60 years, carbonic anhydrase inhibitors are in clinical use for the
treatment of glaucoma, such as the topically acting dorzolamide
and brinzolamide drugs, and the systemic acetazolamide and
methazolamide drugs9 (Figure 1).
Pertaining to its prevalence in diverse natural products, such as
alkaloids, and in different pharmacologically active substances,
quinoline stands out as a promising privileged scaffold that is
endowed with a wide spectrum of biological activities. Just to
name a few, antimalarial12, antileishmanial13, anti-tubercular14,
antidepressant15, anticancer16,17 and antiglaucoma18 actions were
reported for quinoline derivatives. Accordingly, medicinal chemists
embarked on exploring various quinoline-based molecules com-
prehending their potential to develop promising and efficient bio-
active compounds19,20. These efforts led to FDA approval for
several quinoline-based drugs such as the anticancer agent lenva-
tinib, the anti-asthmathic drug montelukast, the antiviral
Clioquinol, and the anaesthetic Dibucain.
Carbonic anhydrases (CA) (CAs, EC 4.2.1.1) are zinc-containing
metalloenzymes that are present in most organisms all over the
tree of life1,2. These metalloenzymes efficiently catalyse the rapid
interconversion of carbon dioxide and water to bicarbonate and
protons. In humans, this fundamental reaction encompasses three
simple chemical entities, CO2, HCO3ꢁ, and Hþ, essential in a host
of physiological and pathological processes, such as calcification,
bone resorption, electrolyte secretion, pH and CO2 homeostasis,
tumorigenicity, and several biosynthetic reactions3–5. Eight distinct
genetic enzymatic families were identified; the a-, b-, c-, d-, f-. g-,
h- and i-CAs3–5. To date, 15 human (h) isoforms of CA have been
identified, which have all belong to the a-class and have different
patterns of tissue distribution and cellular localisation as the fol-
lowing; cytosolic (I, II, III, VII, and XIII), membrane-bound (IV, IX, XII,
and XIV), secreted (VI) and mitochondrial (VA and VB) forms3–5. CA
I and II are present at high concentrations comparing to other CA
isoforms in the erythrocytes cytosol and several other tissues.
Several important pathological consequences result from the
dysfunction of hCA II activity, thus this isoform is an established
drug target for a multitude of diseases, such as oedema6, epi-
In the present study, we report a new series of primary benze-
lepsy7, acute mountain sickness8, and glaucoma, where excessive nesulfonamides incorporating un/substituted ethyl quinoline-3-
CONTACT Mohammad M. Al-Sanea
mmalsanea@ju.edu.samohmah80@gmail.com
College of Pharmacy, Jouf University, Sakaka, Al-Jouf Province, Saudi Arabia;
ꢀ
Claudiu T. Supuran
claudiu.supuran@unifi.it NEUROFARBA Department, Sezione di Scienze Farmaceutiche, Universita degli Studi di Firenze, Via Ugo Schiff
6,Sesto Fiorentino, Florence 50019, Italy
ꢀ
These authors have contributed equally to this work.
Supplemental data for this article can be accessed here.
ß 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

1458
M. M. AL-SANEA ET AL.
Figure 1. Structures of some approved CAIs antiglaucoma drugs, and the target quinolines 6a–f and 11.
carboxylate (6a–6f, Figure 1) as well as the secondary benzenesul- General procedure for preparation of compounds 4a–f
fonamide analogue (11, Figure 1), with the prime goal of develop-
ing effective quinoline-based antiglaucoma candidates targeting
the cystolic isoform hCA II. These quinoline-based benzenesulfona-
mides were evaluated in vitro for their inhibitory activity towards
the physiologically relevant hCA isoforms I and II, using stopped-
flow CO2 hydrase assay.
A solution of compounds 3a–f (1.0 mmol) in POCl3 (6 ml) was
refluxed for 1 h. The mixture was evaporated in vacuo and the
residue was extracted with methylene chloride, crushed ice and
aqueous NH3. The organic layer was dried over Na2SO4 and con-
centrated. The residue was purified by column chromatography
(SiO2, ethyl acetate (EA): n-Hex 10: 1) to get key intermediates
4a-f21,22
.
Materials and methods
General procedures for preparation of the target quinolines
6a–f and 11
Chemistry
To a MW vial, were successively added the appropriate ethyl 4-
chloroquinoline-3-carboxylate derivative 4a-f (0.21 mmol), 3-ami-
nobenzenesulfonamide 5 (0.036 gm, 0.21 mmol) or 3-amino-N-
methylbenzenesulfonamide 10 (0.040 gm, 0.21 mmol), and ethanol
(12 ml) at room temperature. The MW vial was sealed and heated
under MW conditions for 30 min at 150 ꢂC. The mixture was
evaporated in vacuo and the residue was extracted with EA and
NaHCO3 (aq). The organic layer was dried over Na2SO4 and con-
centrated. The residue was purified by column chromatography
(SiO2, EA: n-Hex), in a gradient elution with 1:5 (EA: n-hex) ratio,
to furnish quinolines 6a–f and 11, respectively.
All reaction and manipulations were performed in nitrogen atmos-
phere using standard Schlenk techniques. All reaction solvents
and reagents were purchased from commercial suppliers and used
without further purification. Microwave-assisted synthesis was car-
ried out in a Biotage Initiator þ apparatus operating in single
mode, the microwave cavity producing controlled irradiation at
2.45 GHz (Biotage AB, Uppsala, Sweden). The reactions were run in
sealed vessels. These experiments were performed by employing
magnetic stirring and a fixed hold time using variable power to
reach (during 1 ꢁ 2 min) and then maintain the desired tempera-
ture in the vessel for the programed time period. The temperature
was monitored by an IR sensor focused on a point on the reactor
vial glass. The IR sensor was calibrated to internal solution reac-
tion temperature by the manufacturer. The NMR spectra were
obtained on Bruker Avance 400 (400 MHz 1H and 101 MHz 13 C
NMR). 1H NMR spectra were referenced to tetramethylsilane
(d ¼ 0.00 ppm) as an internal standard and were reported as fol-
lows: chemical shift, multiplicity (b ¼ broad, s ¼ singlet,
d ¼ doublet, t ¼ triplet, dd ¼ doublet of doublet, m ¼ multiplet).
Column chromatography was performed on Merck Silica Gel 60
(230–400 mesh) and eluting solvents for all of these chromato-
graphic methods were noted as appropriated-mixed solvent with
given volume-to-volume ratios. TLC was carried out using glass
sheets pre-coated with silica gel 60 F254 purchased by Merk. High-
resolution spectra were performed on Waters ACQUITY UPLC BEH
C18 1.7 l–Q-TOF SYNAPT G2-Si High Definition Mass
Spectrometry. Compounds 3a-f, 4a-f21–22 and 1023 were previ-
ously prepared.
Ethyl 4-((3-sulphamoylphenyl)amino)quinoline-3-
carboxylate (6a)
White solid, yield: 49%, mp: 183.6 ꢁ 185.0 ꢂC; 1H NMR (DMSO-d6,
400 MHz) d ppm: 1.16 (t, J ¼ 6.8 Hz, 3H, CH2 CH3), 4.05 (q,
J ¼ 6.8 Hz, 2H, CH2CH3), 7.16–7.18 (m, 1H, H-2 of benzenesulfona-
mide), 7.34 (s, 2H, SO2NH2), 7.45–7.56 (m, 4H, H-4,5,6 of benzene-
sulfonamide and H-6 quinoline), 7.80–7.84 (m, 1H, H-7 quinoline),
8.01 (d, J ¼ 8.0 Hz, 1H, H-5 quinoline), 8.10 (d, J ¼ 8.4 Hz, 1H, H-8
quinoline), 9.01 (s, 1H, H-2 quinoline), 9.75 (s, 1H, NH); 13 C NMR
(DMSO-d6, 101 MHz) d ppm: 14.31 (CH3), 61.48, 111.07 (quinoline
C-3), 116.42 (benzenesulfonamide C-2), 119.82 (benzenesulfona-
mide C-4), 121.40 (quinoline C-10), 121.92 (benzenesulfonamide C-
6), 124.88 (quinoline C-5), 126.55 (quinoline C-6), 130.05 (quinoline
C-8), 130.22 (benzenesulfonamide C-5), 131.95 (quinoline C7),
144.44 (benzenesulfonamide C-3), 145.60 (quinoline C-4), 148.12
(benzenesulfonamide C-1), 150.36 (quinoline C-2), 151.38

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1459
(quinoline C-9), 166.81 (C ¼ O); HRMS (ESI) for C18H18N3O4S: calcd Ethyl 7-chloro-6-fluoro-4-((3-sulphamoylphenyl)amino)
372.1018, found: 372.1017 [M þ H]þ.
quinoline-3-carboxylate (6e)
Yellow solid, yield: 55%, mp: 190.0 ꢁ 191.0 ꢂC; 1H NMR (DMSO-d6,
400 MHz) d ppm: 1.08 (t, J ¼ 7.2 Hz, 3H, CH2CH3), 3.91 (q, J ¼ 7.2 Hz,
2H, CH2CH3), 7.18–7.20 (m, 1H, H-2 of benzenesulfonamide),
7.45–7.49 (m, 3H, H-4,5,6 of benzenesulfonamide), 7.36 (s, 2H,
SO2NH2), 8.18 (d, J ¼ 11.2 Hz, H-8 quinoline), 8.25 (d, J ¼ 7.6 Hz,
1H, H-5 quinoline), 8.91 (s, 1H, H-2 quinoline), 9.68 (s, 1H, NH);
13 C NMR (DMSO-d6, 101 MHz) d ppm: 14.22 (CH3), 61.58 (CH2),
110.16, 110.40 (quinoline C-5), 111.47 (quinoline C-3), 116.52
(benzenesulfonamide C-2), 120.18 (quinoline C-10), 121.24 (benze-
nesulfonamide C-4), 121.85 (quinoline C-10), 125.21 (benzenesulfo-
Ethyl 6-methyl-4-((3-sulphamoylphenyl)amino)quinoline-3-
carboxylate (6 b)
Yellow solid, yield: 97%, mp: 223.0 ꢁ 224.5 ꢂC; 1H NMR (DMSO-d6,
400 MHz) d ppm: 1.09 (t, J ¼ 5.6 Hz, 3H, CH2 CH3), 2.40 (s, 3H, CH3),
3.89 (q, J ¼ 5.6 Hz, 2H, CH2CH3), 7.25 (s, 1H, H-2 of benzenesulfona-
mide), 7.39 (s, 2H, SO2NH2), 7.47–7.55 (m, 3H, H-4,5,6 of benzene-
sulfonamide), 7.73–7.74 (m, 1H, H-5 quinoline), 7.96 (s, 1H,
quinoline H-7), 8.26 (s, 1H, H-8 quinoline), 8.88 (s, 1H, H-2 quin-
oline), 10.25 (s, 1H, NH); 13 C NMR (DMSO-d6, 101 MHz) d ppm: namide C-6), 124.41 (benzenesulfonamide C-5), 130.29 (quinoline
C-7), 131.58 (quinoline C-8), 143.76 (benzenesulfonamide C-3),
145.69 (benzenesulfonamide C-1), 147.05, 147.52 (quinoline C-6),
152.27 (quinoline C-9), 153.76 (quinoline C-2), 156.21 (quinoline C-
4), 166.26 (C ¼ O); HRMS (ESI) for C18H16ClFN3O4S: calcd 424.0534,
found: 424.0525 [M þ H]þ.
14.22 (CH2 CH3), 21.73 (CH3), 61.57 (CH2), 111.34 (quinoline C-3),
116.98 (benzenesulfonamide C-2), 120.58 (quinoline C-10), 121.17
(benzenesulfonamide C-4), 122.55 (benzenesulfonamide C-6),
123.97 (quinoline C-6), 127.10 (quinoline C-5), 130.19 (benzenesul-
fonamide C-5), 134.72 (quinoline C-8), 136.89 (quinoline C-7),
143.66 (benzenesulfonamide C-3), 145.60 (benzenesulfonamide C-
1), 144.74 (quinoline C-2), 148.89 (quinoline C-9), 166.02 (C ¼ O);
HRMS (ESI) for C19H20N3O4S: calcd 386.1175, found:
386.1170 [M þ H]þ.
Ethyl 5,7-dichloro-4-((3-sulphamoylphenyl)amino)quinoline-3-
carboxylate (6f)
Yellow solid, yield: 98%, mp: 228.7 ꢁ 230.3 ꢂC; 1H NMR (DMSO-d6,
400 MHz) d ppm: 1.21 (t, J ¼ 7.2 Hz, 3H, CH2CH3), 4.17 (q, J ¼ 7.2 Hz,
2H, CH2CH3), 6.97–6.99 (m, 1H, H-2 of benzenesulfonamide),
7.28–7.37 (m, 3H, H-4,5,6 of benzenesulfonamide), 7.72
(d, J ¼ 6.0 Hz, 1H, H-6 quinoline), 8.08 (s, 1H, H-8 quinoline), 9.09
(s, 1H, H-2 quinoline), 9.83 (s, 1H, NH); 13 C NMR (DMSO-d6,
101 MHz) d ppm: 14.22 (CH3) 62.08 (CH2), 114.54 (quinoline C-3),
117.87 (benzenesulfonamide C-2), 118.79 (quinoline C-10), 120.52
(benzenesulfonamide C-4), 127.44 (benzenesulfonamide C-6),
129.58 (quinoline C-6), 130.43 (quinoline C-5, 8), 131.42 (benzene-
sulfonamide C-5), 136.15 (quinoline C-7), 136.62 (benzenesulfona-
mide C-1), 145.22 (quinoline C-4), 148.09 (quinoline C-9), 152.40
(quinoline C-2), 166.39 (C ¼ O); HRMS (ESI) for C18H16Cl2N3O4S:
calcd 440.0239, found: 440.0237 [M þ H]þ.
Ethyl 6-methoxy-4-((3-sulphamoylphenyl)amino)quinoline-3-
carboxylate (6c)
White solid, yield: 61%, mp: 214.9 ꢁ 216.3 ꢂC; 1H NMR (DMSO-d6,
400 MHz) d ppm: 1.13 (t, J ¼ 6.8 Hz, 3H, CH2 CH3), 3.73 (s, 3H,
OCH3), 3.99 (q, J ¼ 6.8 Hz, 2H, CH2CH3), 7.14–7.16 (m, 1H, H-2 of
benzenesulfonamide), 7.33 (s, 2H, SO2NH2), 7.42–7.48 (m, 4H, H-
4,5,6 of benzenesulfonamide and H-7 quinoline), 7.96 (s, 1H, H-5
quinoline), 7.91–7.93 (m, 1H, H-8 quinoline), 8.84 (s, 1H, quinoline
H-2), 9.95 (s, 1H, NH); 13 C NMR (DMSO-d6, 101 MHz) d ppm: 14.31
(CH2 CH3), 21.73 (CH3), 55.92 (OCH3) 61.40 (CH2), 103.51 (quinoline
C-4), 111.54 (quinoline C-3), 116.36 (benzenesulfonamide C-2),
119.51 (benzenesulfonamide C-4), 121.78 (quinoline C-10), 122.35
(benzenesulfonamide C-6), 123.78 (quinoline C-7), 130.17 (benze-
nesulfonamide C-5), 131.56 (quinoline C-8), 144.36 (benzenesulfo-
namide C-3), 145.55 (quinoline C-9), 146.16 (benzenesulfonamide
C-1), 146.59 (quinoline C-2), 148.90 (quinoline C-4), 157.51 (quin-
oline C-6), 166.90 (C ¼ O); HRMS (ESI) for C19H20N3O5S: calcd
402.1124, found: 402.1126 [M þ H]þ.
Ethyl 7-chloro-6-fluoro-4-((3-(N-methylsulphamoyl)phenyl)
amino)quinoline-3-carboxylate (11)
1
Yellow solid; yield: 40%, H NMR (DMSO-d6, 400 MHz) d ppm: 1.07
(t, J ¼ 6.8 Hz, 3H, CH2CH3), 2.40 (s, 3H, NHCH3), 3.90 (q, J ¼ 6.8 Hz,
2H, CH2CH3), 7.27 (d, J ¼ 7.6 Hz, 1H, H-2 of benzenesulfonamide),
7.41 (s, 1H, NHCH3), 7.49–7.53 (m, 3H, H-4,5,6 of benzenesulfona-
mide), 8.19 (d, J ¼ 11.6 Hz, 1H, H-5 quinoline), 8.26 (d, J ¼ 7.2 Hz,
1H, H-8 quinoline), 8.91 (s, 1H, H-2 quinoline), 9.79 (s, 1H, NH); 13 C
NMR (DMSO-d6, 101 MHz) d ppm: 14.19 (CH2CH3), 29 (NHCH3),
61.52 (CH2), 110.18 (quinoline C-5), 110.42 (quinoline C-5), 111.56
(quinoline C-3), 117.44 (benzenesulfonamide C-2), 121.17 (benze-
nesulfonamide C-4), 121.25 (quinoline C-10), 121.33 (quinoline C-
10), 122.63 (benzenesulfonamide C-6), 125.22 (quinoline C-7),
125.43 (quinoline C-7), 130.61 (benzenesulfonamide C-5), 131.58
(quinoline C-8), 140.89 (quinoline C-8), 144.09 (benzenesulfona-
mide C-3), 146.97 (benzenesulfonamide C-1), 147.02 (quinoline C-
9), 147.54 (quinoline C-2), 152.26 (quinoline C-4), 153.76 (quinoline
C6), 156.21 (quinoline C-6), 166.24 (C ¼ O); HRMS (ESI) for
C19H18ClFN3O4S: calcd 438.0691, found: 438.0693 [M þ H]þ.
Ethyl 6-bromo-4-((3-sulphamoylphenyl)amino)quinoline-3-
carboxylate (6d)
Yellow solid, yield: 71%, mp: 235.6 ꢁ 237.2 ꢂC; 1H NMR (DMSO-d6,
400 MHz) d ppm: 1.07 (t, J ¼ 5.6 Hz, 3H, CH2 CH3), 3.88 (q,
J ¼ 5.6 Hz, 2H, CH2CH3), 7.17 (s, 1H, H-2 of benzenesulfonamide),
7.36 (s, 2H, SO2NH2), 7.45–7.51 (m, 3H, H-4,5,6 of benzenesulfona-
mide), 7.94 (s, 2H, H-7,8 quinoline), 8.53 (s, 1H, H-5 quinoline), 8.92
(s, 1H, H-2 quinoline), 9.71 (s, 1H, NH); 13 C NMR (DMSO-d6,
101 MHz) d ppm: 14.22 (CH3), 61.49 (CH2), 111.61 (quinoline C-3),
116.40 (benzenesulfonamide C-2), 119.81 (quinoline C-10), 119.95,
(benzenesulfonamide C-4), 121.47 (benzenesulfonamide C-6),
123.08 (quinoline C-6), 126.60 (quinoline C-5), 130.21 (benzenesul-
fonamide C-5), 132.13 (quinoline C-8), 134.76 (quinoline C-7),
144.01 (benzenesulfonamide C-3), 145.68 (benzenesulfonamide C-
1), 146.37 (quinoline C-2), 148.91 (quinoline C-9), 152.06 (quinoline
C-4), 166.33 (C ¼ O); HRMS (ESI) for C18H17BrN3O4S: calcd 450.0123,
found: 450.0127 [M þ H]þ.
CA inhibitory assay
An Applied Photophysics stopped-flow instrument has been used
for assaying the CA catalyzed CO2 hydration activity24. Phenol red

1460
M. M. AL-SANEA ET AL.
Scheme 1. Synthesis of target quinolines 6a–f; Reagents and conditions: (i) DEEMM/Ethanol/reflux 1 h; (ii) Diphenyl ether/250 ꢂC/45 min; (iii) POCl3/reflux 1 h; (iv)
Absolute ethyl alcohol/reflux 4 h.
(at a concentration of 0.2 mM) has been used as indicator, working of phosphorus oxychloride to afford the key intermediates ethyl
at the absorbance maximum of 557 nm, with 20 mM Hepes (pH
7.5) as buffer, and 20 mM Na2SO4 (for maintaining constant the
ionic strength), following the initial rates of the CA-catalyzed CO2
hydration reaction for a period of 10–100 s. The CO2 concentra-
tions ranged from 1.7 to 17 mM for the determination of the kin-
etic parameters and inhibition constants. For each inhibitor at
least six traces of the initial 5–10% of the reaction have been
used for determining the initial velocity. The uncatalysed rates
were determined in the same manner and subtracted from the
total observed rates. Stock solutions of inhibitor (0.1 mM) were
prepared in distilled-deionised water and dilutions up to 0.01 nM
were done thereafter with the assay buffer. Inhibitor and enzyme
solutions were pre-incubated together for 15 min at room tem-
perature prior to assay, in order to allow for the formation of the
E-I complex. The inhibition constants were obtained by non-linear
least-squares methods using PRISM 3 and the Cheng-Prusoff equa-
tion, as reported earlier25–29 and represent the mean from at least
three different determinations.
4-chloroquinoline-3-carboxylates 4a–f. The target primary 3-(qui-
nolin-4-ylamino)benzenesulfonamides 6a–f were obtained through
a MW assisted nucleophilic substitution reaction of 3-aminobenze-
nesulfonamide 5 with the appropriate key intermediate 4a–f in
ethyl alcohol (Scheme 1).
In Scheme 2, 3-amino-N-methylbenzenesulfonamide 10 was
prepared as reported earlier13 through a nucleophilic substitution
for 3-nitrobenzenesulphonyl chloride 7 with methylamine, fol-
lowed by a catalytic hydrogenation to the nitro function. The later
reacted with the key intermediate 4e in refluxing ethanol to afford
the target secondary benzenesulfonamide 11 (Scheme 2).
The structures of the newly prepared quinolines 6a–f and 11
were confirmed and elucidated by NMR spectroscopy and high
resolution mass spectroscopy, which were in full agreement with
the postulated structures (Supplementary material).
1H NMR spectra of quinolines 6a-f showed new characteristic
signals at d 7.33– 7.37 ppm, and 9.68–10.25 ppm corresponding to
NH2 and NH groups, respectively, that distinguished the target
quinolines 6a-f from the key intermediates chloroquinolines 4a-f.
Also, the 1H NMR of 7-chloro-6-fluoro-4–(3-methanesulphonylami-
nophenyamino)-quinoline-3-carboxylic acid ethyl ester (11) dis-
played three significant signals at d 2.99, 9.63 and 9.79 ppm
assigned to -NHCH3, -SO2NH- and -NH- protons, respectively.
Results and discussion
Chemistry
The methods adopted for synthesis of the target quinolines 6a–f
and 11 are depicted in Schemes 1 and 2. Firstly, anilines 1a–f
were heated with diethyl ethoxymethylenemalonate in refluxing
ethanol to furnish diethyl 2-((phenylamino)methylene)malonate
derivatives 2a–f which thermally cyclised to the corresponding
ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylates 3a–f via heating
in diphenyl ether. Next, chlorination of quinolinones 3a–f was car-
Biological evaluation
Carbonic anhydrase inhibition
The newly prepared 3-(quinolin-4-ylamino)benzenesulfonamides
6a–f and 11 were evaluated for their ability to inhibit the physio-
ried out under anhydrous condition through heating with excess logically relevant hCA cytosolic isoforms, hCA I and II, by a

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1461
Scheme 2. Synthesis of target quinoline 11; Reagents and conditions: (i) Hunig’s Base/THF/stirring at r.t./1 h; (ii) H2/10% Pd/C/MeOH/r.t.; (iii) Compound 4e/Absolute
ethyl alcohol/reflux 4 h.
stopped-flow CO2 hydrase assay24. The inhibition data of the pre-
pared quinolines and the sulfonamide acetazolamide AAZ (as a
Table 1. Inhibition data of human CA isoforms hCA I and II for quinolines 6a–f
and 11, determined by stopped-flow CO2 hydrase assay, using acetazolamide
(AAZ) as a standard drug.
standard inhibitor) against the two examined isoforms are sum-
marised in Table 1. The following structure-activity relationship
(SAR) could be noted regarding the inhibition data reported in
Table 1:
i. The secondary sulfonamide reported here (11) failed to
inhibit the tested hCA isoforms (hCA I and hCA II) up to
10 lM, which confirmed the crucial role of the primary sul-
fonamide as a zinc-anchoring group, with the additional two
hydrogen bonds with Thr199 and Thr200 residues within the
enzyme active site.
ii. The data presented in Table 1 ascribed to the prepared pri-
ꢀ
KI (nM)
Comp.
R
hCA I
hCA II
223.4
782.3
175.4
3594.8
83.3
>10000
>10000
12.0
mary sulfonamides (6a-6e) weak potency in inhibiting the
ubiquitous cytosolic isoform hCA I with inhibition constants
(KIs) in the micromolar range, in detail, between 4.233 and
9.091 lM, except for the 6-methoxy substituted analog 6c
which arose as a submicromolar hCA I inhibitor with a KI
equals 0.966 lM, which represents 3.8-fold decreased efficacy
to the reference drug AAZ (KI equals 0.250 lM towards hCA
I). On contrary, the 5,7-dichloro substituted primary sulfona-
mide 6f failed to inhibit the hCA I up to 10 lM.
6a
6b
6c
6d
6e
6f
H
6-CH3
6-OCH3
6-Br
7-Cl-6-F
5,7-(Cl)2
–
4233.2
6644.4
966.0
9091.7
7604.6
>10000
>10000
250.0
11
AAZ
–
ꢀMean from three different assays, by a stopped flow technique (errors were in
the range of 5–10% of the reported values).
Noteworthy, the SAR outcomes highlighted that grafting the
strong electron-donating 6-metoxy group (compound 6c; KI
¼ 0.966 lM) resulted in 4.4-fold efficacy enhancement in
compound 6e (KI ¼ 0.083 lM) proved to be the most active
comparison to the unsubstituted analogue 6a (KI
¼
quinoline in inhibiting hCA II. Moreover, grafting a 6-methoxy
4.233 lM). Regarding the impact of substitution of the quin-
oline moiety within the primary sulfonamides series 6a-6f;
the inhibitory activities were decreased in the order of 6-
OCH3 >6-CH3 >7-Cl-6-F > 6-Br >5,7-(Cl)2.
group within the quinoline scaffold (compound 6c; KI
¼
0.083 lM) was advantageous for the inhibitory activity
toward hCA II, similarly to the SAR for hCA I inhibition.
Regarding the substitution effect for the quinoline moiety;
the inhibitory activities towards hCA II were decreased in the
order of 7-Cl-6-F > 6-OCH3 > 6-CH3 > 6-Br > 5,7-(Cl)2.
iii. The second ubiquitous cytosolic isoform examined here was
hCA II. It was apparent from the displayed results (Table 1)
that the tested primary sulfonamides (6a-6e) effectively inter-
fere with hCA II catalytic activities in submicromolar/micro-
molar concentration range (KI values of 0.083 – 3.594 lM),
whereas, no significant inhibition towards hCA II was
revealed for quinoline 6f (KI >10 lM). Nevertheless, among
Conclusion
In summary, we successfully synthesised new benzenesulfona-
substituted mides, bearing un/substituted ethyl quinoline-3-carboxylate
the
tested quinolines,
7-chloro-6-flouro

1462
M. M. AL-SANEA ET AL.
scaffold (6a-f and 11), which were evaluated for their inhibition of
hCA I and hCA II. Both the examined isoforms were inhibited by
the quinolines reported here in variable degrees; hCA I was inhib-
ited with KIs in the range of 0.966–9.091 lM, whereas hCA II in the
range of 0.083–3.594 lM. Among the tested compounds, the pri-
mary 7-chloro-6-flouro substituted sulfonamide derivative 6e (KI ¼
0.083 lM) proved to be the most active quinoline in inhibiting
hCA II, whereas, its secondary sulfonamide analogue 11 failed to
inhibit the hCA II up to 10 lM, confirming the crucial role of the
primary sulphonamido group, as a ZBG, for CA inhibitory activity.
their interaction with the native and cobalt-substituted
enzyme: kinetic and spectroscopic investigations. Eur J Med
Chem 1996;31:1001–10., (c) Supuran CT. How many carbonic
anhydrase inhibition mechanisms exist? J Enzyme Inhib Med
Chem 2016;31:345–60., (d) Supuran CT. Advances in struc-
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Expert Opin Drug Discov 2017;12:61–88., (e) Supuran CT.
Structure and function of carbonic anhydrases. Biochem J
2016;473:2023–32., (f) Neri D, Supuran CT. Interfering with
pH regulation in tumours as a therapeutic strategy. Nat Rev
Drug Discov 2011;10:767–77., (g) Supuran CT, Vullo D,
Manole G, et al. Designing of novel carbonic anhydrase
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Hematol Agents 2004;2:49–68.
Disclosure statement
No potential conflict of interest was reported by the authors.
4. (a) Pastorekova S, Parkkila S, Pastorek J, Supuran CT.
Carbonic anhydrases: current state of the art, therapeutic
applications and future prospects. J Enzyme Inhib Med
Chem 2004;19:199–229., (b) Supuran CT, Capasso C. The eta-
class carbonic anhydrases as drug targets for antimalarial
agents. Expert Opin Ther Targets 2015;19:551–63., (c)
Capasso C, Supuran CT. Bacterial, fungal and protozoan car-
bonic anhydrases as drug targets. Expert Opin Ther Targets
2015;19:1689–704., (d) Supuran CT, Capasso C. Biomedical
applications of prokaryotic carbonic anhydrases. Expert Opin
Ther Pat 2018;28:745–54., (e) Supuran CT, Capasso C. An
overview of the bacterial carbonic anhydrases. Metabolites
2017;7:56.
Funding
This research was supported by Jouf University (Grant 39/480), the
KIST Institutional programs (Grant No. 2E29260) from Korea
Institute of Science and Technology, and by the Creative Fusion
Research Program through the Creative Allied Project funded by
the National Research Council of Science & Technology (CAP-
12–1-KIST).
ORCID
5. (a) Supuran CT. Carbonic anhydrase inhibitors and activators
for novel therapeutic applications. Future Med Chem 2011;3:
1165–80., (b) Akocak S, Lolak N, Bua S, et al. Discovery of
novel 1,3-diaryltriazene sulfonamides as carbonic anhydrase
I, II, VII, and IX inhibitors. J Enzyme Inhib Med Chem 2018;
33:1575–80., (c) Winum JY, Temperini C, El Cheikh K, et al.
Carbonic anhydrase inhibitors: clash with Ala65 as a means
for designing inhibitors with low affinity for the ubiquitous
isozyme II, exemplified by the crystal structure of the topira-
mate sulfamide analogue. J Med Chem 2006;49:7024–31., (d)
Supuran CT. Carbonic anhydrase inhibitors in the treatment
and prophylaxis of obesity. Expert Opin Ther Pat 2003;13:
1545–50.
6. (a) Carta F, Supuran CT. Diuretics with carbonic anhydrase
inhibitory action: a patent and literature review (2005–2013).
Expert Opin Ther Pat 2013;23:681–91., (b) da Silva Cardoso
V, Vermelho AB, Ricci Junior E, et al. Antileishmanial activity
of sulfonamide nanoemulsions targeting the b-carbonic
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Synthesis and biological evaluation of histamine Schiff bases
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Acetazolamide for the treatment of idiopathic intracranial
hypertension. Expert Rev Neurother 2015;15:851–6.
Ahmed Elkamhawy
Claudiu T. Supuran
http://orcid.org/0000-0001-7398-6155
http://orcid.org/0000-0003-4262-0323
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