Macrocyclic sulfone derivatives: Synthesis, characterization, in vitro biological evaluation and molecular docking

Article abstract of DOI:10.1002/ddr.21775

An artificial series of macrocycles based on 4,4′-sulfonyldiphenol intermediate was synthesized using a multistep procedure involving oxidation of bisphenol sulfide, etherification of phenolic hydroxyl groups, and final ring closure with different diamines. Different chemical species having aromatic, heteroaromatic, and aliphatic characters were incorporated into macrocyclic frameworks in the final step of ring closure. This simple and easily executable synthetic strategy was applied to synthesize 15 macrocycles (5a-o) in excellent yields. Characterization of the synthesized products was achieved through well-known modern spectroscopic techniques such as IR, NMR, and Mass. Macrocycles 5m and 5n were found to show significant AChE inhibition with IC₅₀ values of 76.9 ± 0.24 and 71.2 ± 0.77 μM, respectively. Macrocycle 5n was also found to be an active inhibitor of butyrylcholinesterase (BChE) with IC₅₀ score of 55.3 ± 0.54 μM. Among others, macrocycle 5l cyclized with o-phenylenediamine demonstrated moderate inhibition with IC₅₀ value of 81.1 ± 0.54 μM. Increasing interest in studying interactions of macrocycles with different enzymatic targets compelled us to design and synthesize sulfone-based macrocycles that might prove as highly potent class of biologically active compounds.

Full text of DOI:10.1002/ddr.21775

Received: 6 September 2020
DOI: 10.1002/ddr.21775
Revised: 28 November 2020
Accepted: 2 December 2020
R E S E A R C H A R T I C L E
Macrocyclic sulfone derivatives: Synthesis, characterization,
in vitro biological evaluation and molecular docking
1
1
1
2
Muhammad Ibrahim | Abdul Latif | Ammara | Akbar Ali
|
3
4
5
6
Alany Ingrid Ribeiro | Umar Farooq | Farhat Ullah | Ajmal Khan
|
6
1
1
Ahmed Al-Harrasi | Manzoor Ahmad | Mumtaz Ali
1
Department of Chemistry, University of
Abstract
Malakand, Chakdara 18800, Dir Lower, Khyber
Pakhtunkhwa, Pakistan
0
An artificial series of macrocycles based on 4,4 -sulfonyldiphenol intermediate was
synthesized using a multistep procedure involving oxidation of bisphenol sulfide,
etherification of phenolic hydroxyl groups, and final ring closure with different
diamines. Different chemical species having aromatic, heteroaromatic, and aliphatic
characters were incorporated into macrocyclic frameworks in the final step of ring
closure. This simple and easily executable synthetic strategy was applied to synthe-
size 15 macrocycles (5a-o) in excellent yields. Characterization of the synthesized
products was achieved through well-known modern spectroscopic techniques such
as IR, NMR, and Mass. Macrocycles 5m and 5n were found to show significant AChE
inhibition with IC50 values of 76.9 ± 0.24 and 71.2 ± 0.77 μM, respectively. Mac-
rocycle 5n was also found to be an active inhibitor of butyrylcholinesterase (BChE)
with IC50 score of 55.3 ± 0.54 μM. Among others, macrocycle 5l cyclized with
o-phenylenediamine demonstrated moderate inhibition with IC50 value of 81.1
2
Department of Chemistry, University of
Sargodha, Sargodha, 40100, Pakistan
3
Department of Chemistry, Federal University
of S ~a o Carlos, Rod. Washington Luís, Km 265,
S ~a o Carlos, Brazil
4
Department of Chemistry, COMSATS
University Islamabad, Islamabad Campus,
Pakistan
5
Department of Pharmacy, University of
Malakand, Chakdara, Pakistan
6
Natural and Medical Sciences Research
Centre, University of Nizwa, PO Box 33, 616
Birkat Al Mauz, Nizwa, Oman
Correspondence
Abdul Latif and Mumtaz Ali, Department of
Chemistry, University of Malakand, Chakdara
1
8800, Dir Lower, Khyber Pakhtunkhwa,
±
0.54 μM. Increasing interest in studying interactions of macrocycles with different
Pakistan.
enzymatic targets compelled us to design and synthesize sulfone-based macrocycles
that might prove as highly potent class of biologically active compounds.
Email: dralatif2016@gmail.com (A. L.);
mumtazphd@gmail.com (M. A.)
Ahmed Al-Harrasi, Natural and Medical
Sciences Research Centre, University of
Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa,
Oman.
K E Y W O R D S
0
4,4 -sulfonyldiphenol, anticholinesterase activity, etherification, macrocycles, molecular
docking, oxidation, ring-closure
Email: aharrasi@unizwa.edu.om
1
|
INTRODUCTION
therapeutic strategy for AD. Currently, a very few therapeutic agents
such as galantamine, donepezil, and rivastigmine are available as
Alzheimer's disease (AD) has increased at an alarming rate and is now
a worldwide health problem. It is a progressive neurodegenerative dis-
order, characterized initially by selective loss of cholinergic neurons in
the basal forebrain, followed by cognitive and behavioral impairments
that increasingly disrupt activities of daily life, resulting in impaired
memory and behavior, as well as loss of intellectual, social abilities and
eventually death (Zheng et al., 2009). Inhibitors of acetylcholinester-
ase (AChE) and butyrylcholinesterase (BChE) leading to inhibition of
acetylcholine and butyrylcholine breakdown constitutes the main
approved drugs for the treatment of AD. The problem with these
drugs is that they have symptomatic effect only, and this makes it
need of the day to discover and develop new and more effective
inhibitors for the disease.
Macrocycles are considered important scaffolds in modern drug dis-
covery. They bear properties such as good solubility, lipophilicity, meta-
bolic stability, oral bioavailability and desirable pharmacokinetic as well
as pharmacodynamic properties (Yu & Sun, 2013). These properties
make this class of compounds ideal for pharmaceutical industry. Some
Drug Dev Res. 2020;1–13.
wileyonlinelibrary.com/journal/ddr
© 2020 Wiley Periodicals, LLC.
1

2
IBRAHIM ET AL.
of the clinically available macrocyclic antibiotics are azithromycin, eryth-
romycin, vancomycin, daptomycin, bacitracin, spiramycin, and rifampin
of pure compounds was done by spectroscopic techniques such as IR,
1
13
H- and C-NMR and Mass spectrometry.
(
Alvarez-Elcoro & Enzler, 1999; Chopra, 2007; Gulhane et al., 2014;
Jones & Barry, 1987; Rybak et al., 2009; Zuckerman et al., 2011). They
are being used in medicines, as complexing agents in chelation therapy,
in radionuclide therapy, energy storage molecules and as photochromes
0
2.1.2
|
Oxidation of 4,4 -thiodiphenol (1) into to
0
4,4 -sulfonyldiphenol (2)
(
Fernandes et al., 2011; Hirose et al., 2008; Karcz et al., 2014;
0
Mallinson & Collins, 2012; Tanaka et al., 2010; Vlasceanu et al., 2016;
Wilson et al., 2015; Yin et al., 2008). Despite the proven therapeutic
potential, macrocycles are one of the most under-explored and poorly
exploited drug class. The possible reason is that organic chemists con-
sider macrocycle synthesis, a difficult and time-consuming task in terms
of lack of versatile synthetic routes, work up procedures and low yields.
Still, because of their widespread importance in the modern era, chem-
ists are compelled to design new synthetic strategies for the synthesis
of novel macrocyclic drugs.
To a stirred solution of 4,4 -thiodiphenol (1) 0.5 g (0.0023 mol, 1 eq) in
AcOH:CH
3
CN (1:1) was slowly added drop wise a solution of NaIO
4
1.25 g (0.00575 mol, 2.5 eq) in a mixture of AcOH/H
2
O. The reaction
mixture was stirred until the formation of a residue. The completion of
reaction was monitored through TLC using hexane/ethyl acetate solvent
system. After completion, solvent was removed from the reaction mixture
under reduced pressure and the residue was suspended in brine and neu-
tralized with a saturated solution of K
filtered, and residue washed with water and dried in air. The filtrate was
extracted with CH Cl (3 × 20 mL). The combined organic extracts were
dried with anhyd. Na SO , filtered and evaporated in vacuo to give the
corresponding 4,4 -sulfonyldiphenol (2) (white soapy).
2 3
CO . The resulting suspension was
Two important functional groups, a sulfone and an amide are of
special interest to both organic and medicinal chemists. Biological
studies on the recently synthesized sulfones have revealed their anti-
fungal (Xu et al., 2011), antiparasitic (Kerr et al., 2009), antimicrobial
2
2
2
4
0
(
Patil et al., 2010), antiviral (La Regina et al., 2007), antimalarial (Bader
0 0
Synthesis of diethyl-2,2 -(4,4 -sulfonylbis
(4,1-phenylene)bis(oxy))diacetate (4)
et al., 1969), antileprotic (Dhar, 1975), insecticidal, ascarcidal, analge-
sic, and hypnotic (Buehler & Masters, 1939) activities. Similarly, amide
group owes its importance due to its presence in many synthetic
intermediates, biomolecules and active pharmaceutical products
2.1.3
|
0
To a 1000 mg, (4 mmol) solution of 4,4 -sulfonyldiphenol (2) in DMF
(
Grbovi ꢀc et al., 2018). It is noteworthy that combining the two groups
2 3
was added 1656 mg, (6 mmol) of K CO and refluxed for 30 minutes.
into the same molecule might render important biological properties
to the molecule. In a hope to find new molecules that can target cho-
linesterases, we have designed and synthesized 15 macrocyclic com-
pounds based on bisphenol sulfone and tested them for their
inhibition potential against AChE and BChE enzymes. Acetylcholines-
terase (AChE) and butyrylcholinesterase (BChE) from equine serum
were used to explore the enzymes inhibitory potential of the synthe-
sized compounds using Ellman's assay (Chen et al., 2015; Ellman
et al., 1961).
After 30 minutes 1468 mg (6 mmol) of ethyl-2-chloroacetate (3) was
added and the reaction mixture was refluxed for 2–3 hours. The pro-
gress of reaction was monitored by TLC using hexane/ethyl acetate
(6:4) as a solvent system. The reaction was worked up by pouring the
hot mixture into an ice-cold water, thus forming a white precipitate,
which was then filtered and air dried.
Yield: 97%; white solid.
+
HRMS: m/z [M] calcd. For
20 22 8
C H O S: 422.1035; found:
422.1550.
IR (KBr disc, ν cm− ): 3010 (C H Ar), 2930 (C H aliphatic), 1740
1
(
2
OCOR), 1589 (C C Ar), 1290 (Ar SO Ar).
1
2
2
2
|
METHODS
Chemistry
H NMR (DMSO-d
6
, 400 MHz, δ ppm): 1.2 (t, J = 7.2 Hz, 6H,
), 4.90 s (4H, 2 CH ),
2
CH
3
), 4.16 (q, J = 7.4 Hz, 4H, 2 CH
2
2
.1
.1.1
|
7.1 (d, J = 8.0 Hz, 4H, Ar H), 7.83 (d, J = 8.0 Hz, 4H, Ar H).
13
C NMR (100 MHz, DMSO-d
(2 Ar C, Sulfone), 134.0 (2 Ar C, Sulfone), 129.3 (4 Ar C, Sulfone),
15.4 (4 Ar C, Sulfone), 64.2 (2 CH ), 60.0 (2 CH ),
14.0 (2 CH ).
6
): δ (ppm) 169.11 (2
C O), 161.0
|
General
1
2
2
The solvents used were distilled before use. In some cases, dry solvents
were also used. Thin Layer Chromatography was performed to monitor
the progress of reactions and pre-coated Kieselgel-60 HF 254 cards
were used for this purpose. Silica gel 60 (70–230 mesh) was used for
column chromatography to separate and purify products of different
reactions. Melting points were recorded on Gallenkamp digital melting
point apparatus (MGB-595-010-M). The reactions were performed
according to standard procedures using clean glassware and synthetic
grade chemicals. Reagents were purchased from Sigma Aldrich, TCI,
and Acros and were used without further purification. Characterization
3
2.1.4
|
General procedure for macrocyclization of
diacetate (4) with diamines
To a stirred solution of diacetate (4) (0.1 g, 0.237 mmol) various
diamines were dissolved in 50 mL of ethyl alcohol in a 100 mL round
bottom flask. In each case, the reaction mixture was refluxed at
ꢀ
80 C for 4–7 hours. TLC was used to monitor the progress of reaction.

IBRAHIM ET AL.
3
1
The solvent system used for TLC consisted of 40% ethyl acetate and
H NMR (DMSO-d
6
, 400 MHz, δ ppm): 9.3 (s, 4H, NH ), 4.90
60% hexanes. At completion of reaction, the hot reaction mixture was
2
(s, 8H, 4 CH ), 7.16–7.20 (m, 4H, Ar H), 6.73 (d, J = 7.6 Hz, 4H,
poured into ice cold water, immediately obtaining a precipitate of mac-
rocycle. In case of impure products, the precipitates were further purified
through Silica gel 60 (70–230 mesh) column using suitable solvent
systems.
Ar H), 6.88 (d, J = 7.8 Hz, 4H, Ar H), 7.1 (d, J = 8.0 Hz, 8H, Ar H),
7.84 (d, J = 8.0 Hz, 8H, Ar H).
13
C NMR (100 Hz, DMSO-d ): δ (ppm) 169.11 (4 C O), 161.66
6
(4 Ar C, Sulfone), 150 (2 Ar C), 140 (4 Ar C), 134.54 (4 Ar C, Sul-
fone), 131 (12 Ar C), 129.80 (8 Ar C, Sulfone), 115.95 (8 Ar C, Sul-
Synthesis
of
8,20-dithioxo-4,12,16,24-tetraoxa-2,14-dithia-
(1,4)-tetrabenzenacyclotetracosaphane-
7
,9,19,21-tetraaza-1,3,13,15
2
fone), 114 (4 Ar C), 65.19 (4 CH ).
6
,10,18,22-tetraone-2,2,14,14-tetraoxide (5a).
Synthesis of 4,13,17,26-tetraoxa-2,15-dithia-7,8,10,20,22,23-
hexaaza-1,3,14,16(1,4)-tetra benzenacyclohexacosaphane-6,9,11,19,21,
24-hexaone 2,2,15,15-tetraoxide (5d).
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (Thiourea) given above.
ꢀ
Yield: 95% (103.6 mg); white solid; m. p. 140-142 C.
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (semicarbazide/hydrazinecarboxamide)
given above.
+
HRMS: m/z [M] calcd. For C34
28 4
H N O
S
12 4
: 812.0587; found:
8
(
12.2183.
IR (KBr disc, ν cm ): 3270 ( NH ), 3170 ( CSNH ), 3050 cm−1
−
1
Yield: 95% (107.3 mg), white solid; m. p. 170–172 C.
ꢀ
CH
2
), 3010 cm−
1
(
C
H Ar), 1690 cm−1
(
CONH ), 1589 cm−1
R), 1140 cm−1
HRMS: m/z [M] calcd. For C34
+
H N
30 6
O
14
S
2
: 810.1261; found:
(
(
C
C aromatic), 1336 ( CS ), 1249 cm− (Ar
1
O
810.1544.
I R (KBr disc, ν cm− ): 3050 ( CH
CONH ), 1589 (C C aromatic), 1313 (Ar NH ), 1249 (Ar O
1
Ar SO
2
Ar).
2
), 3010 (
C
H Ar), 1690
R),
1
H NMR (DMSO-d
6
, 400 MHz, δ ppm): 9.4 (s, 4H, NH ), 4.90
(
(
s, 8H, 4 CH
2
), 7.1 (d, J = 8.0 Hz, 8H, Ar H), 7.84 (J = 8.0 Hz, 8H,
2
1140 (Ar SO Ar).
1
Ar H 8H, Ar H).
H NMR (DMSO-d , 400 MHz, δ ppm): 10.4, 9.53, 9.3 (s, 6H,
6
13
C NMR (100 MHz, DMSO-d
O), 161.66 (4 Ar C, Sulfone), 134.54 (4 Ar C, Sulfone),
29.80 (8 Ar C, Sulfone), 115.95 (8 Ar C, Sulfone),
5.19 (4 CH ).
Synthesis of 4,12,16,24-tetraoxa-2,14-dithia-7,9,19,21-tetraaza-
,3,13,15(1,4)-tetra benzenacyclotetracosaphane-6,8,10,18,20,22-hexaone-
,2,14,14-tetraoxide (5b).
6
): δ (ppm) 182 (2 > C S), 169.11
NH ), 4.53 (s, 4H,
2
CH
2
), 4.90s (4H,
2
CH
2
), 7.1 (d,
(
4
C
J = 8.0 Hz, 8H, Ar H), 7.84 (d, J = 8.0 Hz, 8H, Ar H).
13
1
6
C NMR (100 Hz, DMSO-d ): δ (ppm) 168.62 (6 C O), 161.16
6
2
(4 Ar C, Sulfone), 134.04 (4 Ar C, Sulfone), 129.30 (8 Ar C, Sul-
fone), 115.45 (8 Ar C, Sulfone), 64.75 (4 CH ).
2
1
Synthesis of 9,21-dithioxo-4,13,17,26-tetraoxa-2,15-dithia-7,8,10,
20,22,23-hexaaza-1,3,14,16(1,4)-tetrabenzenacyclohexacosaphane-6,11,
19,24-tetraone-2,2,15,15-tetraoxide (5e).
2
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (Urea) given above.
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (thiosemicarbazide/hydrazinecarbothio-
amide) given above.
ꢀ
Yield: 92% (98.4 mg); white solid; m. p. 158–160 C.
+
HRMS: m/z [M] calcd. For C34
28 4 14 2
H N O S : 780.1043; found:
ꢀ
7
80.0964.
Yield: 77% (85.5 mg), white solid; m. p. 162–164 C.
IR (KBr disc, ν cm ): 3050 cm−1
−
1
(
CH
), 3010 cm−1
aromatic), 1313
Ar).
, 400 MHz, δ ppm): 9.2 (s, 4H, NH ), 4.90
), 7.11 (d, J = 8.0 Hz, 8H, Ar H), 7.84 (d, J = 8.0 Hz,
(
C
H
HRMS: m/z [M] calcd. For C34
+
H
N
O
S
: 842.0805; found:
2
30
6
12
4
Ar), 1690 cm−
1
(
CONH ), 1589 cm−1 (C
Ar NH ), 1249 cm− (Ar
C
842.1550.
IR (KBr disc, ν cm−1): 3050 ( CH
( CONH ), 1589 (C C aromatic), 1389 ( CS ), 1313 (Ar NH ),
1
R) 1140 cm−1 (Ar SO
(
O
2
2
), 3010 ( C H Ar), 1690
1
H NMR (DMSO-d
s, 8H, 4 CH
H, Ar H).
6
(
2
1249 (Ar
O
R), 1140 (Ar SO
, 400 MHz, δ ppm): 9.3, 9.53, 10.4, (s, 6H,
), 4.53 (s, 4H, 2 CH ), 7.06 (d,
J = 8.0 Hz, 8H, Ar H), 7.8 (d, J = 8.0 Hz, 8H, Ar H).
2
Ar).
1
8
H NMR (DMSO-d
6
13
C NMR (100 Hz, DMSO-d
4 Ar C, Sulfone), 134.54 (4 Ar C, Sulfone), 129.80 (8 Ar C, Sul-
fone), 115.95 (8 Ar C, Sulfone), 65.19 (4 CH ).
Synthesis of 4,14,18,28-tetraoxa-2,9,16,23-tetrathia-7,11,21,
5-tetraaza-1,3,15,17(1,3),8,10,22,24(1,4)-octabenzenacyclooctacosaph
6
): δ (ppm) 169.11 (6
C
O), 161.66
NH ), 4.86 (s, 4H, 2 CH
2
2
(
13
2
C NMR (100 Hz, DMSO-d
O), 161.66 (4 Ar C, Sulfone), 134.54 (4 Ar C, Sulfone),
).
Synthesis of 2,4,9,13,18,20,25,29-octaoxa-11,27-dithia-6,16,22
,32-tetraaza-1,3,5,17,19,21 (1,3),10,12,26,28(1,4)-decabenzenacyclo
6
): δ (ppm) 182 (2 > C S), 169.11
(4
C
2
129.80 (8 Ar C, Sulfone), 115.95 (8 Ar C, Sulfone), 65.19 (4 CH
2
ane-6,12,20,26-tetraone-2,2,9,9,16,16,23,23-octaoxide (5c).
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (Bis-(3-Aminophenyl)sulfone) given above.
dotriacontaphane-7,15,23,31-tetraone-11,11,27, 27-tetraoxide (5f).
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (1,3-Bis(3-Aminophenoxy)benzene) given
above.
ꢀ
Yield: 90% (116.6 mg), white solid; m. p. 150–152 C.
+
HRMS: m/z [M] calcd. For C56
H44N4O16
S
4
: 1156.1635; found:
1
(
156.2242.
IR (KBr disc, ν cm− ): 3050 ( CH
CONH ), 1589 (C aromatic), 1249 (Ar
Ar).
1
ꢀ
2
), 3010 (
C
H Ar), 1690
R), 1140
Yield: 90% (121.5 mg), white solid; m. p. 136–138 C.
+
C
O
HRMS: m/z [M] calcd. For C68
H
52
N
4
O
16
S
2
: 1245.2802; found:
(
Ar SO
2
1245.2069.

4
IBRAHIM ET AL.
+
HRMS: m/z [M] calcd. For C36
80.1594.
IR (KBr disc, ν cm− ): 3050 ( CH
Ar CH2 Ar), 1690 CONH ), 1589 (C
NH CH CH NH ), 1313 (Ar NH ), 1249 (Ar
Ar).
H
36
N
4
O
12
S
2
: 780.1771; found:
7
1
2
), 3010 (
C
H Ar), 2920
aromatic), 1560
R), 1140
(
(
(
(
C
2
2
O
Ar SO
2
1
H NMR (DMSO-d
), 4.56 s (8H, 4 CH
.84 (d, J = 8.0 Hz, 8H, Ar H).
6
, 400 MHz, δ ppm): 8.2 (s, 4H, NH ), 3.60
(
s, 8H, 4 CH
2
2
), 7.11 (d, J = 8.0 Hz, 8H, Ar H),
7
13
C NMR (100 Hz, DMSO-d
4 Ar C, Sulfone), 133.89 (4 Ar C, Sulfone), 129.25 (8 Ar C, Sul-
fone), 115.56 (8 Ar C, Sulfone), 66.92 (4 CH ), 41.21 (4 CH ).
6
): δ (ppm) 167.02 (4 C O), 161.34
(
2
2
Synthesis of 4,14,18,28-tetraoxa-2,16-dithia-7,11,21,25-tetraaza-
,3,15,17(1,4)-tetra benzenacyclooctacosaphane-6,12,20,26-tetraone-
1
4 3 2
SCHEME 1 (a) NaIO , CH COOH/H O (1:2.5), (b) m-CPBA, DCM
2,2,16,16-tetraoxide (5h).
(
1:2.5), (c) CH COOH/H O
3 2 2
(1:3)
Prepared according to general procedure for mac-
rocyclization of diacetate (4) with diamine (1,3-Propyle
nediamine) given above.
IR (KBr disc, ν cm−1): 3050 ( CH2 ), 3010 (
C
H Ar), 2920
aromatic), 1313
Ar), 1140 (Ar SO Ar).
, 400 MHz, δ ppm): 9.23 (s, 4H, 4 NH ),
), 6.17 (dd, J = 8.2 Hz, 6H, Ar H), 6.32 (dd,
Yield: 84% (100.8 mg), white solid; m.p. 122–124 C.
ꢀ
+
(
Ar CH2 Ar), 1690
(
CONH ), 1589 (C
R), 1150 (Ar
C
HRMS: m/z [M] calcd. For C38
H N
40 4
O
12
S
2
: 809.2118; found:
(
Ar NH ), 1249 (Ar
O
O
2
809.2183.
IR (KBr disc, ν cm−1): 3050 ( CH
(Ar CH Ar), 1690 CONH ), 1589 (C
NH CH CH NH ), 1313 (Ar NH ), 1249 (Ar
Ar).
1
H NMR (DMSO-d
6
2
), 3010 (
C
H Ar), 2920
aromatic), 1580
R), 1140
4
.90 (s, 8H, 4 CH
2
2
(
C
J = 8.2 Hz, 6H, Ar H), 6.67 (dd, J = 8.2 Hz, 6H, Ar H), 6.19 (t,
J = 7.8 Hz, 2H, Ar H), 6.98 (t, J = 7.5 Hz, 2H, Ar H), 7.30 (t,
J = 8.3 Hz, 2H, Ar H), 7.11 (d, J = 8.0 Hz, 8H, Ar H), 7.84 (d,
J = 8.0 Hz, 8H, Ar H).
(
2
2
O
(Ar SO
2
1
H NMR (DMSO-d
6
, 400 MHz, δ ppm): 1.75 (q, J = 4.9 Hz, 4H,
), 4.58
2
CH
2
), 8.22 s (4H, NH ), 3.16 (t, J = 7.2 Hz, 8H, 4 CH
2
1
3
C NMR (100 Hz, DMSO-d
6
): δ (ppm) 168.62 (4
C
O), 161.71
(s, 8H, 4 CH2 ), 7.11 (d, J = 8.0 Hz, 8H, Ar H), 7.86 (d, J = 8.0 Hz,
(
4 Ar C, Sulfone), 157.0 (8 Ar C), 150.52 (4 Ar C), 134.04 (4 Ar C,
8H, Ar H).
13
Sulfone), 130.07 (6 Ar C), 129.30 (8 Ar C, Sulfone), 115.45 (8 Ar C,
Sulfone), 112.62 (4 Ar C), 109.60 (4 Ar C), 108.34 (4 Ar C), 106.02
C NMR (100 Hz, DMSO-d
(4 Ar C, Sulfone), 133.92 (4 Ar C, Sulfone), 129.25 (8 Ar C, Sul-
fone), 115.56 (8 Ar C, Sulfone), 66.97 (4 CH ), 40.10 (8 CH ),
6
): δ (ppm) 166.78 (4 C O), 161.32
(
2 Ar C), 64.68 (4 CH
2
).
2
2
Synthesis of 4,13,17,26-tetraoxa-2,15-dithia-7,10,20,23-tetraaza-
,3,14,16(1,4)-tetra benzenacyclohexacosaphane-6,11,19,24-tetraone-
,2,15,15-tetraoxide (5g).
2
36.00 (2 CH ).
9
9
1
2
Synthesis
of
8 H,20 H-4,12,16,24-tetraoxa-2,14-dithia-
7,9,19,21-tetraaza-8,20(2,6)-dipurina-1,3,13,15(1,4)-
tetrabenzenacyclotetracosaphane-6,10,18,22-tetraone
2,2,14,14-tetraoxide (5i).
Prepared according to general procedure for mac-
rocyclization of diacetate (4) with diamine (1,2-Ethylenediamine)
given above.
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (9H-Purine-2,6-diamine) given above.
ꢀ
Yield 80% (92.0 mg), white solid; m. p. 153–155 C.
SCHEME 2 Etherification
0
reaction of 4,4 -sylfonyldiphenol
0
0
2
into diethyl-2,2 -(4,4 -
sulfonylbis(4,1-phenylene)bis
oxy))diacetate 4
(

IBRAHIM ET AL.
5
SCHEME 3 Steps for the
synthesis of macrocycles (5a-o)
SCHEME 4 Proposed mechanistic approach to the synthesis of macrocycles (5a-o)

6
IBRAHIM ET AL.
FIGURE 1 Structures of synthesized macrocycles (5a-o)

IBRAHIM ET AL.
7
TABLE 1 Anticholinesterase activity of compounds 5a-o
J = 8.0 Hz, 8H, Ar H), 7.11 (d, J = 8.0 Hz, 8H, Ar H), 7.84 (d,
J = 8.0 Hz, 8H, Ar H).
a
a
AChE
BChE
13
C NMR (100 Hz, DMSO-d ): δ (ppm) 169.11 (4 C O), 161.66
6
Compound
IC50 (μM)
IC50 (μM)
(
(
(
4 Ar C, Sulfone), 142.8 (24 Ar C), 134.52 (4 Ar C, Sulfone), 130.10,
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
246.3 ± 0.34
576.9 ± 0.54
Not active
387.9 ± 0.55
576.9 ± 0.67
Not active
24 Ar C), 129.81 (8 Ar C, Sulfone), 125, (24 Ar C), 118.10,
24 Ar C), (8 Ar C, Sulfone), 115.95, (24 Ar C), 66.18 (4 CH
2
),
61.60 (4 CH
2
), 30.53 (2 CH ).
2
234.6 ± 0.44
Not active
296.3 ± 0.22
Not active
Synthesis of 4,12,16,24-tetraoxa-2,14-dithia-7,9,19,21-tetraaza-1,3,8,
13,15,20(1,4)-hexa benzenacyclotetracosaphane-6,10,18,22-tetraone-2,2,14,
14-tetraoxide macrocycle (5k).
667.2 ± 0.55
Not active
691.3 ± 0.69
Not active
Prepared according to general procedure for macrocyclization of
g
h
i
diacetate (4) with diamine (p-Phenylendiamine) given above.
457.9 ± 0.66
430.2 ± 0.45
341.6 ± 0.66
422.4 ± 0.51
81.1 ± 0.54
76.9 ± 0.24
71.2 ± 0.77
245.7 ± 0.12
69.7 ± 0.18
569.3 ± 0.54
540.7 ± 0.69
528.0 ± 0.67
570.8 ± 0.15
234.0 ± 0.54
248.6 ± 0.34
55.3 ± 0.54
361.3 ± 0.58
52.3 ± 0.53
ꢀ
Yield: 80% (90.4 mg), violet solid; m. p. 170–174 C.
+
HRMS: m/z [M] calcd. For C44
H N
36 4
O
12
2
S : 876.1771; found:
j
8
76.1973.
IR (KBr disc, ν cm− ): 3050 ( CH
CONH ), 1589 (C C aromatic), 1313 (Ar NH ), 1249 (Ar
k
l
1
2
), 3010 (
C
H Ar), 1690
R),
(
O
m
n
o
2
1140 (Ar SO Ar).
1
H NMR (DMSO-d
6
, 400 MHz, δ ppm): 8.73 (s, 4H, 4 NH ),
), 7.1 (d, J = 8.0 Hz, 8H,
7
.52 (s, 8H, Ar H), 4.90 (s, 8H, 4 CH
2
Galantamine
Ar H), 7.84 (d, J = 8.0 Hz, 8H, Ar H).
13
a
C NMR (100 Hz, DMSO-d
Sulfone), 134.04 (4 Ar C, Sulfone), 134.04, (6 Ar C), 129.30 (8 Ar C, Sulfone),
21.8, (6 Ar C), 115.45 (8 Ar C, Sulfone), 64.68 (4 CH ).
6
): δ (ppm) 169.62 (4 C O), 161.16 (4 Ar C,
Inhibition of AChE and BChE expressed in mean ± SD (n = 3). Significant
activity against each enzyme are shown in bold font.
1
2
Synthesis of 4,12,16,24-tetraoxa-2,14-dithia-7,9,19,21-tetraaza-
1,3,13,15(1,4),8,20(1,3)-hexabenzenacyclotetracosaphane-6,10,18,22-
tetraone-2,2,14,14-tetraoxide (5l).
ꢀ
Yield: 87% (118.0 mg), white solid; m. p. 145–147 C.
+
HRMS: m/z [M] calcd. For C42
H
32
N O S
12 12 2
: 960.1704; found:
9
60.1776.
IR (KBr disc, ν cm− ): 3050 ( CH
CONH ), 1589 (C C aromatic), 1313 (Ar NH ), 1249 (Ar
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (m-phenylenediamnie) given above.
1
2
), 3010 (
C
H Ar), 1690
R),
ꢀ
(
O
Yield: 75% (84.5 mg), white solid; m. p. 178–180 C.
+
1
140 (Ar SO
2
Ar).
HRMS: m/z [M] calcd. For C44
H N
36 4
O
12
2
S : 876.1771; found:
1
H NMR (DMSO-d
6
, 400 MHz, δ ppm): 9.6 (s, 4H, 4 NH ),
CH ), 4.90 (s, 8H,
), 7.1 (d, J = 8.0 Hz, 8H, Ar H), 7.84 (d, J = 8.0 Hz,
H, Ar H).
876.1973.
IR (KBr disc, ν cm− ): 3050 ( CH2 ), 3010 (
CONH ), 1589 (C aromatic), 1313 (Ar NH ), 1249
(Ar R),1140 (Ar SO Ar).
H NMR (DMSO-d , 400 MHz, δ ppm): 9.30 (s, 4H, 4 NH ),
4.84 (s, 8H, 4 CH ), 7.15 (d, J = 8.4 Hz, 4H, Ar H), 7.32 (t,
1
1
4
8
2.76 (s, 2H, 2 NH ), 7.80 (s, 2H, 2
CH
C
C H Ar), 1690
2
(
C
O
1
2
13
C NMR (100 Hz, DMSO-d
6
): δ (ppm) 168.62 (4
C
O), 161.16
6
(
4 Ar C, Sulfone), 152.7, 152.3, 151.8 (6 Ar C), 138.7, (2 Ar C),
2
1
1
34.04 (4 Ar C, Sulfone), 129.30 (8 Ar C, Sulfone), 115.3 (2 Ar C),
15.45 (8 Ar C, Sulfone), 64.68 (4 CH ).
J = 8.6 Hz, 2H, Ar H), 7.56 (d, J = 8.2 Hz, 2H, Ar H), 7.05 (d,
J = 8.1 Hz, 8H, Ar H), 7.78 (d, J = 8.1 Hz, 8H, Ar H).
2
1
3
Synthesis of 4,10,14,20,24,30,34,40-octaoxa-2,22-dithia-7,17,27,
7-tetraaza-1,3,8,16,21, 23,28,36(1,4)-octabenzenacyclotetracontaph
6
C NMR (100 Hz, DMSO-d ): δ (ppm) 169.12 (4 C O), 161.66
3
(4 Ar C, Sulfone), 142.00, (3 Ar C), 134.54 (4 Ar C, Sulfone), 129.80
(8 Ar C, Sulfone), 128.00, 118.00, (9 Ar C), 115.95 (8 Ar C, Sul-
an-6,9,15,18,26,29,35,38-octaone-2,2,22,22-tetraoxide (5j).
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (1,3-propanediyledibenzoate) given above.
2
fone), 113.00, (12 Ar C), 65.18 (4 CH ).
Synthesis of 4,11,15,22-tetraoxa-2,13-dithia-7,8,18,19-tetraaza-
1,3,12,14(1,4)-tetra benzenacyclodocosaphane-6,9,17,20-tetraone-2,2,
13,13-tetraoxide (5m).
ꢀ
Yield: 90% (124.0 mg), white solid; m. p. 113–115 C.
+
HRMS: m/z [M] calcd. For C66
56 4 20 2
H N O S : 1288.2929; found:
1
288.1231.
IR (KBr disc, ν cm− ): 3050 ( CH
Prepared according to general procedure for macrocyclization of
diacetate (4) with diamine (Hydrazine hydrate) given above.
1
2
), 3010 (
C H Ar), 1725
ꢀ
(
ArCOOR), 1690 ( CONH ), 1589 (C C aromatic), 1313 (Ar NH ),
Yield: 90% (100.8 mg), white solid; m. p. 268-270 C.
+
1
249 (Ar
O
R), 1140 (Ar SO
, 400 MHz, δ ppm): 9.85 (s, 4H, 4 NH ),
), 4.22 (t, J = 7.4 Hz, 8H, 4 CH ), 1.9 (q,
), 7.23 (d, J = 8.0 Hz, 8H, Ar H), 7.57 (d,
2
Ar).
HRMS: m/z [M] calcd. For C32
H
28
N
4
O
12
S
2
: 724.1145; found: 724.0021.
H Ar), 1690
CONH ), 1589 (C C aromatic), 1313 (Ar NH ), 1249 (Ar R),
1140 (Ar SO Ar).
1
IR (KBr disc, ν cm−1): 3050 ( CH2 ), 3010 (
C
H NMR (DMSO-d
6
4
.90 (s, 8H, 4 CH
2
2
(
O
J = 7.1 Hz, 4H, 2 CH
2
2

8
IBRAHIM ET AL.
FIGURE 2 (a) 3D view of the docking pose of macrocycle 5n (green colored line-view model) in the binding pocket of AChE (4EY6). (b) Two-
dimensional (2D) interaction diagram for 5n. (c) Ribbon diagram depicting docked pose of 5n (yellow) in the binding cavity (mesh surface) of AChE (4EY6)
1
13
H NMR (DMSO-d
s, 8H, 4 CH ), 7.11 (d, J = 8.0 Hz, 8H, Ar H), 7.84 (d, J = 8.0 Hz,
H, Ar H).
6
, 400 MHz, δ ppm): 9.4 (s, 4H, 4 NH ), 4.90
C NMR (100 Hz, DMSO-d
(8 Ar C, Sulfone), 134.04 (8 Ar C, Sulfone), 129.30 (16 Ar C, Sul-
fone), 115.45 (16 Ar C, Sulfone), 64.68 (8 CH ).
6
): δ (ppm) 168.02 (8 C O), 161.16
(
2
8
2
1
3
C NMR (100 Hz, DMSO-d
4 Ar C, Sulfone), 134.02 (4 Ar C, Sulfone), 129.30 (8 Ar C, Sul-
fone), 115.45 (8 Ar C, Sulfone), 65.19 (4 CH ).
6
): δ (ppm) 169.18 (4
C
O), 161.16
Synthesis of 4,11,15,22,26,33,37,44-octaoxa-2,13,24,35-tetrathia-7,8,18,
19,29,30,40,41-octaaza-1,3,12,14,23,25,34,36(1,4)-octabenzenacyclote
(
2
tratetracontaphan-6,9,17,20,28,31,
tetraoxide (5o).
39,42-octaone-2,2,24,24-
Synthesis of 4,11,15,22,26,33,37,44-octaoxa-2,13,24,35-tetrathia-
,8,18,19,29,30,40,41-octaaza-1,3,12,14,23,25,34,36(1,4)-octabenzena
7
Prepared according to general procedure for macrocyclization of
0
cyclotetratetracontaphan-6,9,17,20,28,31,39,42-octaone- 2,2,13,13,24,
diacetate (4) with diamine (2,2 -((thiobis(4,1-phenylene))bis(oxy))di
2
4,35,35-octaoxide (5n).
(acetohydrazide)) given above.
ꢀ
Prepared according to general procedure for macrocyclization of
Yield: 80% (148.8 mg), white solid; m. p. 235–240 C.
0
+
diacetate (4) with diamine (2,2 -((sulfonylbis(4,1-phenylene))bis(oxy))di
HRMS: m/z [M] calcd. For C64
56 8
H N O
S
20 4
: 1384.2494; found:
(
acetohydrazide)) given above.
1384.1652.
IR (KBr disc, ν cm−1): 3050 ( CH2 ), 3010 (
aromatic), 1140 (Ar SO Ar), 1249 (Ar
ꢀ
Yield: 85% (164.4 mg), white solid; m.p. 226–228 C.
C
H Ar), 1589
R), 1690
+
HRMS: m/z [M] calcd. For C64
H N
56 8
24
O S
4
: 1448.2290; found:
(C
(
C
2
O
1
448.1878.
IR (KBr disc, ν cm− ): 3050 ( CH2 ), 3010 (
CONH ), 1589 (C C aromatic), 1313 (Ar NH ), 1249 (Ar
CONH ), 1313 (Ar NH ).
1
1
C
H Ar), 1690
R),
6
H NMR (DMSO-d , 400 MHz, δ ppm): 9.50 (s, 8H, 8 NH ),
(
O
4.90 (s, 16H, 8 CH
2
), 7.63 (d, J = 8.0 Hz, 8H, Ar H), 6.54 (d,
1
140 (Ar SO
2
Ar).
J = 8.0 Hz, 8H, Ar H), 7.11 (d, J = 8.0 Hz, 8H, Ar H), 7.84 (d,
J = 8.0 Hz, 8H, Ar H).
1
H NMR (DMSO-d
6
, 400 MHz, δ ppm): 9.55 s (8H, 8 NH ),
13
4
.90s (16H, 8 CH
2
), 7.11 (d, J = 8.0 Hz, 16H, Ar H), 7.84 (d,
C NMR (100 Hz, DMSO-d
6
): δ (ppm) 168.62 (8 C O), 161.16
J = 8.0 Hz, 16H, Ar H).
(4 Ar C, Sulfone), 153.52, (6 Ar C) 134.04 (4 Ar C, Sulfone), 129.30

IBRAHIM ET AL.
9
FIGURE 3 (a) 3D view of the docking pose of macrocycle 5m (green colored line-view model) in the binding pocket of AChE (4EY6). (c) Two-
dimensional (2D) interaction diagram for 5m. (c) Ribbon diagram depicting docked pose of 5m (yellow) in the binding cavity (mesh surface) of
AChE (4EY6)
(
8 Ar C, Sulfone), 129.18, 128.00, (12 Ar C), 115.74 (14 Ar C, Sul-
concentrations of compounds and standard that caused 50% inhibi-
tion (IC50) of the two cholinesterase enzymes were expressed as
mean ± SD.
fone), 64.68 (8 CH ).
2
2
.1.5
|
Pharmacology
Molecular docking
The interactions of our synthesized macrocycles with amino acid resi-
dues in the active sites of two target cholinesterase enzymes namely
acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were
studied through molecular docking approach as part of our computer
aided drug design project. A highly efficient software package by the
name Molecular Operating Environment (MOE) was used to dock the
synthesized compounds. Two dimensional structures of macrocycles
(5a-5o) obtained as files with .sdf extensions from ChemDraw Profes-
sional version 16.0 were opened as three dimensional sterostructures
in the program. These structures were first 3D protonated and then
energy minimized using default parameters of the software (gradient:
0.05, Force Field: MMFF94X). The three-dimensional structures of
AChE and BChE were obtained from the protein databank with PDB IDs
of 4EY6 and 4BDS, respectively. The structures of our target enzymes
were prepared in MOE by sequential removal of water molecules, 3D
protonation and energy minimization using default values in the MOE.
Enzyme inhibition
Enzymes and reagents including acetylcholine iodide (AChI), but-
0
yrylcholine chloride (BChCl), 5,5 -dithiobis-(2-nitrobenzoic acid)
(
DTNB) and galantamine were purchased from Sigma Aldrich.
Reported protocol (Ahmad et al., 2018) employing a spectrophoto-
metric method was used to determine enzyme inhibitions of the syn-
thesized macrocycles (5a-o) in comparison to galantamine as
reference standard.
Solutions consisting of DTNB (0.2 mM) in 62 mM sodium phos-
phate buffer (pH 8.0, 880 μL), solution of macrocycles (40 μL) and ace-
tylcholinesterase or butyrylcholinesterase (40 μL) were mixed and
ꢀ
incubated for 15 min (25 C). In each case, the initiation of activity
took place by adding 40 μL acetylcholine (ACh) or butyrylcholine
(
BCh). The hydrolysis of acetylcholine or butyrylcholine was estimated
at a wavelength of 412 nm. Each experiment was repeated thrice and

1
0
IBRAHIM ET AL.
FIGURE 4 (a) Ribbon diagram depicting docked pose of 5l (yellow) in the binding cavity (mesh surface) of AChE (4EY6). (b) 3D view of the
docking pose of macrocycle 5l (green colored line-view model) in the binding pocket of AChE (4EY6). (c) Two-dimensional (2D) interaction
diagram for 5l
0
0
3
3
|
RESULTS AND DISCUSSION
The formation of diethyl-2,2 -(4,4 -sulfonylbis(4,1-phenylene)bis
(
oxy))diacetate (4) was subsequently followed by ring closure in a con-
.1
|
Synthesis and mechanistic rationalization of
densation reaction with various aromatic and aliphatic diamines
using ethyl alcohol as a medium for the reaction under the same con-
ditions (Scheme 3). Under diluted conditions, various diamines were
macrocycles 5a-o
0
0
In light of the importance of sulfonyl functional group, the idea of syn-
thesizing macrocycles deploying this important moiety was developed.
An effective strategy to synthesize sulfone-based macrocycles was
adopted employing previously described methods of oxidation,
etherification, and macrocyclization.
dropped into solution of diethyl-2,2 -(4,4 -sulfonylbis(4,1-phenylene)
bis(oxy))diacetate (4) and the desired macrocyclic products (5a-o)
were obtained in very good yields. The optimized conditions for the
synthesis of macrocycles consisted of stirring of 1 equivalent of the
diacetate with 0.5 equivalent of diamines. Both DMF and EtOH
were used as solvents, but good results in terms of product yield
were obtained with EtOH as it could be very easily removed from
reaction mixture. To investigate the substrate scope and limitations
we have synthesized a total of 15 macrocycles (5a-o) according to
Scheme 3.
Our strategy was to optimize conditions for the three steps in
our protocol. Different oxidizing agents and solvents were
0
employed for oxidation of 4,4 -thiodiphenol (1). The synthesis of
0
4
,4 -sylfonyldiphenol (2) by oxidation with different oxidizing
4 2 2
agents like NaIO , H O and m-chloroperbenzoic acid (m-CPBA)
0
from 4,4 -thiodiphenol (1) at room temperature is shown below in
Scheme 1.
A mechanistic rationalization for the cyclization reaction is
provided in Scheme 4. It is conceivable that the initial step
involves condensation of the carbonyl and a diamine group to
form the desired products through nucleophilic addition reac-
tions. Diamines added to the carbonyl groups lose protons which
are taken up by ethoxide groups from the diacetates, thus
0
0
The etherification of 4,4 -sylfonyldiphenol (2) into diethyl-2,2 -
0
(
4,4 -sulfonylbis(4,1-phenylene)bis(oxy))diacetate (4) was carried out
with ethyl-2-chlororacetate (3) in DMF as a reaction medium under
reflux conditions (Scheme 2).

IBRAHIM ET AL.
11
FIGURE 5 (a) Ribbon diagram depicting docked pose of 5n (yellow) in the binding cavity (mesh surface) of BChE (4BDS) (b) two-dimensional
2D) interaction diagram for 5n. (c) 3D view of the docking pose of macrocycle 5n (green colored line-view model) in the binding pocket of
(
BChE (4BDS)
forming ethyl alcohol and the desired macrocyclic products
demonstrated moderate inhibition with IC50 value of 81.1 ± 0.54 μM. It
is interesting to note that 5k, a macrocyclic analogue of 5l closed with
p-phenylenediamine showed non-significant activity.
(
Figure 1).
3
.2
|
Anticholinesterase activity
3
.3
|
Molecular docking interactions
The synthesized macrocycles were initially tested against two impor-
tant cholinesterase enzymes (AChE & BChE) involved in the neuro-
logical disorder called Alzheimer's. The final results of this assay
were expressed as 50% inhibitory concentration (IC50) values in
micromole (μM) unit as displayed in Table 1. Galantamine was cho-
sen as a dual reference inhibitor for the two enzymes. Low to mod-
erate activity was recorded by the set of compounds (5a-o) as
compared to galantamine. From a structural point of view (Figure 1),
it can be hypothesized that hydrazine-closed macrocycles show sig-
nificant inhibition against the selected enzymes and therefore, indi-
cating importance of −NH − NH− linkage in the inhibition process.
Two such macrocycles 5m and 5n which were symmetric around
hydrazide linkage (−NH − NH−) were found to show significant
AChE inhibition with IC50 values of 76.9 ± 0.24 and 71.2 ± 0.77 μM,
respectively. Macrocycle 5n was also found to be an active inhibitor
of butyrylcholinesterase (BChE) with IC50 score of 55.3 ± 0.54 μM.
Amongst others, macrocycle 5l cyclized with o-phenylenediamine
Based on experimental observations, macrocycles showing significant
cholinesterase inhibitions were further chosen for protein-ligand
interaction studies. MOE docking software with default parameters
was used for transporting ligand molecules (5n, 5m, and 5l) into the
active gorges of both AChE and BChE crystal structures. A total of
five conformations were generated for each ligand and the top ranked
conformations were further subjected to analysis for their protein-
ligand interactions. The most active macrocycle 5n was found to fit
into active site of AChE with a docking score of −11.7884 by esta-
blishing significant interactions with Glu 292, Trp 286, Arg 296, Phe
295, Ser 203, His 447, Glu 202, Trp 86, Ser 125, Tyr 124, Tyr 72, and
Leu 76 as shown in the interaction diagram (Figure 2). Arg 296, Phe
295, and His 447 showed hydrogen bonding interactions with sulfonyl
and carbonyl oxygen atoms of the ligand. Some pi-pi stacking interac-
tions were also found between Trp 86 and Trp 286 and phenyl rings
of the docked ligand.

1
2
IBRAHIM ET AL.
Macrocyle 5m was also active with MOE docking score of
DATA AVAILABILITY STATEMENT
−
9.4188 that can fit in the active gorge of AChE. Upon visual inspec-
The data used to support the findings of this research work have been
included in this article
tion (Figure 3), different types of interactions between 5m and amino
acid residues of AChE such as Ser 203, Gly 122, Gly 121, Trp 86, Ser
1
25, Tyr 124, Asp 74, Tyr 72, and Trp 286 can be seen. Trp 86 showed
ORCID
π-π stacked interaction and Trp 286 showed π-π T-shaped interactions
Mumtaz Ali
https://orcid.org/0000-0002-3329-4039
with phenyl ring. Hydrogen bonding interaction of Gly 122, Gly
1
21, Tyr 72 with docked ligand and some carbon-hydrogen bonding
REFERENCES
interactions can also be observed i.e. Ser 203, Ser 125 and Asp 74 with
Carbonyl oxygen, sulphonyl oxygen and CH of the ligand.
Ahmad, H., Ahmad, S., Ali, M., Latif, A., Shah, S. A. A., Naz, H., ur
Rahman, N., Shaheen, F., Wadood, A., Khan, H. U., & Ahmad, M.
(
2018). Norditerpenoid alkaloids of Delphinium denudatum as cholines-
Macrocycle 5l also showed some acetylcholinesterase inhibition
activity and was successfully docked into the active pocket of AChE
terase inhibitors. Bioorganic Chemistry, 78, 427–435.
Alvarez-Elcoro, S., & Enzler, M. J. (1999). The macrolides: Erythromycin,
clarithromycin, and azithromycin. Mayo Clinic Proceedings, 74(6),
(
4EY6) with a docking score of −7.8816. Various types of interac-
6
13–634.
tions were identified upon visual inspection (Figure 4). Amino acid
residues Ser 293, Tyr 72 and Trp 286 displayed hydrogen bonding
interactions with carbonyl and sulphonyl oxygen of the ligand (5l).
Thr 75 revealed carbon hydrogen bonding interaction with CH and
Leu 76 exhibited π-π T-shaped interaction with phenyl ring. Tyr
Bader, H., Hoops, J. F., Biel, J. H., Koelling, H. H., Stein, R. G., & Singh, T.
0
(
1969). Antimalarials. 3, 3'-Dinitro (or amino)-4, 4 -di (substituted
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Chen, V. P., Gao, Y., Geng, L., Parks, R. J., Pang, Y.-P., & Brimijoin, S.
3
41 showed pi-sulfur interaction, Tyr 124 pi-lone pair interaction
with the docked ligand.
(
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The only macrocycle that showed significant activity against
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a docking score of −11.7884. Upon visual inspection, different inter-
actions were seen (Figure 5) like π-π stacked interaction of Trp 82 and
amide-pi stacked interaction of Gly 116, Gly 283 with phenyl ring. Ile
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6
9, Pro 74 and Pro 84 showed pi-alkyl interaction. Various Hydrogen
bonding interactions i.e. Ser 72, Tyr 128, His 438, carbon hydrogen
bonding interactions such as Gly 117, Gly 197, Leu 286, Pro 285, Pi-
donor hydrogen bonding interaction of Asp 70, Glu 80, Pi-sulfur inter-
action of Phe 329, pi-lone pair interaction of Asn 83 and various van
dar waals interactions with docked ligand can also be displayed.
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4
4
|
CONCLUSIONS
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Popsavin, M., & Kevrešan, S. (2018). Microwave-assisted synthesis of
biologically active amide derivatives of naphthenic acids under neat
conditions. Macedonian Journal of Chemistry and Chemical Engineering,
In conclusion, we have introduced a very mild, straightforward,
sequential, rapid and highly diverse synthetic pathway for the synthe-
sis of macrocycles. These artificial macrocyclic scaffolds were formed
by ring closure reactions via various diamines (aromatic and aliphatic).
The overall sequence used here was to introduce different ring sizes
using readily available starting materials in a three-step procedure. It
is worthy to notice that amongst the synthesized compounds,
hydrazine-based macrocycles (5 m and 5n) can be developed as leads
for drug development against cholinesterases and hence can be con-
sidered as alternate molecules for treating Alzheimer's.
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ACKNOWLEDGMENTS
Karcz, D., Boro nꢀ , B., Matwijczuk, A., Furso, J., Staro nꢀ , J., Ratuszna, A., &
This work was financially supported by the Higher Education Commis-
sion of Pakistan (HEC), under NRPU project # 20-4029, titled “Syn-
thesis, characterization and applications of macrocycles”.
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CONFLICT OF INTEREST
All the authors declare no conflict of interest.

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