Synthesis, characterization, molecular docking and in?vitro antimalarial properties of new carboxamides bearing sulphonamide

Article abstract of DOI:10.1016/j.ejmech.2017.04.029

Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in?vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in?vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08?μM respectively comparable with chloroquine 0.06?μM. Compound 7c was the most potent antioxidant agent with IC₅₀ value of 0.045?mM comparable with 0.34?mM for ascorbic acid. In addition to the successful synthesis of the target molecules using boric acid catalysis, the compounds were found to have antimalarial and antioxidant activities comparable with known antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the treatment of malaria.

Full text of DOI:10.1016/j.ejmech.2017.04.029

Accepted Manuscript
Synthesis, characterization, molecular docking and in vitro antimalarial properties of
new carboxamides bearing sulphonamide
D.I. Ugwu, U.C. Okoro, P.O. Ukoha, S. Okafor, A. Ibezim, N.M. Kumar
PII:
S0223-5234(17)30286-6
10.1016/j.ejmech.2017.04.029
EJMECH 9376
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 21 December 2016
Revised Date: 10 April 2017
Accepted Date: 12 April 2017
Please cite this article as: D.I. Ugwu, U.C. Okoro, P.O. Ukoha, S. Okafor, A. Ibezim, N.M.
Kumar, Synthesis, characterization, molecular docking and in vitro antimalarial properties of new
carboxamides bearing sulphonamide, European Journal of Medicinal Chemistry (2017), doi: 10.1016/
j.ejmech.2017.04.029.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis, characterization, molecular docking and in vitro antimalarial properties of new
carboxamides bearing sulphonamide
D. I. Ugwu1,3*, U. C. Okoro1, P. O. Ukoha1, S. Okafor2, A. Ibezim2 and N. M. Kumar3
1Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka
2Department of Pharmaceutical Chemistry, University of Nigeria, Nsukka
3Department of Chemistry, Indian Institute of Technology, Kanpur
Email: izuchukwu.ugwu@unn.edu.ng, davidu@iitk.ac.in
Abstract
Sulphonamides and carboxamides have shown large number of pharmacological properties
against different types of diseases among which is malaria. Twenty four new carboxamide
derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for
their in silico and in vitro antimalarial and antioxidant properties. The substituted
benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the
benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl
chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-
benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as
a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in vitro
antimalarial studies showed that all synthesized compounds had antimalarial property.
Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08 µM
respectively comparable with chloroquine 0.06 µM. Compound 7c was the most potent
antioxidant agent with IC50 value of 0.045 mM comparable with 0.34 mM for ascorbic acid. In
addition to the successful synthesis of the target molecules using boric acid catalysis, the
compounds were found to have antimalarial and antioxidant activities comparable with known
antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of
reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the
treatment of malaria.
Keywords: antimalarial, antioxidant, carboxamides, plasmepsin II, SAR, sulphonamides
1.0 Introduction
Malaria is among the most serious infectious disease in developing countries. The majority of
malaria cases and death is caused by P. falciparum, only persistent infections are caused by P.
vivax. The development of resistance to virtually all the prophylaxis and curative antimalarial
agents have compromised the efforts made in the control of this debilitating disease. The spread
of multidrug resistant P. falciparum has highlighted the urgent need to develop new antimalarial
drugs. Drug counterfeiting and non-adherence to treatment regimen have played a key role in the
development of resistance specie [1]. For the development of malarial parasite, the degradation
of haemoglobin is a necessary step. Haemoglobin catabolism occurs in the food vacuoles

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catalysed by the enzyme aspartic proteases also known as plasmepsin [2]. Plasmepsin catalyses
the hydrolysis of the bonds linking some important hydrophobic residues in haemoglobins [3].
They are also responsible for the cleavage of small molecule substrates [4]. Their active site
contains two aspartic acid residues which acts respectively as proton donor and proton acceptor
in the hydrolysis of peptide bonds in proteins. Plasmepsin II cleaves haemoglobin between
residues phenylalanine 33 and leucine 34 of α-globin units [5,6]. These roles of plasmepsin II in
degradation of haemoglobin makes it good target for antimalarial drugs.
Various sulphonamide derivatives have been reported as potential antimalarial agent.
Dominguez et al [7], Parai et al [8], Nubia et al [9], Mistry et al [10], Svogie et al [11], de
Oliveira et al [12] and many other researchers have reported derivatives of
benzenesulphonamide possessing antimalarial potential utilizing different mechanism of actions
(fig. 1).
O
R
O
O
O
S
NH2
S
N
O
O
S
R
O
NH
R2
NH
O
N
H
Cl
O
NH
HN
O
CH3
S
O
Cl
NH2
R1
O
MIC 10.00
IC50 1.99
IC50 0.48
IC50 0.027
Cl
Fig. 1: some examples of antimalarial benzenesulphonamides
Oxidative damage is implicated in various pathological events such as cancer and aging [13].
Mutations resulting from damages to biomolecules such as lipids, proteins, enzymes and DNA
in cells and tissues have been linked to high levels of free radicals. Antioxidants have the ability
to interrupt an oxidizing chain reaction or stop free radical formation and as such minimizing
oxidative damage is primary to prevention or treatment of disease attributable to oxidative
damage. Subba et al [14] Siddique et al [15] Alexiou et al [16] Saeedi et al [17] and many others
have reported the synthesis of some benzenesulphonamide derivatives possessing antioxidant
properties (fig. 2).
EtO
O
SO2NHR
R
P
O
OEt
O
O
NH
O
EtO
O
N
S
NH
S
S
R
O
O
O
O
O
NH
CN
OCH3
H3C
91% at 500 micromolar
IC50 24.80
Fig. 2: some examples of antioxidant sulphonamide

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A good number of authors have reported the implications of free radicals through oxidative
stress in the physiopathogenesis of malaria [18-24]. Potter et al [25] suggested that this
involvement may be related to the pathogenic mechanisms triggered by malaria parasite. Keller
et al [26] reported the elevated nitric oxide production in children with malaria. Recent studies
have suggested that the generation of reactive oxygen and nitrogen species associated with
oxidative stress, plays an important role in the development of systemic complications caused by
malaria. Guha et al [27] observed that malaria infections induces the generation of hydroxyl
radicals in the liver which can lead to the induction of oxidative stress and apoptosis. Ataman
and Ginsburg 1993 reported that erythrocytes infected with P. falciparum produced OH· radicals
and H2O2 about twice as compared to normal erythrocyte. Several substances used as
antimalarial are pro-oxidants, which is why they have pharmacological power. This is the case
for chloroquine, primaquine, artemisinin among others. This effect may be due to the drug’s
ability to promote direct production of free radicals [28] or by inhibiting molecules with
antioxidants activity [29].
The prevalence of carboxamide in biological systems, pharmacologically active molecules and
favourable properties of amides makes it one of the most popular and reliable functional group
in all branches of organic chemistry [30]. Carboxamide functionality has been shown to appear
in over 25% of commercial chemotherapeutic agents [31]. This finding makes the amide bond a
sort after bond in the design of new chemotherapeutic agents.
Computational methods have become standard in today’s chemistry tool kit. Molecular docking
is one of the widely used modelling tools for the study of molecular recognition, which aims to
predict the binding mode and binding affinity of a complex formed by two or more constituent
molecules with known structure [32].
It is therefore desirable that an antimalarial agent should possess little antioxidant potential to
trap the reactive oxygen and nitrogen species produced by malaria parasite and the antimalarial
agents.
As a continuation of our search for lead antimalarial agent bearing antioxidant properties, we
report in this work the boric acid catalysed synthesis of carboxamides from unactivated
carboxylic acids bearing sulphonamide functionality. The synergy arising from the successful
incorporation of carboxamide group in compounds containing sulphonamide pharmacophore is
exploited in this research.
2.0 Experimental
2.1 Instrumentation

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All reactions requiring inert atmosphere were carried out under nitrogen atmosphere. Drying of
solvents was achieved using molecular sieve for 48 h. All reagents were purchased from
commercial suppliers, Aldrich, Merck, Fluka, Avra, SD fine and Alfa Aesar. Thin layer
chromatography was carried out using silica plates purchased from Avra. The plates were
visualized under UV light (popular India). FT-IR spectroscopy of the compounds were run in
PerkinElmer Spectrum version 10.03.06 and the bands presented in wavenumber. Proton and
carbon-13 NMR spectroscopy were run in DMSO-d6 and CD3OD, unless otherwise stated on
either Jeol 500 MHz or 400 MHz. The chemical shifts were reported in part per million with
reference to tetramethylsilane. Mass spectroscopy were carried out using micro TOF
electrospray time of flight (ESI-TOF) mass spectrometer, sodium formate was used as the
calibrant. All experiments were carried out at Prof. Sandeep Verma’s Laboratory, department of
Chemistry, Indian Institute of Technology, Kanpur. Melting points were determined using
digital melting point apparatus and were uncorrected.
2.2 General procedure for the synthesis of substituted benzenesulphonamoyl alkanamides
(3a-p)
Sodium carbonate (Na2CO3, 1.590 g, 15 mmol) was added to a solution of amino acids (2a-h,
12.5 mmol) in water (15 mL) with continuous stirring until all the solutes had dissolved. The
o
solution was cooled to -5 C and the appropriate benzenesulphonyl chloride (1a-c, 15 mmol)
was added in four portions over a period of 1 h. The slurry was further stirred at room
temperature for about 4 h. The progress of the reaction was monitored using TLC (MeOH/DCM,
1:9). Upon completion, the mixture was acidified using 20% aqueous hydrochloric acid to pH 2.
The crystals was filtered via suction and washed with pH 2.2 buffer. The pure products (3a-x)
were dried over self-indicating fused silica gel in a desiccator.
2.2.1 2-(4-methylphenylsulphonamido) acetic acid (3a)
o
The amino acid was glycine, yield (2.8410 g, 99.34%), mp, 88.4-88.6 C, FTIR (KBr, cm-1):
3448 (OH of COOH), 3277 (NH), 2957 (C-H aliphatic), 1730 (C=O), 1598, 1440 (C=C), 1354,
1
1321 (2S=O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). H NMR (DMSO-d6)δ: 7.90-7.88 (t,
J=6.3 Hz, 1H, NH), 7.65-7.63 (d, J=8.6 Hz, 2H, ArH), 7.34-7.33 (d, J=8.05 Hz, 2H, ArH), 3.52-
3.51 (d, J=5.7 Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (DMSO-d6)δ: 170.7 (C=O), 143.1, 138.4,
130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0412 (M-H)-,
calculated, 228.0408.
2.2.2 2-(4-methylphenylsulphonamido)-3-phenylpropanoic acid (3b)

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o
The amino acid was L-phenylalanine, yield (3.9848 g, 99.93%), mp, 135.10-135.60 C FTIR
(KBr, cm-1): 3439 (OH of COOH), 3322 (NH), 3025 (C-H aromatic), 2926 (C-H aliphatic), 1713
(C=O), 1597, 1496, 1456 (C=C), 1344, 1331 (2S=O), 1189, 1157 (SO2NH), 1136, 1090, 1052
(C-N, C-O). 1H NMR (DMSO-d6)δ: 8.13-8.11 (d, J= 9.15 Hz, 1H, NH), 7.47-7.45 (d, J=7.45 Hz,
2H, ArH), 7.42-7.41 (d, J= 8.6 Hz, 2H, ArH), 7.21-7.06 (m, 5H, ArH), 3.83-3.81 (dd, J= 3.45,
2.85 Hz, 1H, CH), 2.91-2.87 (dd, J= 5.75, 5.75 Hz, 1H, CHa of CH2), 2.69-2.65 (dd, J=8.6, 8.6
13
Hz, 1H, CHb of CH2), 2.31-2.30 (m, 3H, CH3). C NMR (DMSO-d6)δ: 172.9 (C=O), 142.8,
138.7, 137.2, 129.7, 128.7, 127.0, 126.8, 126.0 (eight aromatic carbons), 57.9, 38.0, 21.5 (three
aliphatic carbons). HRMS-ESI (m/z): 320.0958 (M+H)+, calculated, 320.0959.
2.2.3 3-(1H-indol-2-yl)-2-{[(4-methylphenyl)sulphonyl]amino}propanoic acid (3c)
The amino acid was L-tryptophan, yield (4.3814 g, 97.880%), FTIR (KBr, cm-1): 3385, 3302
(2NH), 2921, 2858 (C-H aliphatic), 1750 (C=O), 1618, 1598, 1494, 1457, 1429 (C=C), 1321,
1
1291 (2S=O), 1163, 1131 (SO2NH), 1082, 1019 (C-N, C-O). H NMR (DMSO-d6) δ: 10.7 (s,
1H, NH of indole), 8.08-8.07 (d, J= 8.60 Hz, 1H, NH of SO2NH), 7.68-7.67 (d, J= 8.05 Hz, 1H,
ArH), 7.44-7.42 (d, J= 8.60 Hz, 2H, ArH), 7.34-7.32 (d, J= 8.00 Hz, 1H, ArH), 7.27-7.23 (t, J=
8.05 Hz, 1H, ArH), 7.14-7.13 (d, J= 8.00 Hz, 2H, ArH), 7.02-6.99 (m, 2H, ArH), 6.90-6.87 (m,
1H, ArH), 3.87-3.82 (dd, J= 7.45, 8.00 Hz, 1H, CH), 3.03-2.98 (dd, J= 6.3, 6.90 Hz, 1H, CHa,
CH2), 2.83-2.79 (dd, J= 7.45, 7.45 Hz, 1H, CHb of CH2), 2.28 (s, 3H, CH3-Ar). 13C NMR
(DMSO-d6) δ: 173.1494 (C=O), 142.7, 138.5, 136.6, 129.6, 127.4, 126.8, 124.4, 121.3, 118.8,
118.3, 111.9, 109.4 (aromatic carbons), 66.9, 57.1, 21.5 (aliphatic carbons). HRMS-ESI (m/z):
359.1060 (m+H)+, calculated, 569.1062
2.2.4 4-Methyl-2-{[(4-methylphenyl)sulfonyl]amino}pentanoic acid (3d)
The amino acid was L-leucine, yield (3.502 g, 98.26%), mp, 114.10-114.50 oC. FTIR (KBr, cm-
1): 3423 (OH of CO2H), 3279 (NH), 2949 (C-H aromatic), 2872 (C-H aliphatic), 1706 (C=O),
1598, 1497, 1458, 1420 (C=C), 1384, 1339 (2S=O), 1168, 1152 (SO2NH), 1122, 1091, 1020 (C-
1
N, C-O). H NMR (DMSO-d6) δ: 7.98-7.97 (d, J= 8.60 Hz, 1H, NH), 7.62-7.60 (d, J= 8.55 Hz,
2H, Ar-H), 7.32-7.31 (d, J= 8.55 Hz, 2H, ArH), 3.62-3.57 (m, 1H, CH-CO2H), 2.33 (s, 3H, CH3-
Ar), 1.55-1.50 (m, 1H, CH), 1.36-1.32 (m, 2H, CH2), 0.77-0.76 (d, J= 6.85 Hz, 3H, CH3), 0.66-
.64 (d, J= 6.30 Hz, 3H, CH3). 13C NMR (DMSO-d6) δ: 173.8 (C=O), 142.9, 138.9, 129.9, 128.6,
127.0, 126.0 (aromatic carbons), 54.5, 41.5, 24.4, 23.1, 21.6 (aliphatic carbons). HRMS-ESI
(m/z): 286.1986 (M+H)+, calculated, 286.1989.
2.2.5 3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}pentanoic acid (3e)

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The amino acid was L-isoleucine, yield (3.412 g, 95.74%), mp, 130.10-130.40 C, FTIR (KBr,
o
cm-1): 3280 (NH), 2970, 2934 (C-H Ar-H), 2883 (C-H aliphatic), 1710 (C=O), 1599, 1496, 1460
1
(C=C), 1385, 1334 (2S=O), 1185, 1161 (SO2NH), 1092, 1058, 1020 (C-N, C-O). H NMR
(DMSO-d6) δ: 7.89-7.87 (d, J= 9.2 Hz, 1H, NH), 7.62-7.61 (d, J= 8.05 Hz, 2H, ArH), 7.32-7.30
(d, J= 8.05 Hz, 2H, ArH), 3.51-3.48 (dd, J= 6.30, 6.30 Hz, 1H, CH-CO2H), 2.33 (s, 3H, CH3-
Ar), 1.62-1.58 (m, 1H, CH), 1.34-1.29 (m, 1H, CHa of CH2), 1.09-1.01 (m, 1H, CHb of CH2),
13
0.76-0.70 (dt, J= 6.85, 7.45H, 6H, 2CH3). C NMR (DMSO-d6) δ: 172.7 (C=O), 142.9, 138.9,
129.8, 127.1 (aromatic carbons), 60.5, 37.4, 24.9, 21.5, 15.9, 11.4 (aliphatic carbons). HRMS-
ESI (m/z): 284.0765 (M-H)-, calculated, 284.0769.
2.2.6 3-Methyl-2-(4-methylphenylsulphonamido)butanoic acid (3f)
The amino acid was L-valine, yield (3.2849 g, 95.56%), mp, 121.90-122.20 oC, FTIR (KBr, cm-
1): 3293 (NH), 2970 (C-H aliphatic), 1708 (C=O), 1598, 1466, 1419 (C=C), 1333, 1289 (2S=O),
1161 (SO2NH), 1089 (C-N or C-O). 1H NMR (DMSO-d6) δ: 7.87-7.85 (d, J=9.75 Hz, 1H, NH),
7.68-7.61 (m, 2H, ArH), 7.33-7.22 (m, 2H, ArH), 3.46-3.43 (dd, J= 5.70, 5.75Hz, 1H, CH-
CO2H), 2.33-2.30 (m, 3H, CH3-Ar), 1.90-1.86 (m, 1H, CH), 0.78-0.64 (m, 6H, 2CH3). 13C NMR
(DMSO-d6) δ: 172.7 (C=O), 142.9, 138.9, 129.8, 127.1, 126.2 (aromatic carbons), 61.7, 30.9,
21.5, 19.5, 18.4 (aliphatic carbons). HRMS-ESI (m/z): 271.0881 (M+H)+, calculated, 271.0894.
2.2.7 4-Hydroxy-1-tosylpyrrolidine-2-carboxylic acid (3g)
o
The amino acid was L-hydroxyproline, yield (3.564 g, 99.86%), mp, 98.40-98.60 C. FTIR
(KBr, cm-1): 3524 (OH), 2931 (C-H aliphatic), 1708 (C=O), 1600, 1444 (C=C), 1347, 1332
1
(2S=O), 1200, 1158 (SO2N), 1090, 1075 (C-N or C-O). H NMR (DMSO-d6) δ: 7.66-7.64 (d,
J= 8.00 Hz, 2H, ArH), 7.38-7.36 (d, J= 8.05 Hz, 2H, ArH), 4.18 (s, 1H, O-H), 4.02-3.99 (t, J=
8.05 Hz, 1H, CH-CO2H), 3.43-3.40 (m, 1H, CH-OH), 3.06-3.04 (d, J=10.3 Hz, 2H, CH2), 2.36
(s, 3H, CH3), 1.92-1.90 (t, 4.6 Hz, 2H, CH2). 13C NMR (DMSO-d6) δ: 173.8 (C=O), 143.7,
135.0, 130.1, 127.9 (aromatic carbons), 68.9, 60.2, 56.8, 21.5 (aliphatic carbons). HRMS-ESI
(m/z): 286.1097 (M+H)+, calculated, 286.1099.
2.2.8 1-Tosylpyrrolidine-2-carboxylic acid (3h)
o
The amino acid was L-proline, yield (3.2989 g, 98.09%), mp, 50.40-50.70 C, FTIR (KBr, cm-
1): 3415 (OH of COOH), 2957 (C-H aliphatic), 1737 (C=O), 1619, 1597, 1494, 1449 (C=C),
1345, 1306 (2S=O), 1199 (SO2N), 1159, 1095, 1013 (C-N, C-O). 1H NMR (DMSO-d6) δ: 7.66-
7.65 (d, J=8.6 Hz, 2H, ArH), 7.36-7.34 (d, J= 8.00 Hz, 2H, ArH), 4.05-4.03 (dd, J= 4.55, 5.15

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Hz, 1H, CH-COOH), 3.31-3.27 (dd, J= 9.75, 5.15Hz, 1H, CHa of CH2-N), 3.11-3.06 (dd, J=
6.85, 7.45 Hz, 1H, CHb of CH2-N), 2.31 (s, 3H, CH3-Ar), 1.81-1.72 (m, 3H), 1.50-1.47 (t,
J=5.15 Hz, 1H). 13C NMR (DMSO-d6) δ: 173.7 (C=O), 143.9, 135.1, 130.3, 127.6 (aromatic
carbons), 66.9, 48.9, 30.9, 24.7, 21.4 (aliphatic carbons). HRMS-ESI (m/z): 269.0726 (m+H)+,
calculated, 269.0731.
2.2.9 2-Benzenesulphonamido acetic acid (3i)
o
The amino acid was glycine, yield (2.6856 g, 99.61%), mp, 170.80-171.40 C. FTIR (KBr, cm-
1): 3317 (NH), 3060, 2974 (C-H aromatic), 2946 (C-H aliphatic), 1728 (C=O), 1587, 1451,
1
1428, 1412 (C=C), 1318, 1247 (S=O), 1158, 1130 (SO2NH), 1095, 1077, 1012 (C-N, C-O). H
NMR (DMSO-d6) δ: 8.02-7.99 (t, J= 12.00 Hz, 1H, NH), 7.77-7.76 (d, J= 7.45 Hz, 2H, ArH),
7.61-7.58 (t, J= 7.45 Hz, 1H, ArH), 7.55-7.52 (t, J= 8.00 Hz, 2H, ArH), 3.55-3.54 (d, J= 6.30
Hz, 2H, CH2). 13C NMR (DMSO-d6) δ: 170.7 (C=O), 141.2, 132.9, 129.6, 126.9 (aromatic
carbons), 44.5 (aliphatic carbon). HRMS-ESI (m/z): 216.1252, calculated, 216.1256.
2.2.10 2-Benzenesulphonamido-3-phenylpropanoic acid (3j)
o
The amino acid was L-phenylalanine, yield (3.8169 g, 100%), mp, 129.10-129.80 C. FTIR
(KBr, cm-1): 3342 (NH), 3195, 3029 (C-H aromatic), 2968 (C-H aliphatic), 1735 (C=O), 1697,
1496, 1447 (C=C), 1375, 1347 (2S=O), 1170, 1108 (SO2NH), 1093, 1028 (C-N, C-O). 1H NMR
(DMSO-d6) δ: 8.26-8.24 (d, J= 8.85 Hz, 1H, NH), 7.54-7.50 (m, 3H, ArH), 7.41-7.38 (t, J= 7.45
Hz, 2H, ArH), 7.18-7.12 (m, 3H, ArH), 7.09-7.08 (d, J= 7.15 Hz, 2H, ArH), 3.87-3.82 (ddd, J=
6.00, 5.75, 6.30 Hz, 1H, CH-CO2H), 2.92-2.88 (dd, J= 5.75, 5.75 Hz, 1H, CHa of CH2), 2.70-
2.65 (dd, J= 9.00, 9.00 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6) δ: 172.8 (C=O), 141.6,
137.3, 132.6, 129.7, 129.4, 128.7, 127.1, 126.7 (aromatic carbons), 57.9, 38.3 (aliphatic
carbons). HRMS-ESI (m/z): 304.0624 (M-H)-, calculated 304.0627.
2.2.11 2-Benzenesulphonamido-3-(1H-indol-3-yl)propanoic acid (3k)
The amino acid was L-tryptophan, yield (4.2805 g, 99.43%), mp, 106.40-106.60 oC. FTIR (KBr,
cm-1): 3366, 3311 (2NH), 3061 (C-H aromatic), 2936 (C-H aliphatic), 1746 (C=O), 1619, 1550,
1451, 1430 (C=C), 1323, 1235 (2S=O), 1214, 1160 (SO2NH), 1127, 1091, 1012 (C-N, C-O). 1H
NMR (DMSO-d6) δ: 10.78 (s, 1H, NH of indole), 8.23-8.21 (d, J= 8.60 Hz, 1H, NH), 7.59-7.57
(m, 2H, ArH), 7.49-7.46 (t, J= 6.85 Hz, 1H, ArH), 7.38-7.35 (m, 2H, ArH), 7.28-7.27 (d, J= 8.60
Hz, 2H, ArH), 7.03-7.00 (m, 2H, ArH), 6.92-6.89 (t, J= 7.40 Hz, 1H, ArH), 3.91-3.87 (m, 1H,
ArH), 3.05-3.01 (dd, J= 6.85, 6.85 Hz, 1H, CHa of CH2), 2.86-2.81 (dd, J= 8.05, 7.45 Hz, 1H,

ACCEPTED MANUSCRIPT
13
CHb of CH2). C NMR (DMSO-d6) δ: 173.1 (C=O), 141.5, 136.6, 132.6, 129.2, 127.5, 126.7,
124.4, 121.4, 118.9, 118.4, 111.9, 109.4 (aromatic carbons), 57.2, 28.8 (aliphatic carbons).
HRMS-ESI (m/z): 344.0835 (M+), calculated 344.0831.
2.2.12 2-Benzenesulphonamido-4-methylpentanoic acid (3l)
o
The amino acid was L-leucine, yield (3.0592 g, 90.20%), mp, 105.60-105.90 C. FTIR (KBr,
cm-1): 3248 (NH), 3068 (C-H aromatic), 2959, 2921, 2874 (C-H aliphatic), 1712 (C=O), 1632,
1469, 1450, 1428 (C=C), 1327, 1314 (2S=O), 1184, 11670 (SO2NH), 1092, 1077 (C-N, C-O).
1H NMR (DMSO-d6) δ: 8.11-8.09 (d, J= 8.72 Hz, 1H, NH), 7.74-7.72 (t, J= 6.88 Hz, 2H, ArH),
7.59-7.49 (m, 3H, ArH), 3.63-3.57 (m, 1H, CH-CO2H), 1.53-1.46 (m, 1H, CH), 1.35-1.31 (m,
13
2H, CH2), 0.78-0.61 (m, 6H, CH3). C NMR (DMSO-d6) δ: 173.8 (C=O), 141.6, 132.8, 129.5,
126.9, 126.1 (aromatic carbons), 54.5, 41.4, 24.4, 23.1, 21.5 (aliphatic carbons). HRMS-ESI
(m/z): 272.1982 (M+H), calculated, 271.1989.
2.2.13 2-Benzenesulphonamido-3-methylpentanoic acid (3m)
The amino acid was L-isoleucine, yield (3.1052 g, 91.55%), mp, 148.00-148.70 oC. FTIR (KBr,
cm-1): 3295 (NH), 2968 (C-H aromatic), 2936, 2883 (C-H aliphatic), 1699 (C=O), 1585, 1450,
1416 (C=C), 1340, 1384 (2S=O), 1168 (SO2NH), 1092, 1026 (C-N, C-O). 1H NMR (DMSO-d6)
δ: 8.01-7.99 (d, J= 9.16 Hz, 1H, NH), 7.74-7.72 (d, J= 8.60 Hz, 2H, ArH), 7.58-7.49 (m, 3H,
ArH), 3.52-3.49 (dd, J= 7.45, 7.45 Hz, 1H, CH-CO2H), 1.62-1.57 (m, 1H, CH), 1.33-1.27 (m,
1H, CHa of CH2), 1.07-1.00 (m, 1H, CHb of CH2), 0.75-0.68 (m, 6H, 2CH3). 13C NMR (DMSO-
d6) δ: 172.7 (C=O), 141.6, 132.8, 129.4, 127.0 (aromatic carbons), 60.5, 37.4, 24.9, 15.9, 11.4
(aliphatic carbons). HRMS-ESI (m/z): 271.0879 (M+), calculated, 271.0878.
2.2.14 2-Benzenesulphonamido-3-methylbutanoic acid (3n)
The amino acid was L-valine, yield (3.2030 g, 99.68%), mp, 143.60-143.80 oC. FTIR (KBr, cm-
1): 3418 (OH CO2H), 3302 (NH), 2969 (C-H aliphatic), 1703 (C=O), 1585, 1451 (C=C), 1338,
1294 (2S=O), 1169, 1143 (SO2NH), 1093, 1042 (C-N, C-O). 1H NMR (DMSO-d6) δ: 7.99-7.97
(d, J= 9.16 Hz, 1H, NH), 7.74-7.72 (d, J= 6.88 Hz, 2H, ArH), 7.58-7.48 (m, 3H, ArH), 3.48-3.45
(dd, J= 6.44, 5.96 Hz, 1H, CH-CO2H), 1.92-1.83 (m, 1H, CH), 0.77-0.73 (m, 6H, CH3). 13C
NMR (DMSO-d6) δ: 172.7 (C=O), 141.7, 132.8, 129.4, 127.0 (aromatic carbons), 61.8, 30.9,
19.5, 18.3 (aliphatic carbons). HRMS-ESI (m/z): 258.1824 (M+H), calculated, 258.1827.
2.2.15 1-(Benzenesulphonyl)-4-hydroxypyrrolidine-2-carboxylic acid (3o)

ACCEPTED MANUSCRIPT
The amino acid was L-4-hydroxyproline, yield (3.3815 g, 99.99%), mp, 159.00-159.90 oC. FTIR
(KBr, cm-1): 3402 (OH), 2993, 2955 (C-H aliphatic), 1714 (C=O), 1589, 1484, 1450 (C=C),
1
1385, 1353 (2S=O), 1195, 1158 (SO2NH), 1158, 1100, 1070 (C-N, C-O). H NMR (DMSO-d6)
δ: 7.78-7.76 (d, J= 7.32 Hz, 2H, ArH), 7.65-7.62 (t, J= 7.36 Hz, 1H, ArH), 7.58-7.54 (t, J= 7.80
Hz, 2H, ArH), 4.18 (s, 1H, OH), 4.06-4.02 (t, J= 7.80 Hz, 1H, CH-CO2H), 3.45-3.41 (m, 1H,
CHOH), 3.10-3.08 (d, J= 11.00 Hz, 2H, CH2-N), 1.98-1.87 (m, 2H, CH2). 13C NMR (DMSO-d6)
δ: 173.8 (C=O), 137.8, 133.5, 129.6, 127.9 (aromatic carbons), 68.9, 60.2, 56.8, 31.2 (aliphatic
carbons). HRMS-ESI (m/z): 271.0518 (M+), calculated, 271.0514.
2.2.16 1-(Benzenesulphonyl)-pyrrolidine-2-carboxylic acid (3p)
The amino acid was L-proline, yield (3.1911 g, 100%). FTIR (KBr, cm-1): 3066 (C-H aromatic),
2983, 2884 (C-H aliphatic), 1730 (C=O), 1627, 1447 (C=C), 1343, 1292 (2S=O), 1199, 1161
(SO2NH), 1095, 1073, 1016 (C-N, C-O). 1H NMR (DMSO-d6) δ: 7.83-7.78 (m, 2H, ArH), 7.67-
7.63 (m, 1H, ArH), 7.59-7.56 (m, 2H, ArH), 4.08-4.05 (dd, J= 4.60, 4.60 Hz, 1H, CH-CO2H),
3.34-3.28 (m, 1H, CHa of CH2N), 3.14-3.08 (m, 1H, CHb of CH2N), 1.86-1.71 (m, 3H), 1.53-
1.47 (m, 1H). 13C NMR (DMSO-d6) δ: 173.7 (C=O), 137.7, 133.6, 129.9, 127.6 (aromatic
carbons), 60.9, 48.9, 30.9, 24.7 (aliphatic carbons). HRMS-ESI (m/z): 256.1679 (M+H),
calculated 256.1682.
2.2.17 2-(4-Nitrophenylsulphonamido)acetic acid (3q)
o
The amino acid was glycine, yield (2.2152 g, 94.59%), mp, 171.90-172.20 C. FTIR (KBr, cm-
1): 3417 (OH of CO2H), 3297 (NH), 3108, 3070 (C-H aromatic), 1732 (C=O), 1605, 1482
(C=C), 1529, 1424 (N-O), 1354, 1333 (2S=O), 1240, 1165 (SO2NH), 1100, 1087, 1014 (C-N, C-
1
O). H NMR (DMSO-d6) δ: 8.44-8.41 (t, J= 4.00 Hz, 1H, NH), 8.37-8.35 (d, J= 9.15 Hz, 2H,
ArH), 8.02-8.01 (d, J= 8.6 Hz, 2H, ArH), 3.67-3.66 (d, J= 4.00 Hz, 2H, CH2). 13C NMR
(DMSO-d6) δ: 170.7 (C=O), 150.0, 147.0, 128.7, 124.9 (aromatic carbons), 44.3 (aliphatic
carbon). HRMS-ESI (m/z): 261.3108 (M+H), Calculated 261.3112.
2.2.18 2-(4-Nitrophenylsulphonamido)-3-phenylpropanoic acid (3r)
o
The amino acid was L-phenylalanine, yield (3.1530 g, 99.99%), mp, 100.10-100.50 C. FTIR
(KBr, cm-1): 3417 (OH of CO2H), 3253 (NH), 3182, 3111 (C-H aromatic), 1753 (C=O), 1607,
1456, 1435 (C=C), 1525, 1403 (N-O), 1347, 1311 (2S=O), 1164, 1124 (SO2NH), 1103, 1093 (C-
1
N, C-O). H NMR (DMSO-d6) δ: 8.69-8.67 (d, J= 8.6 Hz, 1H, NH), 8.17-8.15 (d, J= 9.15 Hz,
2H, ArH), 7.72-7.70 (d, J= 8.6 Hz, 2H, ArH), 7.11-7.06 (m, 5H, ArH), 3.95-3.90 (ddd, J= 5.2,
4.6, 5.15 Hz, 1H, CH-CH2), 2.97-2.93 (dd, J= 5.15, 5.15 Hz, 1H, CHa of CH2), 2.70-2.65 (dd, J=

ACCEPTED MANUSCRIPT
9.75, 9.75 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6) δ: 172.7 (C=O), 149.6, 147.1, 137.2,
129.7, 128.6, 128.2, 126.9, 124.7 (aromatic carbons), 58.2, 38.1 (aliphatic carbons). HRMS-ESI
(m/z): 368.2347 (M+NH4)+, calculated, 368.2349.
2.2.19 3-(1H-Indol-2-yl)-2-(4-nitrophenylsulphonamido)propanoic acid (3s)
The amino acid was L-tryptophan, yield (3.4253 g, 97.94%), mp, 226.90-227.20 oC. FTIR (KBr,
cm-1): 3448 (OH of CO2H), 3380, 3295 (2NH), 3108 (C-H of aromatic), 1710 (C=O), 1607,
1459 (C=C), 1525, 1424 (N-O), 1348, 1332 (2S=O), 1167, 1119 (SO2NH), 1092, 1014 (C-N, C-
O). 1H NMR (DMSO-d6) δ: 10.66 (s, 1H, NH, indole), 8.61-8.59 (d, J= 8.00 Hz, 1H, NH), 7.86-
7.84 (m, 2H, ArH), 7.50-7.46 (m, 2H, ArH), 7.24-7.23 (d, J= 7.45 Hz, 1H, ArH), 7.06-7.04 (d,
J= 8.00 Hz, 1H, ArH), 6.99 (s, 1H, ArH), 6.89-6.82 (m, 2H, ArH), 3.92-3.87 (ddd, J= 4.00, 2.85,
4.6 Hz, 1H, CH-CO2H), 3.06-3.02 (dd, J= 4.6, 4.6 Hz, 1H, CHa of CH2), 2.81-2.76 (dd, J= 10.3,
13
9.75 Hz, 1H, CHb of CH2). C NMR (DMSO-d6) δ: 173.3 (C=O), 148.9, 146.4, 136.5, 127.4,
126.9, 124.9, 123.8, 121.2, 118.8, 118.2, 111.7, 109.2 (aromatic carbons), 57.0, 28.4 (aliphatic
carbons). HRMS-ESI (m/z): 390.3285 (M+H)+, calculated, 390.3289.
2.2.20 4-Methyl-2-nitrophenylsulphonamido)pentanoic acid (3t)
o
The amino acid was L-leucine, yield (2.8461 g, 99.98%), mp, 142.90-143.20 C. FTIR (KBr,
cm-1): 3272 (NH), 3113, 3097, 3074 (C-H aromatic), 2934, 2878 (C-H aliphatic), 1714 (C=O),
1658, 1606, 1469 (C=C), 1531, 1417 (N-O), 1356, 1307 (2S=O), 1168, 1156 (SO2NH), 1108,
1
1091, 1010 (C-N, C-O). H NMR (DMSO-d6) δ: 8.55-8.54 (d, J= 9.15 Hz, 1H, NH), 8.37-8.35
(d, J= 8.6 Hz, 2H, ArH), 7.99-7.97 (d, J= 8.6 Hz, 2H, ArH), 3.74-3.69 (m, 1H, CH-CO2H), 1.59-
1.53 (m, 1H, CH(CH3)2), 1.41-1.37 (m, 2H, CH2), 0.81-0.71 (m, 6H, 2CH3). 13C NMR (DMSO-
d6) δ: 173.4 (C=O), 149.9, 147.3, 128.7, 124.8 (aromatic carbons), 54.7, 41.2, 24.5, 23.1, 21.4
(aliphatic carbons). HRMS-ESI (m/z): 315.1265 (M-H)-, calculated, 315.1268.
2.2.21 3-Methyl-2-(4-nitrophenylsulphonamido)pentanoic acid (3u)
The amino acid was L-isoleucine, yield (2.7894 g, 97.97%), mp, 131.40-131.70 oC. FTIR (KBr,
cm-1): 3271 (NH), 3110, 2967 (C-H aromatic), 2879, 2858 (C-H aliphatic), 1705 (C=O), 1647,
1607, 1472 (C=C), 1528, 1428 (N-O), 1361, 1351 (2S=O), 1175, 1142 (SO2NH), 1092, 1011 (C-
1
N, C-O). H NMR (DMSO-d6) δ: 8.43-8.42 (d, J= 9.15 Hz, 1H, NH), 8.36-8.34 (d, J= 8.60 Hz,
2H, ArH), 7.99-7.98 (d, J= 8.55 Hz, 2H, ArH), 3.62-3.59 (t, J= 6.00 Hz, 1H, CH-CO2H), 1.68-
1.65 (m, 1H, CH), 1.35-1.30 (m, 1H, CHa of CH2), 1.12-1.03 (m, 1H, CHb of CH2), 0.78-0.73
(m, 6H, 2CH3). 13C NMR (DMSO-d6) δ: 172.4 (C=O), 149.9, 147.2, 128.7, 124.8 (aromatic

ACCEPTED MANUSCRIPT
carbons), 60.9, 37.3, 24.8, 15.9, 11.5 (aliphatic carbons). HRMS-ESI (m/z): 317.2387 (M+H)+,
calculated, 317.2393.
2.2.22 3-Methyl-2-(4-nitrophenylsulphonamido)butanoic acid (3v)
The amino acid was L-valine, yield (2.7200 g, 99.97 %), mp, 182.60-182.90 oC. FTIR (KBr, cm-
1): 3415 (OH CO2H), 3278 (NH), 3113, 2969 (C-H aromatic), 2931, 2873 (C-H aliphatic), 1711
(C=O), 1638, 1607, 1411 (C=C), 1532, 1463 (N-O), 1356, 1312 (2S=O), 1169, 1146 (SO2NH),
1107, 1091, 1062, 1013 (C-N, C-O). 1H NMR (DMSO-d6) δ: 8.44-8.42 (d, J= 9.15 Hz, 1H, NH),
8.36-8.34 (d, J= 8.6 Hz, 2H, ArH), 7.99-7.98 (d, J= 9.15 Hz, 2H, ArH), 3.58-3.55 (dd, J= 5.7,
6.3 Hz, 1H, CH-CO2H), 1.98-1.91 (m, 1H, CH (CH3)2), 0.81-0.76 (m, 6H, 2CH3). 13C NMR
(DMSO-d6) δ: 172.4 (C=O), 149.9, 147.3, 128.7, 124.8 (aromatic carbons), 61.9, 30.8, 19.6,
18.3 (aliphatic carbons). HRMS-ESI (m/z): 320. 1982 (M+NH4), calculated, 320.1987.
2.2.23 4-Hydroxy-1-(4-nitrophenylsulphonyl)pyrrolidine-2-carboxylic acid (3w)
o
The amino acid was L-hydroxyproline, yield (2.8459 g, 99.97%), mp, 199.80-200.20 C. FTIR
(KBr, cm-1): 3491 (OH), 3416 (OH of CO2H), 3117, 3024 (C-H aromatic), 2966, 2767 (C-H
aliphatic), 1750 (C=O), 1638, 1608, 1457 (C=C), 1527, 1427 (N-O), 1359, 1331 (2S=O), 1184,
1
1164 (SO2N), 1136, 1112, 1090, 1015, 1005 (C-N, C-O). H NMR (DMSO-d6) δ: 8.38-3.36 (d,
J= 9.15 Hz, 2H, ArH), 8.04-8.02 (d, J= 8.60 Hz, 2H, ArH), 4.17 (s, 1H, OH), 4.13-4.10 (t, J= 8.6
Hz, 1H, CH-CO2H), 3.47-3.44 (dd, J= 3.45, 3.40 Hz, 1H, CHOH), 3.21-3.19 (d, J= 10.90 Hz,
13
2H, CH2N), 2.04-2.00 (m, 1H, CHa, CH2), 1.93-1.88 (m, 1H, CHb of CH2). C NMR (DMSO-
d6) δ: 173.5, 150.3, 143.6, 129.5, 124.8 (aromatic carbons), 69.0, 60.4, 57.1 (aliphatic carbons).
HRMS-ESI (m/z): 303.2987 (M+H)+, calculated, 303.2991.
2.2.24 1-(4-Nitrophenylsulphonyl)pyrrolidine-2-carboxylic acid (3x)
o
The amino acid was L-proline, yield (2.6051 g, 96.39%), mp, 149.90-150.30 C. FTIR (KBr,
cm-1): 3415 (OH of CO2H), 3111 (C-H aromatic), 2899, 2648 (C-H aliphatic), 1723 (C=O),
1641, 1604, (C=C), 1533, 1447 (N-O), 1353, 1305 (2S=O), 1199, 1165 (SO2N), 1072, 1024,
1
1008 (C-N, C-O). H NMR (DMSO-d6) δ: 8.40-8.36 (m, 2H, ArH), 8.07-8.05 (m, 2H, ArH),
4.19-4.17 (m, 1H, CH-CO2H), 3.40-3.36 (m, 1H, CHa of CH2), 3.23-3.18 (m, 1H, CHb of CH2),
1.99-1.92 (m, 1H, CHa of CH2), 1.87-1.76 (m, 2H, CH2), 1.65-1.60 (m, 1H, CH). 13C NMR
(DMSO-d6) δ: 173.4 (C=O), 150.4, 143.8, 129.2, 125.1 (aromatic carbons), 61.1, 48.9, 30.9,
24.7 (aliphatic carbons). HRMS-ESI (m/z): 301.3421 (M+H)+, calculated, 301.3427.

ACCEPTED MANUSCRIPT
2.3 General Procedure for the Synthesis of N-benzoyl Derivatives of
Benzenesulphonamides (5a-f, i-n and q-v)
Appropriate benzenesulphonamides (3a-f, i-n and q-v, 1.0 mmol) was dissolved in NaOH (10%,
10 mL) in a 50 mL round bottom flask. Benzoyl chloride (4, 1.1 mmol, 0.2 mL) was transferred
into the solution of appropriate benzenesulphonamide and stirred at room temperature. The
reaction progress was monitored by TLC (3% MeOH/DCM) to the disappearance of the
benzenesulphonamide spot. Upon completion, the solution was transferred into a beaker
containing crushed ice and then acidified to pH of 3 with concentrated hydrochloric acid. The
solid was collected via suction filtration and transferred into a beaker containing CCl4 (10 mL)
and covered with watch glass boiled for 10 min. the mixture was allowed to cool slightly and
then filtered. The products (5a-f, i-n and q-v) obtained were washed with 10-20 mL of CCl4 and
dried over fused self-indicating silica gel in a dessicator.
2.3.1 {Benzoyl[(4-methylphenyl)sulfonyl]amino}acetic acid (5a)
Yield (0.3281 g, 98.49%), mp, 104.60-104.90 oC, FTIR (KBr, cm-1): 3072 (C-H aromatic), 1729,
1687 (2C=O), 1601, 1583, 1453, 1423 (C=C), 1327, 1293 (2S=O), 1157, 1186 (SO2N), 1128,
1
1094, 1073, 1001 (C-N, C-O). H NMR (DMSO-d6) δ: 7.65-7.63 (d, J=8.6 Hz, 2H, ArH), 7.57-
7.43 (m, 5H, ArH), 7.34-7.33 (d, J=8.05 Hz, 2H, ArH), 3.52-3.51 (d, J=5.7 Hz, CH2), 2.34 (s,
3H, CH3). 13C NMR (DMSO-d6) δ: 170.7, 167.8 (2C=O), 143.1, 138.4, 133.4, 131.3, 130.0,
129.8, 129.1, 127.1 (aromatic carbons), 44.3, 21.5 (aliphatic carbons). HRMS-ESI (m/z):
333.0679 (M+), calculated, 333.0671.
2.3.2 2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-3-phenylpropanoic acid (5b)
Yield (0.4201 g, 99.31%), mp, 100.50-100.80 oC, FTIR (KBr, cm-1): 3443 (OH of CO2H), 3072
(C-H aromatic), 1732, 1689 (2C=O), 1603, 1585, 1497, 1454, 1425 (C=C), 1344, 1327, (2S=O),
1187, 1168, 1158 (SO2N), 1128, 1090, 1027 (C-N, C-O). 1H NMR (DMSO-d6) δ: 7.92-7.91 (m,
3H, ArH), 7.60-7.57 (t, J= 7.45 Hz, 2H, ArH), 7.48-7.41 (m, 5H, ArH), 7.20-7.15 (m, 3H, ArH),
7.09-7.07 (d, J= 7.45 Hz, 1H, ArH), 3.83-3.80 (t, J= 6.30 Hz, 1H, CH-CO2H), 2.91-2.87 (dd, J=
5.75, 5.75 Hz, 1H, CHa of CH2), 2.70-2.65 (dd, J= 9.15, 8.55 Hz, 1H, CHb of CH2), 2.30 (s, 3H,
CH3-Ar). 13C NMR (DMSO-d6) δ: 172.8, 167.8 (2C=O), 142.8, 138.7, 137.3, 133.4, 133.2,
131.3, 129.8, 129.7, 129.1, 128.7, 127.0, 126.8 (aromatic carbons), 57.9, 38.4, 21.5 (aliphatic
carbons). HRMS-ESI (m/z): 424.2150 (M+H), calculated, 424.2159.
2.3.3
3-(1H-indol-2-yl)-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]propanoic
acid (5c)

ACCEPTED MANUSCRIPT
o
Yield (0.4609 g, 99.74%), mp, 108.60-109.20 C, FTIR (KBr, cm-1): 3335 (NH), 3072 (C-H
aromatic), 1761, 1688 (2C=O), 1619, 1602, 1584, 1454, 1424 (C=C), 1326, 1292 (2S=O), 1178,
1
1160 (SO2N), 1128, 1073, 1027 (C-N, C-O). H NMR (DMSO-d6) δ: 10.73 (s, 1H, NH of
indole), 7.92-7.91 (t, J= 7.45 Hz, 3H, ArH), 7.60-7.57 (t, J= 7.45 Hz, 2H, ArH), 7.48-7.42 (m,
5H, ArH), 7.27-7.23 (t, J= 8.60 Hz, 1H, ArH), 7.14-7.12 (d, J= 8.05 Hz, 1H, ArH), 7.02-6.99 (t,
J= 7.45 Hz, 1H, ArH), 6.90-6.87 (t, J= 7.45 Hz, 1H, ArH), 3.87-3.82 (dd, J= 7.45, 8.05 Hz, 1H,
ArH), 3.03-2.98 (dd, J= 6.30, 6.30 Hz, 1H, CHa of CH2), 2.83-2.79 (dd, J= 8.05, 8.00 Hz, 1H,
CHb of CH2), 2.28 (s, 3H, CH3-Ar). 13C NMR (DMSO-d6) δ: 173.1, 167.8 (2C=O), 142.7, 138.5,
136.6, 133.4, 131.3, 129.8, 129.6, 129.1, 127.4, 126.8, 124.4, 121.3, 118.8, 118.3, 111.9, 109.4
(aromatic carbons), 57.1, 28.8, 21.5 (aliphatic carbons). HRMS-ESI (m/z): 480.2135 (M+NH4),
calculated, 480.2132.
2.3.4 4-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]pentanoic acid (5d)
o
Yield (0.3889 g, 99.92%), mp, 98.90-100.10 C, FTIR (KBr, cm-1): 3415 (OH of CO2H), 2968
(C-H aromatic), 2676 (C-H aliphatic), 1705, 1688 (2C=O), 1619, 1602, 1584, 1454, 1424
1
(C=C), 1327, 1292 (2S=O), 1161, 1128 (SO2N), 1091, 1073, 1027 (C-N, C-O). H NMR
(DMSO-d6) δ: 7.92-7.90 (t, J= 6.90 Hz, 3H, ArH), 7.62-7.57 (m, 2H, ArH), 7.48-7.45 (t, J= 8.00
Hz, 3H, ArH), 7.32-7.31 (d, J= 8.00 Hz, 1H, ArH), 3.62-3.57 (dd, J= 8.05, 8.55 Hz, 1H, CH-
CO2H), 1.55-1.50 (m, 1H, CH), 1.36-1.30 (m, 2H, CH2), 0.77-0.76 (d, J= 6.30 Hz, 3H, CH3),
0.66-0.64 (d, J= 6.30 Hz, 3H, CH3). 13C NMR (DMSO-d6) δ: 173.8, 167.8 (2C=O), 142.9, 138.9,
133.4, 131.3, 129.9, 129.8, 129.1, 127.0 (aromatic carbons), 54.5, 41.5, 24.4, 23.1, 21.6, 21.5
(aliphatic carbons). HRMS-ESI (m/z): 390.2354 (M+H), calculated, 390.2351.
2.3.5 3-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]pentanoic acid (5e)
o
Yield (0.3890 g, 99.95%), mp, 98.10-98.50 C, FTIR (KBr, cm-1): 3415 (OH of CO2H), 3072,
2970 (C-H of aromatic), 1707, 1688 (2C=O), 1602, 1584, 1496, 1454, 1424 (C=C), 1328, 1292
(2S=O), 1186, 1161 (SO2N), 1128, 1092, 1073, 1027 (C-N, C-O). 1H NMR (DMSO-d6) δ: 7.92-
7.87 (m, 3H, ArH), 7.62-7.57 (m, 2H, ArH), 7.48-7.45 (t, J= 8.00 Hz, 3H, ArH), 7.31-7.30 (d, J=
8.00 Hz, 1H, ArH), 3.49-3.48 (d, J= 2.3 Hz, 1H, CH-CO2H), 2.33 (s, 3H, CH3-Ar), 1.64-1.58
(m, 1H, CH), 1.34-1.27 (m, 1H, CHa of CH2), 1.09-1.00 (m, 1H, CHb of CH2), 0.76-0.70 (dt, J=
13
6.30, 6.90 Hz, 6H, 2CH3). C NMR (DMSO-d6) δ: 172.7, 167.8 (2C=O), 142.9, 138.9, 133.4,
131.3, 129.8, 129.8, 129.1, 127.1 (aromatic carbons), 60.5, 37.5, 24.9, 21.5, 15.9, 11.4 (aliphatic
carbons). HRMS-ESI (m/z): 388.0894 (M-H), calculated, 388.0892.
2.3.6 3-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]butanoic acid acid (5f)

ACCEPTED MANUSCRIPT
Yield (0.372 g, 99.20%), mp, 97.30-97.80 oC, FTIR (KBr, cm-1): 3415 (OH, CO2H), 2970 (C-H
aliphatic), 1706, 1688 (2C=O), 1618, 1602, 1584, 1454, 1424 (C=C), 1328, 1292 (2S=O), 1185,
1
1161 (SO2N), 1127, 1087, 1073 (C-N, C-O). H NMR (DMSO-d6) δ: 7.92-7.91 (d, J= 7.45 Hz,
2H, ArH), 7.63-7.57 (m, 4H, ArH), 7.48-7.45 (t, J= 8.00 Hz, 2H, ArH), 7.31-7.29 (d, J= 8.00
Hz), 3.45-3.44 (d, J= 4.60 Hz, 1H, CH-CO2H), 1.90-1.85 (m, 1H, CH), 0.84-0.70 (m, 6H, CH3).
13C NMR (DMSO-d6) δ: 172.7, 167.8 (2C=O), 142.9, 138.9, 133.4, 131.3, 129.8, 129.3, 129.1,
127.1 (aromatic carbons), 61.7, 30.9, 21.5, 19.5, 18.4 (aliphatic carbons). HRMS-ESI (m/z):
375.1148 (M+), calculated, 375.1140.
2.3.7 2-[N-(benzenesulfonyl)-1-phenylformamido]acetic acid (5i)
o
Yield (0.2999 g, 93.92%), mp, 121.60-121.80 C, FTIR (KBr, cm-1): 3073, 3011 (C-H
aromatic), 2837 (C-H aliphatic), 1732, 1688 (2C=O), 1619, 1603, 1584, 1454, 1425 (C=C),
1327, 1293 (2S=O), 1186, 1128 (SO2N), 1101, 1073, 1027 (C-N, C-O). 1H NMR (DMSO-d6) δ:
7.92-7.90 (t, J= 8.20 Hz, 4H, ArH), 7.60-7.56 (m, 2H, ArH), 7.48-7.44 (t, J= 7.80 Hz, 4H, ArH),
3.54 (s, 2H, CH2). 13C NMR (DMSO-d6) δ: 174.7, 167.8 (2C=O) 154.1, 151.1, 133.4, 131.3,
129.8, 129.1, 119.4, 112.8 (eight aromatic carbons), 59.0 (aliphatic carbon). HRMS-ESI (m/z):
320.1628 (M+H), calculated, 320.1625.
2.3.8 2-[N-(benzenesulphonyl)-1-phenylformamido]-3-phenylpropanoic acid (5j)
o
Yield (0.4090 g, 99.90%), mp, 94.10-94.90 C, FTIR (KBr, cm-1): 3342 (OH of COOH), 3073,
3029 (C-H aromatic), 2968 (C-H aliphatic), 1735, 1688 (C=O), 1603, 1584, 1496, 1453, 1425
1
(C=C), 1376, 1348 (2S=O), 1170, 1108 (SO2N), 1094, 1073, 1027, 1000 (C-N, C-O). H NMR
(DMSO-d6) δ: 7.92-7.90 (d, J=8.00 Hz, 4H, ArH), 7.60-7.57 (t, J= 7.45 Hz, 2H, ArH), 7.54-7.50
(t, J= 8.00 Hz, 1H, ArH), 7.47-7.45 (m, 4H, ArH), 7.41-7.38 (t, J= 8.00 Hz, 1H, ArH), 7.17-7.13
(m, 2H, ArH), 7.09-7.08 (d, J= 6.30 Hz, 1H, ArH), 3.85-3.82 (t, J= 5.75 Hz, 1H, CH-COOH),
2.92-2.88 (dd, J= 5.70, 5.70 Hz, 1H, CHa of CH2), 2.70-2.65 (dd, J= 9.15, 9.15 Hz, 1H, CHb of
13
CH2). C NMR (DMSO-d6) δ: 172.8, 167.8 (2C=O), 141.5, 137.2, 133.4, 132.6, 131.3, 129.8,
129.7, 129.4, 129.1, 128.7, 127.1, 126.7 (twelve aromatic carbons), 57.9, 38.3 (aliphatic
carbons). HRMS-ESI (m/z): 410.1874 (M+H), calculated 410.1879.
2.3.9 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-(1H-indol-2-yl)propanoic acid (5k)
Yield (0.4480 g, 99.89%), mp, 110.90-111.40 oC, FTIR (KBr, cm-1): 3385 (OH of COOH), 3305
(NH of indole), 3072 (C-H of aromatic), 2839 (C-H aliphatic), 1747, 1687 (2C=O), 1602, 1584,
1
1454, 1425 (C=C), 1339, 1292 (2S=O), 1162, 1129 (SO2N), 1083, 1027 (C-O, C-N). H NMR
(DMSOd6) δ: 10.79 (s, 1H, NH), 7.92-7.90 (m, 3H, ArH), 7.60-7.56 (m, 2H, ArH), 7.49-7.45

ACCEPTED MANUSCRIPT
(m, 3H, ArH), 7.38-7.35 (t, J= 7.45 Hz, 2H, ArH), 7.28-7.25 (m, 2H, ArH), 7.02-6.99 (t, J= 6.85
Hz, 2H, ArH), 6.91-6.88 (t, J= 7.45 Hz, 1H, ArH), 3.90-3.86 (dd, J= 7.45, 8.05 Hz, 1H, CH-
COOH), 3.04-3.00 (dd, J= 6.85, 6.30 Hz, 1H, CHa of CH2), 2.84-2.80 (dd, J= 7.45, 7.45 Hz, 1H,
CHb of CH2). 13C NMR (DMSO-d6) δ: 173.1, 167.9 (2C=O), 141.4, 136.6, 133.4, 132.6, 131.3,
129.8, 129.2, 129.1, 127.5, 126.7, 124.4, 121.4, 118.9, 118.4, 111.9, 109.4 (sixteen aromatic
carbons), 57.2, 28.8 (aromatic carbons). HRMS-ESI (m/z): 449.2109 (M+H), calculated,
449.2111.
2.3.10 2-[N-(benzenesulfonyl)-1-phenylformamido]-4-methylpentanoic acid (5l)
o
Yield (0.3659 g, 97.86%), mp, 90.40-90.70 C, FTIR (KBr, cm-1): 3072 (C-H aromatic), 2959,
2874, 2838 (C-H aliphatic), 1721, 1687 (2C=O), 1603, 1584, 1454, 1426 (C=C), 1327, 1292
1
(2S=O), 1186, 1128 (SO2N), 1093, 1074, 1027 (C-N, C-O). H NMR (DMSO-d6) δ: 7.92-7.90
(t, J= 8.60 Hz, 3H, ArH), 7.75-7.73 (d, J= 7.45 Hz, 1H, ArH), 7.59-7.56 (m, 2H, ArH), 7.53-7.50
(t, J= 8.05 Hz, ArH), 7.47-7.44 (t, J= 8.00 Hz, 3H, ArH), 3.64-3.59 (m, 1H, CH-COOH), 1.53-
13
1.48 (m, 1H, CH), 1.38-1.29 (m, 2H, CH2), 0.83-0.61 (m, 6H, CH3). C NMR (DMSO-d6) δ:
173.8, 167.9 (2C=O), 141.6, 133.4, 132.8, 131.3, 129.8, 129.5, 129.1, 126.9 (eight aromatic
carbons), 54.5, 41.4, 24.3, 23.1, 21.5 (five aliphatic carbons). HRMS-ESI (m/z): 376.2140
(M+H), calculated, 376.2144.
2.3.11 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methylpentanoic acid (5m)
o
Yield (0.3750 g, 99.89%), mp, 87.40-88.10 C, FTIR (KBr, cm-1): 3295 (OH of COOH), 3072
(C-H aromatic), 2969, 2883 (C-H aliphatic), 1723, 1698 (C=O), 1619, 1603, 1584, 1454, 1425
1
(C=C), 1327, 1293 (2S=O), 1169, 1129 (SO2N), 1092, 1074, 1027 (C-N, C-O). H NMR
(DMSO-d6) δ: 7.90-7.89 (d, J= 7.15 Hz, 2H, ArH), 7.73-7.72 (d, J= 7.15 Hz, 1H, ArH), 7.58-
7.54 (m, 2H, ArH), 7.51-7.43 (m, 5H, ArH), 3.51-3.49 (t, J= 6.30 Hz, 1H, CH-COOH), 1.62-
1.58 (m, 1H, CH), 1.30-1.25 (m, 1H, CHa, CH2), 1.06-0.99 (m, 1H, CHb, CH2), 0.73-0.72 (d, J=
6.90 Hz, 3H, CH3-CH), 0.68-0.66 (t, J= 7.45 Hz, 3H, CH3-CH2). 13C NMR (DMSO-d6) δ: 172.7,
167.9 (2C=O), 141.5, 133.4, 132.8, 131.2, 129.8, 129.4, 129.1, 126.9 (eight aromatic carbons),
60.5, 37.4, 24.8, 15.8, 11.3 (five aliphatic carbons). HRMS-ESI (m/z): 376.2141 (M+H),
calculated, 376.2146.
2.3.12 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methylpentanoic acid (5n)
o
Yield (0.3050 g, 84.37%), mp, 104.60-104.90 C, FTIR (KBr, cm-1): 3302 (OH of COOH),
3073, 2970 (C-H aromatic), 2877 (C-H aliphatic), 1734, 1688 (2C=O), 1603, 1584, 1454, 1425

ACCEPTED MANUSCRIPT
(C=C), 1327, 1293 (2S=O), 1169, 1129 (SO2N), 1128, 1093, 1074 (C-O, C-N). 1H NMR
(DMSO-d6) δ: 7.92-7.91 (m, 3H, ArH), 7.75-7.73 (t, J= 7.45 Hz, 1H, ArH), 7.60-7.55 (m, 2H,
ArH), 7.52-7.50 (d, J= 7.45 Hz, 1H, ArH), 7.49-7.45 (m, 3H, ArH), 3.50-3.48 (d, J= 6.30 Hz,
1H, CH-COOH), 1.91-1.86 (m, 1H, CH), 0.78-0.73 (m, 6H, 2CH3). 13C NMR (DMSO-d6) δ:
172.7, 167.8 (2C=O), 141.7, 133.4, 132.8, 131.3, 129.8, 129.4, 129.1, 127.0 (eight aromatic
carbons), 61.8, 30.9, 19.5, 18.4 (aliphatic carbons). HRMS-ESI (m/z): 360.1984 (M-H),
calculated, 360.1983.
2.3.13 2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]acetic acid (5q)
o
Yield (0.2126 g, 58.36%), mp, 135.00-135.50 C, FTIR (KBr, cm-1): 3310 (OH of COOH),
3073, 3009 (C-H aromatic), 2839 (C-H aliphatic), 1703, 1688 (2C=O), 1604, 1584, 1422 (C=C),
1
1527, 1454 (N-O), 1327, 1290 (2S=O), 1181, 1163 (SO2N), 1128, 1106, 1074 (C-N, C-O). H
NMR (DMSO-d6) δ: 8.37-8.35 (d, 8.60 Hz, 2H, ArH), 8.02-8.00 (d, J= 8.60 Hz, 2H, ArH), 7.92-
7.90 (d, J= 6.85 Hz, 2H, ArH), 7.60-7.57 (t, J= 7.45 Hz, 1H, ArH), 7.48-7.45 (t, J= 8.05 Hz, 2H,
ArH), 3.67 (s, 2H, CH2). 13C NMR (DMSO-d6) δ: 170.7, 167.8 (2C=O), 150.0, 147.0, 133.4,
131.3, 129.8, 129.1, 128.7, 124.9 (aromatic carbons), 44.3 (CH2). HRMS-ESI (m/z): 363.0254
(M-H), calculated, 363.0265.
2.3.14 2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-3-phenylpropanoic acid (5r)
Yield (0.4545 g, 100%), mp, 122.50-122.80 oC, FTIR (KBr, cm-1): 3309 (OH of COOH), 3113,
3073, 3008 (C-H aromatic), 2840 (C-H aliphatic), 1703, 1685 (2C=O), 1604, 1584, 1454, 1421
(C=C), 1527 (N-O), 1327, 1289 (2S=O), 1181, 1163 (SO2N), 1128, 1106 1074, 1027 (C-N, C-
1
O). H NMR (DMSO-d6) δ: 8.17-8.15 (m, 2H, ArH), 7.92-7.89 (t, J= 7.36 Hz, 2H, ArH), 7.71-
7.69 (m, 2H, ArH), 7.60-7.56 (m, 1H, ArH), 7.48-7.44 (m, 2H, ArH), 7.11-7.04 (m, 5H, ArH),
3.95-3.89 (m, 1H, CH-CO2H), 2.97-2.92 (dd, J= 4.60, 4.56 Hz, 1H, CHa of CH2), 2.70-2.64 (dd,
J= 10.08, 10.08 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6) δ: 172.7, 167.8 (2C=O), 149.6,
147.1, 137.2, 133.4, 131.3, 129.8, 129.7, 129.1, 128.6, 128.2, 126.9, 124.7 (twelve aromatic
carbons), 58.2, 38.1 (two aliphatic carbons). HRMS-ESI (m/z): 455.1936 (M+H), calculated,
455.1940.
2.3.15 3-(1H-indol-2-yl)-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]propanoic acid
(5s)
Yield (0.4932 g, 99.64%), mp, 153.30-153.90 oC, FTIR (KBr, cm-1): 3448 (OH of COOH), 3294
(NH of indole), 3072 (C-H aromatic), 1705, 1688 (C=O), 1605, 1584, 1454, 1425 (C=C), 1525

ACCEPTED MANUSCRIPT
1
(N-O), 1327, 1292 (2S=O),1179, 1167 (SO2N), 1129, 1092, 1073, 1027 (C-N, C-O). H NMR
(DMSO-d6) δ: 10.68 (s, 1H, NH of indole), 7.92-7.89 (m, 3H, ArH), 7.86-7.84 (m, 1H, ArH),
7.60-7.56 (m, 2H, ArH), 7.48-7.44 (m, 3H, ArH), 7.23-7.22 (d, J= 7.80 Hz, 1H, ArH), 7.05-7.03
(d, J= 7.80 Hz, 1H, ArH), 6.99-6.98 (d, J= 2.32 Hz, 1H, ArH), 6.89-6.81 (m, 2H, ArH), 3.90-
3.86 (m, 1H, CH-COOH), 3.06-3.01 (dd, J= 4.12, 4.12 Hz, 1H, CHa of CH2), 2.81-2.75 (dd, J=
10.08, 10.56 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6) δ: 173.3, 167.8 (2C=O), 148.9, 144.7,
138.9, 136.5, 133.4, 132.8, 131.3, 129.8, 129.1, 127.3, 124.9, 123.8, 122.4, 118.8, 118.2, 111.7
(sixteen aromatic carbons), 46.4, 36.8 (two aliphatic carbons). HRMS-ESI (m/z): 494.1045
(M+H), calculated 494.1042.
2.3.16 3-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]pentanoic acid (5t)
o
Yield (0.4201 g, 99.93%), mp, 110.40-110.60 C, FTIR (KBr, cm-1): 3293 (OH of COOH),
3117, 3072 (C-H aromatic), 2968, 2882 (C-H aliphatic), 1730, 1691 (2C=O), 1619, 1604, 1454,
1410 (C=C), 1531 (N-O), 1349, 1310 (2S=O), 1182, 1129 (SO2N), 1105, 1073, 1027, 1012 (C-
N, C-O). 1H NMR (DMSO-d6) δ: 8.36-8.34 (d, J= 8.68 Hz, 2H, ArH), 7.99-7.97 (d, J= 8.72 Hz,
2H, ArH), 7.91-7.89 (t, J= 7.32 Hz, 2H, ArH), 7.58-7.56 (t, J=7.32 Hz, 1H, ArH), 7.48-7.44 (t,
J= 7.72 Hz, 2H, ArH), 3.60-3.59 (d, J= 2.28 Hz, CH-COOH), 1.70-1.64 (m, 1H, CH), 1.34-1.28
(m, 1H, CHa of CH2), 1.24-1.01 (m, 1H, CHb of CH2), 0.78-0.72 (m, 6H, 2CH3). 13C NMR
(DMSO-d6) δ: 172.4, 167.8 (2C=O), 149.9, 147.2, 133.4, 131.3, 129.8, 129.1, 128.7, 124.8
(eight aromatic carbons) 60.9, 37.3, 24.8, 15.9, 11.5 (five aliphatic carbons). HRMS-ESI (m/z):
420.0995 (M+), calculated, 420.0991.
2.3.17 4-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]pentanoic acid (5u)
o
Yield (0.4204 g, 100%), mp, 116.30-116.70 C, FTIR (KBr, cm-1):3412 (OH of COOH), 2960
(C-H aliphatic), 1721, 1689 (2C=O), 1603, 1584, 1454, 1410 (C=C), 1531 (N-O), 1348, 1323
(2S=O), 1177, 1149 (SO2N), 1126, 1091, 1074, 1026 (C-N, C-O). 1H NMR (DMSO-d6) δ: 8.36-
8.34 (d, J= 8.72 Hz, 2H, ArH), 7.99-7.96 (d, J= 9.16 Hz, 2H, ArH), 7.91-7.89 (t, J= 6.88 Hz, 2H,
ArH), 7.60-7.56 (t, J= 7.36 Hz, 1H, ArH), 7.48-7.44 (m, 2H, ArH), 3.76-3.70 (t, J= 5.48 Hz, 1H,
CH-COOH), 1.59-1.52 (m, 1H, CHa of CH2), 1.43-1.34 (m, 1H, CHb of CH2), 0.80-0.79 (d, J=
13
6.44 Hz, 3H, CH3), 0.71-0.70 (d, J= 6.40 Hz, 3H, CH3). C NMR (DMSO-d6) δ: 173.3, 167.8
(2C=O), 149.9, 147.3, 133.4, 131.3, 129.8, 129.1, 128.7, 124.9 (eight aromatic carbons), 54.7,
41.2, 24.4, 23.1, 21.4 (five aliphatic carbons). HRMS-ESI (m/z): 420.0999 (M+), calculated,
420.0991.
2.3.18 3-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]butanoic acid (5v)

ACCEPTED MANUSCRIPT
o
Yield (0.4063 g, 99.98%), mp, 114.10-114.40 C, FTIR (KBr, cm-1): 3277 (OH of COOH),
3112, 3073 (C-H aromatic), 2969, 2874 (C-H aliphatic), 1710, 1687 (2C=O), 1606, 1584, 1454,
1424 (C=C), 1532 (N-O), 1356, 1327 (2S=O), 1169, 1146 (SO2N), 1129, 1091, 1063, 1027,
1
1013, 1000 (C-N, C-O). H NMR (DMSO-d6) δ: 8.36-8.33 (d, J=9.16 Hz, 2H, ArH), 8.01-7.99
(d, J=8.72 Hz, 2H, ArH), 7.91-7.89 (t, J= 6.88 Hz, 2H, ArH), 7.60-7.56 (t, J= 7.32 Hz, 2H,
ArH), 7.48-7.44 (m, 2H, ArH), 3.57-3.56 (d, J= 2.76Hz, 1H, CH-COOH), 1.98-1.90 (m, 1H,
CH), 0.81-0.75 (m, 6H, 2CH3). 13C NMR (DMSO-d6) δ: 172.4, 167.8 (2C=O), 149.9, 147.3,
133.4, 131.3, 129.8, 129.1, 128.7, 124.8 (eight aromatic carbons), 61.9, 30.8, 19.6, 18.3 (four
aliphatic carbons). HRMS-ESI (m/z): 405.0732 (M-H), calculated, 405.0736.
2.4 Boric acid catalysed Synthesis of Carboxamide derivatives from carboxylic acid and 4-
aminoacetophenone
To a suspension of N-benzoyl-substituted-benzenesulphonamides (5a-f, i-n and q-v, 1.0 mmol)
or proline derived benzenesulphonamide (3g-h, 3o-p and 3w-x, 1.0 mmol) in dry toluene (40
mL) equipped with Dean-Stark apparatus for azeotropic removal of water, was added 4-
aminoacetophenone (6, 1.0 mmol) and boric acid (0.1 mmol) at room temperature and then
refluxed for 10 h. On completion (as monitored by TLC), reaction mixture was precipitated into
amides by adding about 40 mL n-hexane. The carboxamides (7a-x) were obtained via suction
filtration, washed with n-hexane and dried over fused silica gel or concentrated using rotary
evaporator and dried over vacuum in the case of oily products.
2.4.1
(7a)
N-(4-acetylphenyl)-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]acetamide
o
Yield (0.4500 g, 99.98%), mp, 137.60-137.80 C, FTIR (KBr, cm-1): 3226 (NH), 2919 (C-H
aliphatic), 1771, 1754, 1682 (3C=O), 1628, 1597, 1517, 1444 (C=C), 1318, 1279 (2S=O), 1196,
1
1154 (SO2N), 1094, 1074, 1039, 1016 (C-O, C-N). H NMR (DMSO-d6) δ: 7.68-7.58 (m, 5H,
ArH), 7.34-7.29 (m, 3H, ArH), 7.23-7.20 (t, J= 7.45 Hz, 1H, ArH), 7.15-7.10 (m, 2H, ArH),
6.53-6.51 (d, J= 8.6 Hz, 2H, ArH), 3.50 (s, 2H, CH2), 2.34 (s, 3H, CH3-C=O), 2.33 (s, 3H, CH3-
Ar). 13C NMR (DMSO-d6) δ: 187.6, 171.4, 167.5 (3C=O), 143.1, 142.5, 138.2, 131.1, 130.0,
129.7, 129.4, 128.7, 127.5, 127.1, 125.8, 112.9 (twelve aromatic carbons), 48.4, 26.3, 21.3 (three
aliphatic carbons). HRMS-ESI (m/z): 450.1498 (M+), calculated, 450.1499.
2.4.2
N-(4-acetylphenyl)-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-3-phenyl
propanamide (7b)
o
Yield (0.2425 g, 89.78%), mp, 84.20-84.60 C, FTIR (KBr, cm-1): 3394 (NH), 3026 (C-H
aromatic), 2926 (C-H aliphatic), 1713, 1693, 1639 (3C=O), 1595, 1965, 1516, 1425 (C=C),

ACCEPTED MANUSCRIPT
1
1344, 1331 (2S=O), 1178, 1167 (SO2N), 1090 (C-O, C-N). H NMR (DMSO-d6) δ: 7.91-7.90
(d, J= 6.85 Hz, 1H, ArH), 7.78-7.77 (d, J= 8.05 Hz, 2H, ArH), 7.69-7.68 (d, J= 8.00 Hz, 1H,
ArH), 7.63-7.57 (m, 2H, ArH), 7.48-7.40 (m, 2H, ArH), 7.33-7.32 (d, J= 8.00 Hz, 2H), 7.25-
7.05 (m, 5H, ArH), 6.92-6.90 (m, 1H, ArH), 6.53-6.52 (d, J= 8.60 Hz, 2H, ArH), 6.47 (s, 1H,
NH), 3.55-3.53 (dd, J= 2.85, 2.90 Hz, 1H, CH), 3.16-3.11 (dd, J= 9.75, 10.30 Hz, 1H, CHa of
CH2), 2.91-2.87 (dd, J= 4.60, 6.85 Hz, 1H, CHb of CH2), 2.34 (s, 3H, CH3-C=O), 2.30 (s, 3H,
CH3-Ar). 13C NMR (DMSO-d6) δ: 195.5 (C=O of acetophenone), 172.8 (C=O of carboxamide),
167.8 (C=O of benzamide), 154.2, 142.8, 138.7, 137.3, 133.4, 131.3, 131.1, 129.8, 129.7, 129.4,
129.1, 128.7, 127.0, 126.8, 125.4, 113.0 (sixteen aromatic carbons), 57.9, 38.4, 26.4, 21.5 (four
aliphatic carbons). HRMS-ESI (m/z): 540.1256 (M+), calculated, 540.1258.
2.4.3
N-(4-acetylphenyl)-3-(1H-indol-2-yl)-2-[N-(4-methylbenzenesulphonyl)-1-phenyl
formamido]propanamide (7c)
o
Yield (0.5001 g, 86.34%), mp, 121.40-121.90 C, FTIR (KBr, cm-1): 3366, 3223 (2NH), 1753,
1728, 1623 (3C=O), 1595, 1517, 1493, 1458 (C=C), 1360, 1318 (2S=O), 1179, 1156 (SO2N),
1091, 1018 (C-O, C-N). 1H NMR (DMSO-d6) δ: 10.72 (s, 1H, NH of indole), 8.10 (s, 1H, NH of
amide), 7.93-7.92 (d, J= 7.45 Hz, 1H, ArH), 7.65-7.63 (d, 8.60 Hz, 3H, ArH), 7.46-7.42 (m, 3H,
ArH), 7.29-7.23 (m, 3H, ArH), 7.11-7.10 (d, J= 8.00 Hz, 2H, ArH), 7.03-6.99 (m, 2H, ArH),
6.90-6.87 (t, J= 7.45 Hz, 1H, ArH), 6.57-6.56 (d, J= 8.55 Hz, 3H, ArH), 3.88-3.85 (t, J= 6.85
Hz, 1H, CH-C=O), 3.06-3.02 (dd, J= 6.30, 6.30 Hz, 1H, CHa of CH2), 2.86-2.81 (dd, J= 8.00,
13
7.45 Hz, 1H, CHb of CH2), 2.34 (s, 3H, CH3-C=O), 2.2424 (CH3-Ar). C NMR (DMSO-d6) δ:
196.1 (C=O of acetophenone), 173.3 (C=O of carboxamide), 168.0 (C=O of benzamide), 154.1,
142.9, 138.2, 136.6, 133.4, 131.2, 129.9, 129.8, 129.4, 129.1, 127.4, 126.8, 125.5, 124.5, 121.5,
118.9, 118.3, 113.2, 111.9, 109.3 (twenty aromatic carbons), 57.1, 28.8, 26.3, 21.4 (four
aliphatic carbons). HRMS-ESI (m/z): 579.1476 (M+), calculated, 579.1475.
2.4.4
N-(4-acetylphenyl)-4-methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]
pentanamide (7d)
o
Yield (0.3562 g, 70.36%), mp, 129.50-130.10 C, FTIR (KBr, cm-1): 3368 (NH), 3062 (C-H
aromatic), 2957, 2869 (C-H aliphatic), 1725, 1698, 1678 (3C=O), 1598, 1556, 1517, 1496, 1451
1
(C=C), 1316, 1289 (2S=O), 1179, 1156 (SO2N), 1092, 1069, 1039, 1017 (C-N, C-O). H NMR
(DMSO-d6) δ: 7.92-7.90 (d, J= 7.80 Hz, 1H, ArH), 7.74-7.70 (t, J= 8.28 Hz, 1H, ArH), 7.62-7.56
(m, 3H, ArH), 7.50-7.44 (m, 3H, ArH), 7.32-7.08 (m, 5H, ArH), 6.69-6.67 (d, J= 8.24 Hz, 1H,
ArH), 3.60-3.57 (t, J= 3.2 Hz, 1H, CH-C=O), 2.31 (s, 3H, CH3-C=O), 2.25 (s, 3H, CH3-Ar),
13
1.57-1.53 (m, 1H, CH), 1.36-1.33 (m, 2H, CH2), 0.80-0.64 (m, 6H, 2CH3). C NMR (DMSO-
d6) δ: 195.5 (C=O of acetophenone), 173.8 (C=O of carboxamide), 167.8 (C=O of benzamide),

ACCEPTED MANUSCRIPT
154.1, 142.9, 138.8, 137.9, 133.4, 129.8, 129.4, 129.1, 128.7, 128.0, 127.0, 125.8 (twelve
aromatic carbons), 54.4, 41.4, 26.4, 24.4, 23.1, 21.6 (six aliphatic carbons). HRMS-ESI (m/z):
506.1417 (M+), calculated, 506.1423.
2.4.5
N-(4-acetylphenyl)-3-methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]
pentanamide (7e)
o
Yield (0.4201 g, 82.99%), mp, 64.90-65.30 C, FTIR (KBr, cm-1): 3398 (NH), 3274 (C-H
aromatic), 2970 (C-H aliphatic), 1752, 1697, 1641 (3C=O), 1598, 1454, 1418 (C=C), 1335,
1284 (2S=O), 1178, 1162 (SO2N), 1128, 1092, 1074, 1026 (C-N, C-O). 1H NMR (DMSO-d6) δ:
7.92-7.88 (m, 3H, ArH), 7.63-7.56 (m, 5H, ArH), 7.48-7.44 (t, J= 7.80 Hz, 2H, ArH), 7.31-7.29
(d, J= 8.24 Hz, 1H, ArH), 6.53-6.51 (d, J= 8.72 Hz, 2H, ArH), 3.51-3.47 (m, 1H, CH-C=O),
1.64-1.59 (m, 1H, CH), 1.34-1.27 (m, 1H, CHa of CH2), 1.08-1.01 (m, 1H, CHb of CH2), 0.75-
13
0.68 (dt, J=6.88, 7.36 Hz, 6H, 2CH3). C NMR (DMSO-d6) δ: 195.4 (C=O of acetophenone),
172.7 (C=O of carboxamide), 167.8 (C=O of benzamide), 154.1, 142.9, 138.8, 133.4, 131.3,
131.1, 129.8, 129.8, 129.1, 127.1, 125.4, 112.9 (twelve aromatic carbons), 60.5, 37.4, 26.4, 24.9,
21.5, 15.9, 11.4 (seven aliphatic carbons). HRMS-ESI (m/z): 506.1366 (M+), calculated,
506.1363.
2.4.6
N-(4-acetylphenyl)-3-methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]
butanamide (7f)
o
Yield (0.3899 g, 79.22%), mp, 75.20-75.90 C, FTIR (KBr, cm-1): 3395 (NH), 2970 (C-H
aliphatic), 1708, 1653, 1640 (3C=O), 1592, 1564, 1518, 1495, 1466, 1437 (C=C), 1361, 1333
(2S=O), 1179, 1161 (SO2N), 1090, 1020 (C-N, C-O). 1H NMR (DMSO-d6) δ: 7.92-7.85 (m, 2H,
ArH), 7.63-7.56 (m, 5H, ArH), 7.48-7.44 (t, J= 7.80 Hz, 1H, ArH), 7.31-7.29 (d, J= 8.24 Hz, 2H,
ArH), 6.53-6.51 (d, J= 8.72 Hz, 3H, ArH), 5.98 (s, 1H, NH), 3.45-3.43 (d, J= 5.96 Hz, 1H, CH-
C=O), 2.33 (s, 3H, CH3-C=O), 2.32 (s, 3H, CH3-Ar), 1.92-1.83 (m, 1H, CH), 0.78-0.73 (m, 6H,
13
2CH3). C NMR (DMSO-d6) δ: 195.4 (C=O of acetophenone), 172.7 (C=O of carboxamide),
167.8 (C=O of benzamide), 154.1, 147.5, 142.9, 138.9, 133.4, 131.3, 131.1, 129.8, 129.1, 127.1,
125.4, 112.9 (twelve aromatic carbons), 61.8, 30.9, 26.4, 21.5, 19.5, 18.4 (six aliphatic carbons).
HRMS-ESI (m/z): 492.1716 (M+), calculated, 492.1718.
2.4.7
N-(4-acetylphenyl)-4-hydroxy-1-(4-methylbenzenesulfonyl)pyrrolidine-2-
carboxamide (7g)
o
Yield (0.4000 g, 99.48%), mp, 122.20-122.70 C, FTIR (KBr, cm-1): 3454 (OH), 3390 (NH),
2985, 2960, 2738 (C-H aliphatic), 1757, 1638 (2C=O), 1598, 1496, 1469, 1448, 1402 (C=C),
1345, 1330 (2S=O), 1180, 1156 (SO2N), 1126, 1091, 1071, 1017 (C-N, C-O). 1H NMR (DMSO-
d6) δ: 7.65-7.61 (m, 2H, ArH), 7.37-7.35 (d, J=7.80 Hz, 2H, ArH), 7.19-7.12 (m, 2H, ArH),

ACCEPTED MANUSCRIPT
6.52-6.51 (d, J= 7.32 Hz, 2H, ArH), 4.17 (s, 1H, OH), 4.01-3.98 (t, J= 7.80 Hz, 1H, CH-C=O),
3.43-3.39 (m, 1H, CH-OH), 3.06-3.03 (d, J= 10.56 Hz, 2H, CH2-N), 2.35 (s, 3H, CH3-C=O),
2.34 (s, 3H, CH3-Ar), 1.92-1.86 (m, 2H, CH2). 13C NMR (DMSO-d6) δ: 195.5 (C=O of
acetophenone), 173.8 (C=O of carboxamide), 154.1, 143.7, 134.9, 131.1, 130.1, 127.9, 125.3,
112.9 (eight aromatic carbons), 68.9, 60.2, 56.8, 26.4, 21.5 (five aliphatic carbons). HRMS-ESI
(m/z): 403.1303 (M+H), calculated, 403.1304.
2.4.8 N-(4-acetylphenyl)-1-(4-methylbenzenesulfonyl)pyrrolidine-2-carboxamide (7h)
Yield (0.3808 g, 98.63%), oil, FTIR (KBr, cm-1): 3376 (NH), 3233 (C-H aromatic), 1737, 1629
(C=O), 1596, 1495, 1443 (C=C), 1339, 1307 (2S=O), 1178, 1158 (SO2N), 1094, 1011 (C-N, C-
O). 1H NMR (DMSO-d6) δ: 7.67-7.62 (m, 4H, ArH), 7.37-7.35 (d, J= 8.28 Hz, 2H, ArH), 6.55-
6.53 (d, J= 8.68 Hz, 2H, ArH), 4.04-4.02 (m, 1H, CH-C=O), 3.32-3.27 (m, 1H, CHa of CH2N),
3.11-3.05 (m, 1H, CHb of CH2N), 2.33 (s, 3H, CH3-C=O), 2.23 (s, 3H, CH3-Ar), 1.84-1.70 (m,
13
3H), 1.50-1.46 (m, 1H). C NMR (DMSO-d6) δ: 195.6 (C=O of acetophenone), 173.8 (C=O of
carboxamide), 154.1, 144.2, 135.1, 131.1, 130.3, 127.7, 125.4, 113.0 (eight aromatic carbons),
60.9, 48.9, 30.9, 26.3, 24.7, 21.5 (six aliphatic carbons). HRMS-ESI (m/z): 387.1375 (M+H),
calculated, 387.1374.
2.4.9 N-(4-acetylphenyl)-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]acetamide (7i)
Yield (0.4791 g, 99.58%), mp, 99.10-99.70 oC FTIR (KBr, cm-1): 3372 (NH), 1736, 1700, 1667
(3C=O), 1594, 1412 (2S=O), 1528 (NO2), 1350, 1311 (2S=O), 1165, 1108 (SO2N), 1091, 1108
(C-N). 1H NMR (DMSO-d6) δ: 8.36-8.34 (m, 4H, ArH), 8.02-7.99 (t, J= 6.88 Hz, 5H), 7.63-7.60
(d, J= 8.20 Hz, 2H), 6.52-6.50 (d, J= 8.72 Hz, 2H, ArH), 5.97 (s, 1H, NH), 3.66 (s, 2H, CH2),
2.33 (s, 3H, CH3). 13C NMR (DMSO-d6) δ: 195.6 (C=O of acetophenone), 170.7 (C=O of
carboxamide), 167.4 (C=O of benzamide), 154.1, 149.9, 146.9, 146.1, 131.1, 129.4, 128.9,
128.7, 128.6, 125.8, 124.9, 124.7, 113.0 (twelve aromatic carbons), 44.2, 26.4 (two aliphatic
carbons). HRMS-ESI (m/z): 504.2429 (M+Na), calculated, 504.2431.
2.4.10
N-(4-acetylphenyl)-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-3-phenyl
propanamide (7j)
o
Yield (0.5621 g, 98.42%), mp, 105.70-106.20 C FTIR (KBr, cm-1): 3371 (NH), 3104 (C-H
aromatic), 1746, 1700, 1675 (3C=O), 1594, 1454 (C=C), 1527 (NO2), 1349, 1307 (2S=O), 1177,
1
1161 (SO2N), 1092, 1064, 1043 (C-N). H NMR (DMSO-d6) δ: 8.36-8.34 (d, J= 8.60 Hz, 1H,
ArH), 8.18-8.09 (m, 2H, ArH), 7.96-7.91 (m, 1H, ArH), 7.72-7.63 (m, 2H, ArH), 7.24-7.20 (m,
4H, ArH), 7.17-7.09 (m, 4H, ArH), 7.04-7.03 (d, J= 5.15 Hz, 2H, ArH), 6.90-6.88 (m, 1H, ArH),
6.56-6.54 (d, J= 8.55 Hz, 1H, ArH), 3.79-3.76 (dd, J= 8.60 Hz, 3.40 Hz, 1H, CH-C=O), 3.25-
3.20 (dd, J= 9.70, 5.10 Hz, 1H, CHa, CH2), 3.00-2.95 (dd, J= 8.00, 11.45 Hz, 1H, CHb of CH2),

ACCEPTED MANUSCRIPT
2.26 (s, 3H, CH3). 13C NMR (DMSO-d6) δ: 196.1 (C=O of acetophenone), 173.1 (C=O of
carboxamide), 165.1 (C=O benzamide), 138.9, 137.9, 136.8, 131.1, 129.9, 129.7, 129.4, 129.2,
128.7314, 128.6, 128.2, 125.8, 124.8, 124.7, 124.4, 113.3 (sixteen aromatic carbons), 60.4, 35.5,
26.4 (three aliphatic carbons). HRMS-ESI (m/z): 571.1119 (M+), calculated, 571.1123.
2.4.11
N-(4-acetylphenyl)-3-(1H-indol-2-yl)-2-[N-(4-nitrobenzenesulfonyl)-1-phenyl
formamido]propanamide (7k)
o
Yield (0.6100 g, 99.97%), mp, 202.20-202.80 C FTIR (KBr, cm-1): 3447 (NH of indole), 3381
(NH of carboxamide), 3108 (C-H aromatic), 2926 (C-H aliphatic), 1710, 1689, 1621 (3C=O),
1595, 1557, 1459, 1424 (C=C), 1526 (NO2), 1348, 1312 (2S=O), 1178, 1167 (SO2N), 1093,
1
1013 (C-N). H NMR (DMSO-d6) δ: 10.65 (s, 1H, NH), 8.62-8.60 (d, J= 8.24 Hz, 2H, ArH),
7.91-7.84 (m, 3H, ArH), 7.76-7.70 (m, 1H, ArH), 7.63-7.61 (d, J 8.72 Hz, 1H, ArH), 7.47-7.45
(d, J= 8.72 Hz, 2H, ArH), 7.24-7.22 (d, J= 7.80 Hz, 1H, ArH), 7.14-6.99 (m, 3H, ArH), 6.88-
6.74 (m, 3H, ArH), 6.53-6.51 (d, J= 8.72 Hz, 2H, ArH), 3.91-3.87 (dd, J= 9.64, 5.96 Hz, 1H,
CH-C=O), 3.06-3.01 (dd, J= 4.16, 3.64 Hz, 1H, CHa of CH2), 2.81-2.75 (dd, J= 10.52, 10.52 Hz,
1H, CHb of CH2), 2.33 (s, 3H, CH3-C=O). 13C NMR (DMSO-d6) δ: 195.4 (C=O of
acetophenone), 173.3 (C=O of carboxamide), 164.9 (C=O of benzamide), 148.9, 146.4, 140.8,
138.9, 136.5, 135.2, 133.7, 131.1, 129.4, 127.4, 126.9, 124.9, 123.8, 121.2, 118.8, 118.2, 115.8,
113.1, 111.7, 109.2 (twenty aromatic carbons), 57.1, 28.4, 26.4 (three aliphatic carbons).
HRMS-ESI (m/z): 628.1016 (M+NH4), calculated, 628.1018.
2.4.12
N-(4-acetylphenyl)-4-methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]
pentanamide (7l)
o
Yield (0.5092 g, 94.79%), mp, 126.70-126.90 C FTIR (KBr, cm-1): 3373 (NH), 3232 (C-H
aromatic), 2958, 2870 (C-H aliphatic), 1742, 1698, 1656 (3C=O), 1596, 1556, 1467 (C=C),
1
1528 (NO2), 1350, 1307 (2S=O), 1181, 1163 (SO2N), 1090, 1064, 1012 (C-N). H NMR
(DMSO-d6) δ: 8.37-8.32 (m, 4H, ArH), 8.06-7.98 (m, 3H, ArH), 7.65-7.63 (d, J= 8.60 Hz, 2H,
ArH), 7.23-7.11 (m, 3H, ArH), 6.57-6.55 (d, J= 8.60 Hz, 2H, ArH), 3.99-3.97 (t, J= 3.50 Hz, 1H,
CH-C=O), 3.53-3.50 (m, 1H, CH(CH3)2), 2.35 (s, 3H, CH3-C=O), 1.76-1.71 (m, 1H, CHa of
CH2), 1.45-1.35 (m, 1H, CHb of CH2), 0.84-0.68 (m, 6H, 2CH3). 13C NMR (DMSO-d6) δ: 195.5
(C=O of acetophenone), 173.6 (C=O of carboxamide), 166.8 (C=O of benzamide), 153.5, 149.9,
149.6, 146.8, 131.1, 129.4, 129.2, 128.7, 125.8, 124.9, 124.7, 113.4 (twelve aromatic carbons),
58.9, 26.4, 24.8, 23.9, 21.9 (five aliphatic carbons). HRMS-ESI (m/z): 560.1337 (M+Na),
calculated, 560.1339.
2.4.13
N-(4-acetylphenyl)-3-methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]
pentanamide (7m)

ACCEPTED MANUSCRIPT
Yield (0.5184 g, 96.50%), mp, 142.90-143.20 oC FTIR (KBr, cm-1): 3373 (NH), 2968, 2887 (C-
H aliphatic), 1745, 1688, 1666 (3C=O), 1596, 1556, 1467 (C=C), 1523 (NO2), 1350, 1307
1
(2S=O), 1181, 1163 (SO2N), 1090, 1064 (C-N). H NMR (DMSO-d6) δ: 8.44-8.30 (m, 3H,
ArH), 8.08-7.98 (m, 3H, ArH), 7.64-7.62 (d, J= 5.04 Hz, 1H, ArH), 7.21-7.09 (m, 2H, ArH),
6.57-6.55 (d, J= 8.24 Hz, 2H, ArH), 3.61-3.59 (t, J= 3.24 Hz, 1H, CH-C=O), 2.34 (s, 3H, CH3-
C=O), 1.71-1.64 (m, 1H, CH), 1.35-1.29 (m, 1H, CHa of CH2), 1.11-1.03 (m, 1H, CHb of CH2),
13
0.81-0.71 (m, 6H, 2CH3). C NMR (DMSO-d6) δ: 195.6 (C=O of acetophenone), 172.4 (C=O
of carboxamide), 167.9 (C=O of benzamide), 153.5, 149.9, 149.6, 147.2, 137.9, 131.1, 129.4,
128.7, 125.8, 124.8, 124.5, 113.4 (twelve aromatic carbons), 60.9, 37.3, 26.4, 24.8, 15.9, 11.4
(six aliphatic carbons). HRMS-ESI (m/z): 537.1220 (M+), calculated, 537.1224.
2.4.14
N-(4-acetylphenyl)-3-methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]
butanamide (7n)
Yield (0.5209 g, 99.58%), mp, 187.50-187.70 oC FTIR (KBr, cm-1): 3376 (NH), 2968, 2887 (C-
H aliphatic), 1745, 1688, 1666 (3C=O), 1596, 1556, 1467 (C=C), 1523 (NO2), 1350, 1307
1
(2S=O), 1181, 1163 (SO2N), 1090, 1064 (C-N). H NMR (DMSO-d6) δ: 8.43-8.30 (m, 5H,
ArH), 8.07-7.98 (m, 4H, ArH), 7.63-7.61 (d, J= 8.72 Hz, 2H, ArH), 6.53-6.51 (d, J= 8.72 Hz,
2H, ArH), 3.53-3.55 (m, 1H, CH-C=O), 2.34 (s, 3H, CH3-C=O), 1.98-1.92 (m, 1H, CH(CH3)2),
13
0.80-0.75 (m, 6H, 2CH3). C NMR (DMSO-d6) δ: 196.0 (C=O of acetophenone), 172.4 (C=O
of carboxamide), 169.4 (C=O of benzamide), 153.9, 149.9, 149.5, 147.2, 131.1, 128.7, 128.6,
126.7, 124.8, 124.5, 119.4, 113.1 (twelve aromatic carbons), 61.9, 30.8, 26.1, 19.6, 18.3 (five
aliphatic carbons). HRMS-ESI (m/z): 523.1476 (M+), calculated, 523.1473.
2.4.15 N-(4-acetylphenyl)-4-hydroxy-1-(4-nitrobenzenesulfonyl)pyrrolidine-2-carboxamide
(7o)
Yield (0.4331 g, 100%), mp, 160.80-161.20 oC FTIR (KBr, cm-1): 3480 (OH), 3415 (NH), 3115
(C-H aromatic), 1748, 1689 (2C=O), 1595, 1403 (C=C), 1527 (NO2), 1358, 1332 (2S=O), 1184,
1
1162 (SO2N), 1090, 1070, 1016, 1006 (C-N, C-O). H NMR (DMSO-d6) δ: 8.37-8.27 (m, 2H,
ArH), 8.04-8.01 (d, J= 8.72 Hz, 2H, ArH), 7.63-7.60 (d, J= 8.72 Hz, 1H, ArH), 7.22-7.10 (m,
2H, ArH), 6.56-6.50 (m, 1H, ArH), 5.98 (s, 1H, NH), 4.22 (s, 1H, OH), 4.12-4.08 (t, J= 7.76 Hz,
1H, CH-C=O), 3.46-3.43 (m, 1H, CH-OH), 3.21-3.18 (d, J= 11.00 Hz, 2H, CH2-N), 2.33 (s, 3H,
CH3-C=O), 2.03-1.99 (t, J= 7.76 Hz, 1H, CHa of CH2CHN), 1.93-1.86 (m, 1H, CHb of
CH2CHN). 13C NMR (DMSO-d6) δ: 195.5 (C=O of acetophenone), 173.5 (C=O of
carboxamide), 150.3, 143.6, 131.1, 129.5, 128.7, 125.8, 124.8, 112.9 (eight aromatic carbons),
69.0, 60.5, 57.1, 26.4, 21.6 (five aliphatic carbons). HRMS-ESI (m/z): 456.2067 (M+Na),
calculated, 456.2069.

ACCEPTED MANUSCRIPT
2.4.16 N-(4-acetylphenyl)-1-(4-nitrobenzenesulfonyl)pyrrolidine-2-carboxamide (7p)
o
Yield (0.4170 g, 99.98%), mp, 99.30-99.90 C FTIR (KBr, cm-1): 3378 (NH), 3105 (C-H
aromatic), 2957 (C-H aliphatic), 1732, 1684 (2C=O), 1597, 1446, 1402 (C=C), 1529 (NO2),
1350, 1310 (2S=O), 1162, 1092 (SO2N), 1010 (C-N). 1H NMR (DMSO-d6) δ: 8.38-8.29 (m, 2H,
ArH), 8.07-8.05 (d, J= 8.68 Hz, 2H, ArH), 7.22-7.08 (m, 4H, ArH), 6.28 (s, 1H, NH), 4.18-4.15
(dd, J= 3.68, 3.68 Hz, 1H, CH-C=O), 3.39-3.34 (t, J= 5.04 Hz, 1H, CHa of CH2N), 3.23-3.17
(dd, J= 7.36, 6.88 Hz, 1H, CHb of CH2N), 2.25 (s, 3H, CH3-C=O), 1.99-1.92 (m, 1H, CHa of
CH2CHC=O), 1.84-1.77 (m, 2H, CH2), 1.63-1.60 (m, 1H, CHb of CH2CHC=O). 13C NMR
(DMSO-d6) δ: 198.4 (C=O of acetophenone), 173.5 (C=O of carboxamide), 150.4, 143.9, 137.9,
131.1, 129.4, 129.2, 128.7, 125.8, 125.1, 112.9 (ten aromatic carbons), 61.2, 48.9, 30.9, 24.7,
21.6 (five aliphatic carbons). HRMS-ESI (m/z): 416.0919 (M-H), calculated, 416.0923.
2.4.17 N-(4-acetylphenyl)-2-[N-(benzenesulfonyl)-1-phenylformamido]acetamide (7q)
o
Yield (0.4005 g, 91.75%), mp, 150.40-150.70 C, FTIR (KBr, cm-1): 3361 (NH), 3223 (C-H
aromatic), 1732, 1683, 1623 (C=O), 1591, 1516, 1445, 1408 (C=C), 1361, 1280 (2S=O), 1214,
1
1176 (SO2N), 1071, 1024 (C-N, C-O). H NMR (DMSO-d6) δ: 7.68-7.58 (m, 5H, ArH), 7.34-
7.29 (m, 3H, ArH), 7.23-7.20 (t, J= 7.45 Hz, 1H, ArH), 7.15-7.10 (m, 2H, ArH), 6.53-6.51 (d, J=
13
8.6 Hz, 2H, ArH), 3.50 (s, 2H, CH2), 2.34 (s, 3H, CH3-C=O). C NMR (DMSO-d6) δ: 192.8
(C=O of acetophenone), 171.2 (C=O of carboxamide), 162.6 (C=O of benzamide), 155.6, 152.1,
145.5, 140.9, 132.5, 131.1, 130.9, 129.3, 127.4, 119.9, 112.8, 104.3 (twelve aromatic carbons),
48.8, 26.3 (two aliphatic carbons). HRMS-ESI (m/z): 437.1746 (M+H), calculated, 437.1749.
2.4.18
N-(4-acetylphenyl)-2-[N-(benzenesulfonyl)-1-phenylformamido]-3-phenyl
propanamide (7r)
Yield (0.4862 g, 92.33%), mp, 61.20-61.70 oC, FTIR (KBr, cm-1): 3392 (NH), 3225, 3063 (C-H
aromatic), 2967 (C-H aliphatic), 1735, 1700, 1650 (3C=O), 1594, 1565, 1514, 1497, 1481, 1447
1
(C=C), 1375, 1348 (2S=O), 1170, 1108 (SO2N), 1093, 1027 (C-N). H NMR (DMSO-d6) δ:
7.92-7.90 (d, J= 6.88 Hz, 2H, ArH), 7.63-7.61 (d, J= 8.72 Hz, 2H, ArH), 7.54-7.46 (m, 5H,
ArH), 7.41-7.37 (t, J= 7.80 Hz, 2H, ArH), 7.19-7.13 (m, 4H, ArH), 7.09-7.07 (m, 2H, ArH),
6.53-6.51 (d, J= 8.68 Hz, 2H, ArH), 5.99 (s, 1H, NH), 3.86-3.80 (dd, J= 9.16, 6.84 Hz, 1H, CH-
C=O), 2.92-2.87 (dd, J= 5.96, 5.96 Hz, 1H, CHa of CH2), 2.70-2.64 (dd, J=9.2, 9.16 Hz, CHa of
CH2), 2.34 (s, 3H, CH3). 13C NMR (DMSO-d6) δ: 195.5 (C=O of acetophenone), 172.8 (C=O of
carboxamide), 167.9 (C=O of benzamide), 154.1, 141.5, 137.3, 133.4, 132.7, 131.1, 129.8,
129.7, 129.4, 129.1, 128.7, 128.5, 127.1, 126.7, 125.4, 112.9 (sixteen aromatic carbons), 57.9,
38.3, 26.4 (three aliphatic carbons). HRMS-ESI (m/z): 526.1569 (M+), calculated, 526.1562.

ACCEPTED MANUSCRIPT
2.4.19
N-(4-acetylphenyl)-2-[N-(benzenesulfonyl)-1-phenylformamido]-3-(1H-indol-2-yl)
propanamide (7s)
o
Yield (0.4986 g, 88.15%), mp, 114.20-114.80 C, FTIR (KBr, cm-1): 3382, 3326 (2NH), 3059
(C-H aromatic), 2924 (C-H aliphatic), 1729, 1689, 1622 (3C=O), 1595, 1491, 1458, 1448, 1424
1
(C=C), 1309, 1286 (2S=O), 1231, 1158 (SO2N), 1091, 1011 (C-N). H NMR (DMSO-d6) δ:
10.76 (s, 1H, NH of indole), 7.94-7.93 (d, J= 6.85 Hz, 3H, ArH), 7.65-7.64 (d, J= 8.60 Hz, 2H,
ArH), 7.60-7.58 (d, J=8.05 Hz, 2H, ArH), 7.49-7.46 (t, J=7.45 Hz, 2H, ArH), 7.38-7.35 (t, J=
7.45 Hz, 2H, ArH), 7.30-7.28 (d, J= 8.00 Hz, 2H, ArH), 7.04-7.01 (m, 2H, ArH), 6.93-6.90 (t, J=
8.05 Hz, 1H, ArH), 6.56-6.54 (d, J= 8.60 Hz, 3H, ArH), 5.98 (s, 1H, NH of amide), 3.94-3.89
(dd, J= 7.45, 7.45 Hz, 1H, CH-C=O), 3.07-3.03 (dd, J= 6.3, 6.3 Hz, 1H, CHa of CH2), 2.87-2.83
(dd, J= 7.45, 7.45 Hz, 1H, CHb of CH2), 2.35 (s, 3H, CH3-C=O). 13C NMR (DMSO-d6) δ: 195.6
(C=O of acetophenone), 173.1 (C=O of carboxamide), 167.9 (C=O of benzamide), 154.1, 141.5,
136.6, 132.6, 131.1, 129.8, 129.4, 129.2, 129.1, 128.7, 127.5, 126.7, 125.4, 124.5, 121.4, 118.9,
118.4, 113.0, 111.9, 109.4 (twenty aromatic carbons), 57.2, 28.8, 26.4 (three aliphatic carbons).
HRMS-ESI (m/z): 565.1692 (M+), calculated, 565.1671.
2.4.20
N-(4-acetylphenyl)-2-[N-(benzenesulfonyl)-1-phenylformamido]-4-methyl
pentanamide (7t)
Yield (0.3998 g, 81.16%), mp, 212.70-212.90 oC, FTIR (KBr, cm-1): 3392 (NH), 2964, 2876 (C-
H aliphatic), 1759, 1736, 1673 (3C=O), 1597, 1448 (C=C), 1385, 1364 (2S=O), 1160, 1142
1
(SO2N), 1095, 1072, 1022 (C-N). H NMR (DMSO-d6) δ: 7.92-7.91 (d, J= 7.32 Hz, 2H, ArH),
7.75-7.73 (d, J=7.32 Hz, 2H, ArH), 7.64-7.62 (d, J= 8.24 Hz, 2H, ArH), 7.55-7.42 (m, 5H, ArH),
6.55-6.53 (d, J= 8.24 Hz, 3H, ArH), 3.65-3.60 (t, J= 7.36 Hz, 1H, CH-C=O), 2.33 (s, 3H, CH3-
C=O), 1.54-1.47 (m, 1H, CH), 1.36-1.32 (m, 2H, CH2), 0.82-0.60 (m, 6H, 2CH3). 13C NMR
(DMSO-d6) δ: 195.6 (C=O of acetophenone), 173.8 (C=O of carboxamide), 167.9 (C=O of
benzamide), 154.1, 141.6, 133.4, 132.8, 131.1, 129.8, 129.5, 129.2, 129.1, 126.9, 125.4, 113.0
(twelve aromatic carbons), 54.5, 41.4, 26.3, 24.4, 23.3 (five aliphatic carbons). HRMS-ESI
(m/z): 515.2961 (M+Na), calculated, 515.2965.
2.4.21
N-(4-acetylphenyl)-2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl
pentanamide (7u)
Yield (0.4105 g, 83.33%), mp, 270.00-270.60 oC, FTIR (KBr, cm-1): 3392 (NH), 2964, 2876 (C-
H aliphatic), 1759, 1736, 1682 (3C=O), 1597, 1448 (C=C), 1385, 1364 (2S=O), 1160, 1142
1
(SO2N), 1095, 1072, 1021 (C-N). H NMR (DMSO-d6) δ: 7.74-7.73 (t, J= 7.45 Hz, 3H, ArH),
7.63-7.61 (d, J= 9.15 Hz, 1H, ArH), 7.58-7.55 (m, 1H, ArH), 7.53-7.50 (m, 3H, ArH), 7.23-7.20
(t, J=7.45 Hz, 2H, ArH), 7.15-7.09 (m, 2H, ArH), 6.53-6.51 (d, J= 8.55 Hz, 2H, ArH), 6.10 (s,

ACCEPTED MANUSCRIPT
1H, NH), 3.51-3.50 (d, J= 6.30 Hz, 1H, CH-C=O), 2.34 (s, 3H, CH3-Ar), 1.63-1.59 (m, 1H, CH),
1.31-1.28 (m, 1H, CHa of CH2), 1.07-1.01 (m, 1H, CHb of CH2), 0.75-0.69 (dt, J= 6.85, 7.45 Hz,
6H, 2CH3). 13C NMR (DMSO-d6) δ: 196.7 (C=O of acetophenone), 172.7 (C=O of
carboxamide), 168.6 (C=O of benzamide), 141.7, 139.5, 137.9, 133.8, 132.8, 129.4, 128.7,
127.0, 125.8, 125.7, 112.9, 109.4 (twelve aromatic carbons), 60.5, 37.4, 24.9, 21.6, 15.9, 11.4
(six aromatic carbons). HRMS-ESI (m/z): 492.1238 (M+), calculated, 492.1239.
2.4.22
N-(4-acetylphenyl)-2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl
butanamide (7v)
Yield (0.3896 g, 81.40%), mp, black oil, FTIR (KBr, cm-1): 3368 (NH), 3228 (C-H aromatic),
2963 (C-H aliphatic), 1729, 1698, 1626 (3C=O), 1595, 1516, 1447 (C=C), 1360, 1309 (2S=O),
1
1177, 1158 (SO2N), 1093, 1056 (C-N). H NMR (DMSO-d6) δ: 7.97-7.91 (m, 2H, ArH), 7.75-
7.73 (t, J= 6.88 Hz, 2H, ArH), 7.64-7.62 (m, 3H, ArH), 7.57-7.45 (m, 5H, ArH), 6.55-6.52 (t, J=
6.88 Hz, 2H, ArH), 3.49-3.48 (d, J= 3.24 Hz, 1H CH-C=O), 2.33 (s, 3H, CH3-C=O), 1.92-1.87
(m, 1H, CH), 0.78-0.73 (m, 6H, 2CH3). 13C NMR (DMSO-d6) δ: 195.6 (C=O of acetophenone),
172.7 (C=O of carboxamide), 167.9 (C=O of benzamide), 154.1, 141.6, 133.4, 132.8, 131.1,
129.8, 129.4, 129.1, 128.9, 127.0, 125.4, 113.0 (twelve aromatic carbons), 61.8, 30.9, 26.3, 19.5,
18.3 (five aliphatic carbons). HRMS-ESI (m/z): 501.2299 (M+Na), calculated, 501.2231.
2.4.23 N-(4-acetylphenyl)-1-(benzenesulfonyl)-4-hydroxypyrrolidine-2-carboxamide (7w)
Yield (0.3881 g, 100%), mp, 117.20-117.60 oC, FTIR (KBr, cm-1): 3402 (OH), 3221 (NH), 2993
(C-H aromatic), 2955, 2673 (C-H aliphatic), 1713, 1694 (2C=O), 1596, 1449 (C=C), 1353, 1338
1
(2S=O), 1212, 1195 (SO2N), 1099, 1070, 1010 (C-N). H NMR (DMSO-d6) δ: 7.84-7.71 (m,
2H, ArH), 7.65-7.55 (m, 5H, ArH), 6.55-6.53 (d, J= 8.24 Hz, 2H, ArH), 4.18 (s, 1H, OH), 4.06-
4.03 (t, J= 6.40 Hz, 1H, CH-C=O), 3.45-3.42 (m, 2H, CH2), 3.10-3.08 (m, 1H, CH-OH), 2.34 (s,
3H, CH3-C=O), 1.94-1.88 (m, 2H, CH2). 13C NMR (DMSO-d6) δ: 195.5 (C=O of acetophenone),
173.8 (C=O of carboxamide), 154.1, 137.9, 133.4, 131.1, 129.8, 127.9, 125.3, 113.0 (eight
aromatic carbons), 68.9, 60.3, 56.8, 26.4 (four aliphatic carbons). HRMS-ESI (m/s): 389.1185
(M+H), calculated, 389.1189.
2.4.24 N-(4-acetylphenyl)-1-(benzenesulfonyl)pyrrolidine-2-carboxamide (7x)
Yield (0.3724 g, 99.97%), yellowish oil, FTIR (KBr, cm-1): 3230 (NH), 3115 (C-H aromatic),
1748, 1689 (C=O), 1595, 1527, 1403 (C=C), 1358, 1332 (2S=O), 1184, 1162 (SO2N), 1090,
1070, 1016, 1006 (C-N). 1H NMR (DMSO-d6) δ: 7.80-7.78 (d, J= 7.45 Hz, 2H, ArH), 7.66-7.56
(m, 5H, ArH), 6.56-6.54 (d, J=8.55 Hz, 2H, ArH), 4.09-4.06 (m, 1H, CH-C=O), 3.32-3.29 (t, J=
6.90 Hz, 1H, CHa of CH2-N), 3.13-3.09 (m, 1H, CHb of CH2-N), 2.33 (s, 3H, CH3-C=O), 1.83-
1.74 (m, 3H), 1.51-1.48 (t, J= 5.70 Hz, CH). 13C NMR (DMSO-d6) δ: 195.7 (C=O of

ACCEPTED MANUSCRIPT
acetophenone), 173.7 (C=O of carboxamide), 154.1, 137.9, 133.6, 131.1, 129.9, 127.6, 125.4,
113.1 (eight aromatic carbons), 60.9, 48.9, 30.6, 26.3, 24.8 (five aliphatic carbons). HRMS-ESI
(m/z): 373.1219 (M+H), calculated, 373.1219.
2.5 Docking studies
The docking study was performed using BioVia discovery studio client version 4.5 software.
The X-ray crystallographic structures plasmepsin II (4Z22) proteins bound was acquired from
the protein data bank (PDB) at a resolution of 2.73 Å. The active site was defined with a 8.500
Å radius around the bound inhibitor which covered all the active sites amino acids of the
proteins. A grid-based molecular docking method was used to dock the small molecules into the
protein active site. All water molecules, bound inhibitors and other hetero atoms were removed
from the macromolecule and polar hydrogen atoms were added. The designed structures were
also verified for its valency, missing hydrogen and any structural disorders like connectivity and
bond orders. A final minimization of the ligand in the rigid receptor using non-softened potential
was performed. For each final pose, the CHARMm energy (interaction energy plus ligand strain)
and the interaction energy alone was calculated. The poses were sorted by CHARMm energy
and the top scoring (most negative with least root square mean deviation) poses were selected.
2.6 In vitro antimalarial studies
The antimalarial activities of the new carboxamides were determined by their inhibition of
parasite growth using chloroquine resistant strain of Plasmodium falciparum. Effects of
inhibitors on parasite development were determined as follows. Sorbitol synchronized, 0.1%
parasitemia, ring stage P. falciparum strain W2 parasites were cultured under the atmosphere of
3% O2, 6% CO2 and 91% N2 in RPMI-1640 medium supplemented with 10% human serum in
the presence of inhibitors for 48 h without media change. Inhibitors were added from 1000×
DMSO stocks. After 48 h, the culture medium was removed and replaced with 1%
formaldehyde in PBS pH 7.4 for an additional 48 h at room temperature to fix cells. Fixed
parasites were transferred into 0.1% Triton-X-100 in PBS containing 1 nM YOYO-1 dye
(Molecular Probes). Parasitemia was determined from dot plots (forward scatter vs.
fluorescence) acquired on a FACS sort flow cytometer using Cell Quest software (Beckton
Dickinson). The MIC of compounds were the minimum concentration at which more than 99%
of the parasites, relative to the control, were inhibited from developing to schizonts (parasites
with six or more chromatin dots) [33].
2.7 Antioxidant

ACCEPTED MANUSCRIPT
The new carboxamides were screened for free radical scavenging activity by 2,2-diphenyl-1-
picrylhydrazyl (DPPH) method [34]. Compounds of different concentrations were prepared in
distilled ethanol, 1 mL of each compound solutions having different concentrations (1.0, 2.0,
3.0, 4.0 and 5.0 mg/mL) were taken in different test tubes, 4 mL of 0.1 mM ethanol solution of
DPPH was added and shaken vigorously. The test tubes were then incubated in the dark room
temperature for 20 min. A DPPH blank was prepared without the compound and ethanol was
used for the baseline correction. Changes (decrease) in the absorbance at 517 nm were measured
using a UV-Visible spectrometer. The radical scavenging activities were expressed as the
inhibition percentage and were calculated using:
DPPH radical scavenging activity (%) = [(Ac-As)/Ac] *100,
Where Ac = absorbance of control and As = absorbance of samples
3.0 Results and Discussion
3.1 Chemistry
R1
OH
O
O
HO
O
i. Na2CO3, 0 oC, 1 h
rt, 4 h
O
S
S
O
Cl
R
NH
H2N
+
ii. HCl
R1
R
O
1a-c
3a-x
2a-h
i. NaOH (10%)
O
Cl
CH3
O
4
O
ii. HCl
CH3
R1
NH
R1
N
OH
O
H2N
O
S
O
6
R
N
O
R
S
B(OH)3, dry toluene
ii. n-hexane
O
O
O
O
7a-x
R= H, CH3, NO2
5a-f, i-m, q-v
Scheme 1: Protocol for the synthesis of new carboxamide derivatives bearing sulphonamide
functionalities.