Synthesis, characterization and in vitro antitrypanosomal activities of new carboxamides bearing quinoline moiety

Article abstract of DOI:10.1371/journal.pone.0191234

The reported toxicities of current antitrypanosomal drugs and the emergence of drug resistant trypanosomes underscore the need for the development of new antitrypanosomal agents. We report herein the synthesis and antitrypanosomal activity of 24 new amide derivatives of 3-aminoquinoline, bearing substituted benzenesulphonamide. Nine of the new derivatives showed comparable antitrypanosomal activities at IC₅₀ range of 1–6 nM (melarsoprol 5 nM). Compound 11n and 11v are more promising antitrypanosomal agents with IC₅₀ 1.0 nM than the rest of the reported derivatives. The novel compounds showed satisfactory predicted physico-chemical properties including oral bioavailability, permeability and transport properties.

Full text of DOI:10.1371/journal.pone.0191234

RESEARCH ARTICLE
Synthesis, characterization and in vitro
antitrypanosomal activities of new
carboxamides bearing quinoline moiety
David Izuchukwu Ugwu1,2*, Uchechukwu Chris Okoro1, Narendra Kumar Mishra2
1 Medicinal Chemistry Unit, Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka,
Nigeria, 2 Department of Chemistry, Indian Institute of Technology, Kanpur, India
* izuchukwu.ugwu@unn.edu.ng
Abstract
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The reported toxicities of current antitrypanosomal drugs and the emergence of drug resis-
tant trypanosomes underscore the need for the development of new antitrypanosomal
agents. We report herein the synthesis and antitrypanosomal activity of 24 new amide deriv-
atives of 3-aminoquinoline, bearing substituted benzenesulphonamide. Nine of the new
derivatives showed comparable antitrypanosomal activities at IC50 range of 1–6 nM (melar-
soprol 5 nM). Compound 11n and 11v are more promising antitrypanosomal agents with
IC50 1.0 nM than the rest of the reported derivatives. The novel compounds showed satis-
factory predicted physico-chemical properties including oral bioavailability, permeability and
transport properties.
OPEN ACCESS
Citation: Ugwu DI, Okoro UC, Mishra NK (2018)
Synthesis, characterization and in vitro
antitrypanosomal activities of new carboxamides
bearing quinoline moiety. PLoS ONE 13(1):
e0191234. https://doi.org/10.1371/journal.
pone.0191234
Editor: Giovanni Maga, Istituto di Genetica
Introduction
Molecolare, ITALY
Trypanosomes are parasitic protozoa that cause Chagas disease in central and South America
and sleeping sickness in sub-Saharan Africa leading to morbidity and mortality of millions of
people [1]. Trypanosoma brucei gambiense and T. b. rhodesiense are the etiological agents of
sleeping sickness in humans in sub-Saharan Africa. About half a million people are infected
with sleeping sickness leading to the death of almost 100,000 people annually [2]. Despite the
fact that in the past 24 years, the number of incidence for both Chagas and human African try-
panosomiasis (HAT) has significantly declined, primarily due to vector control initiatives [3],
the development of new chemotherapeutic agent for the treatment of sleeping sickness and
Chagas disease is urgently needed because of the undesirable toxic side effects of known anti-
trypanosomal drugs, and the emergence of drug-resistant trypanosomes.
Received: September 14, 2017
Accepted: December 29, 2017
Published: January 11, 2018
Copyright: © 2018 Ugwu et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Benznidazole (1), melarsoprol (2), pentamidine (3) and nifurtimox (4) are the leading che-
motherapeutic agent used in the treatment of Chagas and sleeping sickness. Benznidazole (1)
is primarily used for the treatment of Chagas disease. Melarsoprol (2) has a high number of
associated side effects [4] including but not limited to brain dysfunction, convulsion, numb-
ness, rashes, kidney and liver problems [5]. About 1–5% of people die from adverse effects
related to melarsoprol treatment [6]. Pentamidine (3) is usually applied at the early stage of the
parasite before it crosses to central nervous system. It is not recommended in early pregnancy
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
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Synthesis of new anti-trypanosomal agents
because of the associated side effects [7]. The most common side effects of concern is wheez-
ing, hypotension, severe arrhythmias and heart failure [8, 9]. Pentamidine has also been linked
to azotemia, renal failure, hepatomegaly, hepatitis, seizures and hypoglycemia [9]. In addition
to the side effects of pentamidine, it is also costly with the inhalation powder costing up to
122.84 USD and a vial for injection costing 45.31 USD in the United States [10]. Nifurtimox
(4) takes 30 to 60 days administration to treat Chagas disease [11]. This long term use does
increase chances of adverse effects like gastrointestinal and neurological disorder [12]. It is
also reported that administration of nifurtimox in sleeping sickness leads to relapsing in half of
the patients treated [13]. The use of nifurtimox in pregnancy is usually avoided because of the
associated side effects [14]. Nifurtimox has also been linked to central nervous system distur-
bances, peripheral neuropathy, confusion, seizures, impotency, depression and numbness
[15–17]. Eflornithine (5) is the only new drug introduced for the treatment of sleeping sickness
but was ineffective against T. b. rhodesiense [18].
As there is no immediate prospect for vaccines, chemotherapy is the only way to fight
trypanosomes. This enzyme is responsible for the major proteolytic activity of all life cycle
stages of this parasite [19]. Brucipain is localized in the lysosomes of blood stream forms of T.
brucei [20]. It induces calcium activation signals that allows blood brain barrier to open up to
parasite crossing [21]. This makes this enzyme a good target for the treatment of human Afri-
can trypanosomiasis.
In line with the call for the synthesis of new chemotherapeutic agent for the treatment of
human African trypanosomiasis, Ajibade and Kolawole [22] reported antitrypanosomal activi-
ties of some sulfadiazine complex. Papadopoulou et al [23] also reported the antitrypanosomal
activities of some amides and sulphonamides. Some of the derivatives reported by this group
were more potent up to 58-fold than benznidazole (1).
Since benznidazole (1) contains an amide functionality and nifurtimox (4) contains a sul-
fone group, synergistic antitrypanosomal activity arising from successful combination of
amide of benznidazole and sulfone of nifurtimox motivated this research. This expectation
was supported by the work of Papadopoulou which showed comparable antitrypanosomal
activity when amide groups were replaced with sulphonamides. This finding suggests that suc-
cessful combination of the functionalities would possibly lead to a synergy. Werbovetz et al
[24] reported oryzalin (6) as the most active antiparasitic agent. It showed GI50 values of 0.41
and 0.73 μM in vitro against two strains of T. brucei with a selectivity index of 40–80 thereby
making it a promising lead. This compound possess both amide and sulphonamide functional-
ity. The structures of most widely used commercial antitrypanosomal drugs are shown in
Fig 1.
From the forgoing, there is need to synthesize new antitrypanosomal agents that will retain
high potency of melarsoprol and other commercial antitrypanosomal agents while having an
improved toxicity profile.
As a continuation of our search for lead antitrypanosomal agents, we report in this work
fascinating antitrypanosomal activities of newly synthesized 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.
Experimental
Instrumentation
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
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Synthesis of new anti-trypanosomal agents
Fig 1. Examples of commercial antitrypanosomal agents. A representation of some compounds used as
antitrypanosomal agent.
https://doi.org/10.1371/journal.pone.0191234.g001
commercial suppliers, Aldrich, Merck, Fluka, Avra, SD fine and Alfa Aesar. Thin layer chro-
matography 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 PerkinEl-
mer Spectrum version 10.03.06 and the bands presented in wavenumber. Proton and carbon-
13 NMR spectroscopy were run in DMSOd6 and CD3OD, unless otherwise stated on either
Jeol 500 MHz or 400 MHz. The chemical shifts were reported in part per million with refer-
ence to tetramethylsilane. Mass spectroscopy were carried out using micro TOF electrospray
time of flight (ESI-TOF) mass spectrometer (Aerodyne Research Inc. USA), sodium formate
was used as the calibrant. All experiments were carried out at Prof. Sandeep Verma’s Labora-
tory, department of Chemistry, Indian Institute of Technology, Kanpur. Melting points were
determined using digital melting point apparatus (Stuart, SMP20) and were uncorrected.
General procedure for the synthesis of substituted benzenesulphonamoyl
alkanamides (7a-x)
Sodium carbonate (Na2CO3, 1.590 g, 15 mmol) was added to a solution of amino acids (6a-h,
12.5 mmol) in water (15 mL) with continuous stirring until all the solutes dissolved. The solu-
tion was cooled to -5˚C and an appropriate benzenesulphonyl chloride (5a-c, 15 mmol) was
added in four portions over a period of 1 h. The slurry was further stirred at room temperature
for 4 h. The progress of the reaction was monitored by using TLC (MeOH/DCM, 1:9). Upon
completion, the mixture was acidified using 20% aqueous hydrochloric acid to pH 2. The crys-
tals was filtered via suction and washed with pH 2.2 buffer. The pure products (7a-x) were
dried over self-indicating fused silica gel in a desiccator.
2-(4-methylphenylsulphonamido) acetic acid (7a). The amino acid was glycine, yield
(2.8410 g, 99.34%), appearance white needles, 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, 1321
(2S = O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). 1H NMR (500 MHz, DMSO-d6) δ: 7.89 (t,
J = 6.3 Hz, 1H, NH), 7.64 (d, J = 8.6 Hz, 2H, ArH), 7.33 (d, J = 8.05 Hz, 2H, ArH), 3.51 (d,
J = 5.7 Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (500 MHz, DMSO-d6) δ: 170.8 (C = O), 143.1,
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Synthesis of new anti-trypanosomal agents
138.4, 130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0410
(M-H)-, calculated, 228.0408.
2-(4-methylphenylsulphonamido)-3-phenylpropanoic acid (7b). The amino acid
was L-phenylalanine, yield (3.9848 g, 99.93%), appearance, off-white powder, mp, 135.10–
135.40˚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, 500 MHz) δ: 8.12 (d, J = 9.15
Hz, 1H, NH), 7.46 (d, J = 7.45 Hz, 2H, ArH), 7.42 (d, J = 8.6 Hz, 2H, ArH), 7.14 (m, 5H, ArH),
3.82 (dd, J = 3.45, 2.85 Hz, 1H, CH), 2.89 (dd, J = 5.75, 5.75 Hz, 1H, CHa of CH2), 2.67 (dd,
J = 8.6, 8.6 Hz, 1H, CHb of CH2), 2.31 (m, 3H, CH3). 13C NMR (DMSO-d6, 500 MHz) δ: 172.8
(C = O), 142.8, 138.7, 137.3, 129.7, 128.7, 126.9, 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, 320.0951.
3-(1H-indol-2-yl)-2-{[(4-methylphenyl)sulphonyl]amino}propanoic acid (7c). The
amino acid was L-tryptophan, yield (4.3814 g, 97.880%), appearance, yellowish liquid, FTIR
(KBr, cm-1): 3385, 3302 (2NH), 2921, 2858 (C-H aliphatic), 1750 (C = O), 1618, 1598, 1494,
1457, 1429 (C = C), 1321, 1291 (2S = O), 1163, 1131 (SO2NH), 1082, 1019 (C-N, C-O). 1H
NMR (DMSO-d6, 500 MHz) δ: 10.73 (s, 1H, NH of indole), 8.07 (d, J = 8.60 Hz, 1H, NH of
SO2NH), 7.67 (d, J = 8.05 Hz, 1H, ArH), 7.42 (d, J = 8.60 Hz, 2H, ArH), 7.33 (d, J = 8.00 Hz,
1H, ArH), 7.25 (t, J = 8.05 Hz, 1H, ArH), 7.13 (d, J = 8.00 Hz, 2H, ArH), 7.05–7.01 (m, 2H,
ArH), 6.90 (m, 1H, ArH), 3.84 (dd, J = 7.45, 8.00 Hz, 1H, CH), 3.00 (dd, J = 6.3, 6.90 Hz, 1H,
CHa, CH2), 2.81 (dd, J = 7.45, 7.45 Hz, 1H, CHb of CH2), 2.28 (s, 3H, CH3-Ar). 13C NMR
(DMSO-d6, 500 MHz) δ: 173.2 (C = O), 142.7, 138.5, 136.6, 129.6, 127.4, 126.8, 124.5, 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, 359.1064.
4-Methyl-2-{[(4-methylphenyl)sulfonyl]amino}pentanoic acid (7d). The amino acid
was L-leucine, yield (3.502 g, 98.26%), appearance, off-white powder, mp, 114.10–114.50˚C.
FTIR (KBr, cm-1): 3423 (OH of CO2H), 3279 (NH), 2949 (C-H aromatic), 2872 (C-H ali-
phatic), 1706 (C = O), 1598, 1497, 1458, 1420 (C = C), 1384, 1339 (2S = O), 1168, 1152
(SO2NH), 1122, 1091, 1020 (C-N, C-O). 1H NMR (DMSO-d6, 500 MHz) δ: 7.97 (d, J = 8.60
Hz, 1H, NH), 7.61 (d, J = 8.55 Hz, 2H, Ar-H), 7.31 (d, J = 8.55 Hz, 2H, ArH), 3.60 (m, 1H,
CH-CO2H), 2.33 (s, 3H, CH3-Ar), 1.53 (m, 1H, CH), 1.34 (m, 2H, CH2), 0.76 (d, J = 6.85 Hz,
3H, CH3), 0.65 (d, J = 6.30 Hz, 3H, CH3). 13C NMR (DMSO-d6, 500 MHz) 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, 286.1988.
3-methyl-2-{[(4-methylphenyl)sulfonyl]amino}pentanoic acid (7e). The amino acid
was L-isoleucine, yield (3.412 g, 95.74%), appearance, off-white, mp, 130.10–130.50˚C, FTIR
(KBr, cm-1): 3280 (NH), 2970, 2934 (C-H Ar-H), 2883 (C-H aliphatic), 1710 (C = O), 1599,
1496, 1460 (C = C), 1385, 1334 (2S = O), 1185, 1161 (SO2NH), 1092, 1058, 1020 (C-N, C-O).
1H NMR (DMSO-d6) δ: 7.87 (d, J = 9.2 Hz, 1H, NH), 7.61 (d, J = 8.05 Hz, 2H, ArH), 7.31 (d,
J = 8.05 Hz, 2H, ArH), 3.49 (dd, J = 6.30, 6.30 Hz, 1H, CH-CO2H), 2.33 (s, 3H, CH3-Ar), 1.60
(m, 1H, CH), 1.31 (m, 1H, CHa of CH2), 1.05 (m, 1H, CHb of CH2), 0.73 (dt, J = 6.85, 7.45H,
6H, 2CH3). 13C NMR (DMSO-d6, 500 MHz) δ: 172.7 (C = O), 142.9, 138.9, 129.8, 127.1
(aromatic carbons), 60.5, 37.5, 24.9, 21.5, 15.9, 11.4 (aliphatic carbons). HRMS-ESI (m/z):
284.0765 (m-H)-, calculated, 284.0769.
3-Methyl-2-(4-methylphenylsulphonamido)butanoic acid (7f). The amino acid was L-
valine, yield (3.2849 g, 95.56%), appearance, off-white, mp, 121.9–122.20˚C, 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, 500 MHz) δ: 7.86 (d, J = 9.75 Hz,
1H, NH), 7.65 (m, 2H, ArH), 7.28 (m, 2H, ArH), 3.45 (dd, J = 5.70, 5.75Hz, 1H, CH-CO2H),
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Synthesis of new anti-trypanosomal agents
2.31 (m, 3H, CH3-Ar), 1.88 (m, 1H, CH), 0.71 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 500
MHz) 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+), calculated, 271.0889.
4-Hydroxy-1-tosylpyrrolidine-2-carboxylic acid (7g). The amino acid was L-hydroxy-
proline, yield (3.564 g, 99.86%), appearance, white needles, 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
(2S = O), 1200, 1158 (SO2N), 1090, 1075 (C-N or C-O). 1H NMR (DMSO-d6, 400 MHz) δ:
7.65 (d, J = 8.00 Hz, 2H, ArH), 7.37 (d, J = 8.05 Hz, 2H, ArH), 4.18 (s, 1H, O-H), 4.01 (t,
J = 8.05 Hz, 1H, CH-CO2H), 3.42 (m, 1H, CH-OH), 3.05 (d, J = 10.3 Hz, 2H, CH2), 2.36 (s,
3H, CH3), 1.91 (t, 4.6 Hz, 2H, CH2). 13C NMR (DMSO-d6, 400 MHz) 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, 286.1097.
1-Tosylpyrrolidine-2-carboxylic acid (7h). The amino acid was L-proline, yield (3.2989
g, 98.09%), appearance, yellowish powder, mp, 50.4–50.80˚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, 500 MHz) δ: 7.65
(d, J = 8.6 Hz, 2H, ArH), 7.35 (d, J = 8.00 Hz, 2H, ArH), 4.04 (dd, J = 4.55, 5.15 Hz, 1H,
CH-COOH), 3.29 (dd, J = 9.75, 5.15Hz, 1H, CHa of CH2-N), 3.09 (dd, J = 6.85, 7.45 Hz, 1H,
CHb of CH2-N), 2.31 (s, 3H, CH3-Ar), 1.77 (m, 3H), 1.48 (t, J = 5.15 Hz, 1H). 13C NMR
(DMSO-d6, 500 MHz) 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,
269.0726.
2-Benzenesulphonamido acetic acid (7i). The amino acid was glycine, yield (2.6856 g,
99.61%), appearance, off-white powder, mp, 170.80–170.90˚C. FTIR (KBr, cm-1): 3317 (NH),
3060, 2974 (C-H aromatic), 2946 (C-H aliphatic), 1728 (C = O), 1587, 1451, 1428, 1412
(C = C), 1318, 1247 (S = O), 1158, 1130 (SO2NH), 1095, 1077, 1012 (C-N, C-O). 1H NMR
(DMSO-d6, 500 MHz) δ: 8.01 (t, J = 12.00 Hz, 1H, NH), 7.76 (d, J = 7.45 Hz, 2H, ArH), 7.59 (t,
J = 7.45 Hz, 1H, ArH), 7.54 (t, J = 8.00 Hz, 2H, ArH), 3.55 (d, J = 6.30 Hz, 2H, CH2). 13C NMR
(DMSO-d6, 500 MHz) δ: 170.7 (C = O), 141.2, 132.9, 129.6, 126.9 (aromatic carbons), 44.5 (ali-
phatic carbon). HRMS-ESI (m/z): 216.1252, calculated 216.1257.
2-Benzenesulphonamido-3-phenylpropanoic acid (7j). The amino acid was L-phenylal-
anine, yield (3.8169 g, 100%), appearance, off-white powder, mp, 129.10–129.50˚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, 500 MHz) δ: 8.25 (d, J = 8.85 Hz, 1H, NH), 7.52 (m, 3H, ArH), 7.40 (t,
J = 7.45 Hz, 2H, ArH), 7.15 (m, 3H, ArH), 7.08 (d, J = 7.15 Hz, 2H, ArH), 3.84 (ddd, J = 6.00,
5.75, 6.30 Hz, 1H, CH-CO2H), 2.90 (dd, J = 5.75, 5.75 Hz, 1H, CHa of CH2), 2.67 (dd, J = 9.00,
9.00 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6, 500 MHz) 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 304.0628.
2-Benzenesulphonamido-3-(1H-indol-3-yl)propanoic acid (7k). The amino acid was L-
tryptophan, yield (4.2805 g, 99.43%), appearance, faint yellow powder, mp, 106.40–106.70˚C.
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, 500 MHz) δ: 10.78 (s, 1H, NH of indole), 8.22
(d, J = 8.60 Hz, 1H, NH), 7.57 (m, 2H, ArH), 7.48 (t, J = 6.85 Hz, 1H, ArH), 7.37 (m, 2H, ArH),
7.27 (d, J = 8.60 Hz, 2H, ArH), 7.01 (m, 2H, ArH), 6.90 (t, J = 7.40 Hz, 1H, ArH), 3.89 (m, 1H,
ArH), 3.03 (dd, J = 6.85, 6.85 Hz, 1H, CHa of CH2), 2.83 (dd, J = 8.05, 7.45 Hz, 1H, CHb of
CH2). 13C NMR (DMSO-d6, 500 MHz) δ: 173.1 (C = O), 141.5, 136.6, 132.6, 129.2, 127.5,
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Synthesis of new anti-trypanosomal agents
126.7, 124.5, 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-Benzenesulphonamido-4-methylpentanoic acid (7l). The amino acid was L-leucine,
yield (3.0592 g, 90.20%), appearance, off-white powder, mp, 105.60˚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, 400MHz) δ: 8.09 (d, J = 8.72 Hz, 1H, NH), 7.72 (t, J = 6.88 Hz, 2H, ArH), 7.54 (m,
3H, ArH), 3.60 (m, 1H, CH-CO2H), 1.50 (m, 1H, CH), 1.33 (m, 2H, CH2), 0.70 (m, 6H, CH3).
13C NMR (DMSO-d6, 400MHz) 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, 272.1983.
2-Benzenesulphonamido-3-methylpentanoic acid (7m). The amino acid was L-isoleu-
cine, yield (3.1052 g, 91.55%), appearance, off-white powder, mp, 148.00–148.30˚C. 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, 400 MHz) δ: 8.00 (d, J = 9.16 Hz, 1H, NH), 7.72 (d, J = 8.60 Hz, 2H, ArH), 7.54
(m, 3H, ArH), 3.50 (dd, J = 7.45, 7.45 Hz, 1H, CH-CO2H), 1.60 (m, 1H, CH), 1.30 (m, 1H,
CHa of CH2), 1.04 (m, 1H, CHb of CH2), 0.71 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400MHz)
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 (ali-
phatic carbons). HRMS-ESI (m/z): 271.0879 (M+), calculated, 271.0878.
2-Benzenesulphonamido-3-methylbutanoic acid (7n). The amino acid was L-valine,
yield (3.2030 g, 99.68%), appearance, white needles, mp, 143.60–143.90˚C. 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, 400MHz)
δ: 7.97 (d, J = 9.16 Hz, 1H, NH), 7.73 (d, J = 6.88 Hz, 2H, ArH), 7.53 (m, 3H, ArH), 3.46 (dd,
J = 6.44, 5.96 Hz, 1H, CH-CO2H), 1.88 (m, 1H, CH), 0.75 (m, 6H, CH3). 13C NMR (DMSO-d6,
400MHz) δ: 172.7 (C = O), 141.7, 132.8, 129.4, 127.0 (aromatic carbons), 61.8, 30.9, 19.5, 18.4
(aliphatic carbons). HRMS-ESI (m/z): 258.1824 (M+H), calculated, 258.1827.
1-(Benzenesulphonyl)-4-hydroxypyrrolidine-2-carboxylic acid (7o). The amino acid
was L-4-hydroxyproline, yield (3.3815 g, 99.99%), appearance, white powder, mp, 159.00˚C.
FTIR (KBr, cm-1): 3402 (OH), 2993, 2955 (C-H aliphatic), 1714 (C = O), 1589, 1484, 1450
(C = C), 1385, 1353 (2S = O), 1195, 1158 (SO2NH), 1158, 1100, 1070 (C-N, C-O). 1H NMR
(DMSO-d6, 400MHz) δ: 7.77 (d, J = 7.32 Hz, 2H, ArH), 7.63 (t, J = 7.36 Hz, 1H, ArH), 7.56
(t, J = 7.80 Hz, 2H, ArH), 4.18 (s, 1H, OH), 4.04 (t, J = 7.80 Hz, 1H, CH-CO2H), 3.43 (m, 1H,
CHOH), 3.09 (d, J = 11.00 Hz, 2H, CH2-N), 1.92 (m, 2H, CH2). 13C NMR (DMSO-d6,
400MHz) 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.
1-(Benzenesulphonyl)-pyrrolidine-2-carboxylic acid (7p). The amino acid was L-pro-
line, yield (3.1911 g, 100%), appearance, yellowish oil. 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, 400MHz) δ: 7.80 (m, 2H, ArH),
7.65 (m, 1H, ArH), 7.58 (m, 2H, ArH), 4.07 (dd, J = 4.60, 4.60 Hz, 1H, CH-CO2H), 3.31 (m,
1H, CHa of CH2N), 3.11 (m, 1H, CHb of CH2N), 1.78 (m, 3H), 1.50 (m, 1H). 13C NMR
(DMSO-d6, 400MHz) δ: 173.7 (C = O), 137.8, 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 256.1680.
2-(4-Nitrophenylsulphonamido)acetic acid (7q). The amino acid was glycine, yield
(2.2152 g, 94.59%), appearance, off-white powder, mp, 171.9–172.30˚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,
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Synthesis of new anti-trypanosomal agents
C-O). 1H NMR (DMSO-d6, 400 MHz) δ: 8.42 (t, J = 4.00 Hz, 1H, NH), 8.35 (d, J = 9.15 Hz,
2H, ArH), 8.01 (d, J = 8.6 Hz, 2H, ArH), 3.66 (d, J = 4.00 Hz, 2H, CH2). 13C NMR (DMSO-d6,
400 MHz) δ: 170.7 (C = O), 150.0, 147.0, 128.7, 124.9 (aromatic carbons), 44.2 (aliphatic car-
bon). HRMS-ESI (m/z): 261.0261 (M+H), Calculated 261.0265.
2-(4-Nitrophenylsulphonamido)-3-phenylpropanoic acid (7r). The amino acid was L-
phenylalanine, yield (3.1530 g, 99.99%), appearance, off-white powder, mp, 100.10–100.40˚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-N, C-O). 1H NMR (DMSO-d6, 400 MHz) δ: 8.68 (d, J = 8.6 Hz, 1H, NH), 8.16 (d,
J = 9.15 Hz, 2H, ArH), 7.70 (d, J = 8.6 Hz, 2H, ArH), 7.08 (m, 5H, ArH), 3.93 (ddd, J = 5.2, 4.6,
5.15 Hz, 1H, CH-CH2), 2.95 (dd, J = 5.15, 5.15 Hz, 1H, CHa of CH2), 2.67 (dd, J = 9.75, 9.75
Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6, 400 MHz) δ: 172.7 (C = O), 149.7, 147.2, 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 368.2341.
3-(1H-Indol-2-yl)-2-(4-nitrophenylsulphonamido)propanoic acid (7s). The amino acid
was L-tryptophan, yield (3.4253 g, 97.94%), appearance, pale yellow powder, mp, 226.90–
227.20˚C. 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, 400 MHz) δ: 10.66 (s, 1H, NH,
indole), 8.60 (d, J = 8.00 Hz, 1H, NH), 7.85 (m, 2H, ArH), 7.48 (m, 2H, ArH), 7.23 (d, J = 7.45
Hz, 1H, ArH), 7.04 (d, J = 8.00 Hz, 1H, ArH), 6.99 (s, 1H, ArH), 6.85 (m, 2H, ArH), 3.89 (ddd,
J = 4.00, 2.85, 4.6 Hz, 1H, CH-CO2H), 3.04 (dd, J = 4.6, 4.6 Hz, 1H, CHa of CH2), 2.79 (dd,
J = 10.3, 9.75 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6, 400 MHz) 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): 390.0126 (M+H)+, calculated 390.0124.
4-Methyl-2-nitrophenylsulphonamido)pentanoic acid (7t). The amino acid was L-leu-
cine, yield (2.8461 g, 99.98%), appearance, white powder, 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,
1091, 1010 (C-N, C-O). 1H NMR (DMSO-d6, 400 MHz) δ: 8.54 (d, J = 9.15 Hz, 1H, NH), 8.35
(d, J = 8.6 Hz, 2H, ArH), 7.98 (d, J = 8.6 Hz, 2H, ArH), 3.68 (m, 1H, CH-CO2H), 1.56 (m, 1H,
CH(CH3)2), 1.38 (m, 2H, CH2), 0.76 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400 MHz) δ: 173.4
(C = O), 149.9, 147.3, 128.7, 124.9 (aromatic carbons), 54.7, 41.2, 24.5, 23.1, 21.4 (aliphatic car-
bons). HRMS-ESI (m/z): 315.1265 (M-H)-, calculated 315.1266.
3-Methyl-2-(4-nitrophenylsulphonamido)pentanoic acid (7u). The amino acid was L-
isoleucine, yield (2.7894 g, 97.97%), appearance, white powder, mp, 131.40–131.70˚C. 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-N, C-O). 1H NMR (DMSO-d6, 400 MHz) δ: 8.42 (d, J = 9.15 Hz, 1H, NH), 8.35 (d,
J = 8.60 Hz, 2H, ArH), 7.99 (d, J = 8.55 Hz, 2H, ArH), 3.61 (t, J = 6.00 Hz, 1H, CH-CO2H),
1.67 (m, 1H, CH), 1.32 (m, 1H, CHa of CH2), 1.07 (m, 1H, CHb of CH2), 0.75 (m, 6H, 2CH3).
13C NMR (DMSO-d6, 400 MHz) δ: 172.4 (C = O), 149.9, 147.2, 128.7, 124.8 (aromatic car-
bons), 60.9, 37.3, 24.9, 15.9, 11.5 (aliphatic carbons). HRMS-ESI (m/z): 317.2387 (M+H)+, cal-
culated 317.2386.
3-Methyl-2-(4-nitrophenylsulphonamido)butanoic acid (7v). The amino acid was L-
valine, yield (2.7200 g, 99.97%), appearance, white needles, mp, 182.60–182.90˚C. 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, 400 MHz) δ: 8.4367–
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Synthesis of new anti-trypanosomal agents
8.4184 (d, J = 9.15 Hz, 1H, NH), 8.3577–8.3405 (d, J = 8.6 Hz, 2H, ArH), 7.9992–7.9809 (d,
J = 9.15 Hz, 2H, ArH), 3.5845–3.5536 (dd, J = 5.7, 6.3 Hz, 1H, CH-CO2H), 1.9756–1.9091 (m,
1H, CH (CH3)2), 0.8063–0.7559 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400 MHz) 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): 320.0579 (M+NH4), calculated, 320.0573.
4-Hydroxy-1-(4-nitrophenylsulphonyl)pyrrolidine-2-carboxylic acid (7w). The amino
acid was L-hydroxyproline, yield (2.8459 g, 99.97%), appearance, white needles, mp, 199.8–
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, 1164 (SO2N), 1136, 1112, 1090, 1015, 1005 (C-N, C-O). 1H NMR
(DMSO-d6, 500 MHz) δ: 8.36 (d, J = 9.15 Hz, 2H, ArH), 8.03 (d, J = 8.60 Hz, 2H, ArH), 4.17 (s,
1H, OH), 4.11 (t, J = 8.6 Hz, 1H, CH-CO2H), 3.45 (dd, J = 3.45, 3.40 Hz, 1H, CHOH), 3.20 (d,
J = 10.90 Hz, 2H, CH2N), 2.02 (m, 1H, CHa, CH2), 1.91 (m, 1H, CHb of CH2). 13C NMR
(DMSO-d6, 500 MHz) δ: 173.5, 150.3, 143.6, 129.5, 124.9 (aromatic carbons), 69.0, 60.4, 57.1
(aliphatic carbons). HRMS-ESI (m/z): 303.2987 (M+H)+, calculated 303.2984.
1-(4-Nitrophenylsulphonyl)pyrrolidine-2-carboxylic acid (7x). The amino acid was L-
proline, yield (2.6051 g, 96.39%), appearance, off-white needles, mp, 149.90–150.20˚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, 1008 (C-N, C-O). 1H NMR (DMSO-d6, 500 MHz) δ: 8.38 (m, 2H, ArH), 8.06 (m, 2H,
ArH), 4.18 (m, 1H, CH-CO2H), 3.37 (m, 1H, CHa of CH2), 3.20 (m, 1H, CHb of CH2), 1.96
(m, 1H, CHa of CH2), 1.81 (m, 2H, CH2), 1.63 (m, 1H, CH). 13C NMR (DMSO-d6, 500 MHz)
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): 301.0144 (M+H)+, calculated, 301.0143.
General procedure for the synthesis of N-benzoyl derivatives of
benzenesulphonamides (9a-f, i-n and q-v)
Appropriate benzenesulphonamides (7a-f, i-n and q-v, 1.0 mmol) was dissolved in NaOH
(10%, 10 mL) in a 50 mL round bottom flask and benzoyl chloride (8, 1.1 mmol, 0.2 mL) was
added into the solution 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 acidi-
fied to pH 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 (9a-f, i-n and
q-v) obtained were washed with 10–20 mL CCl4 and dried over fused self-indicating silica gel
in a desiccator.
{Benzoyl[(4-methylphenyl)sulfonyl]amino}acetic acid (9a). Yield (0.3281 g, 98.49%),
appearance, white powder, mp, 104.60–104.80˚C, 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, 1094, 1073, 1001 (C-N, C-O). 1H NMR (DMSO-d6, 500MHz) δ: 7.64 (d, J = 8.6 Hz, 2H,
ArH), 7.50 (m, 5H, ArH), 7.33 (d, J = 8.05 Hz, 2H, ArH), 3.51 (d, J = 5.7 Hz, CH2), 2.34 (s, 3H,
CH3). 13C NMR (DMSO-d6, 500MHz) δ: 170.8, 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-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-3-phenylpropanoic acid (9b).
Yield (0.4201 g, 99.31%), appearance, white powder, mp, 100.50–100.70˚C, FTIR (KBr, cm-1):
3443 (OH of CO2H), 3072 (C-H aromatic), 1732, 1689 (2C = O), 1603, 1585, 1497, 1454, 1425
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Synthesis of new anti-trypanosomal agents
(C = C), 1344, 1327, (2S = O), 1187, 1168, 1158 (SO2N), 1128, 1090, 1027 (C-N, C-O). 1H
NMR (DMSO-d6, 500MHz) δ: 7.91 (m, 3H, ArH), 7.59 (t, J = 7.45 Hz, 2H, ArH), 7.45 (m, 5H,
ArH), 17 (m, 3H, ArH), 7.08 (d, J = 7.45 Hz, 1H, ArH), 3.81 (t, J = 6.30 Hz, 1H, CH-CO2H),
2.89 (dd, J = 5.75, 5.75 Hz, 1H, CHa of CH2), 2.67 (dd, J = 9.15, 8.55 Hz, 1H, CHb of CH2), 2.30
(s, 3H, CH3-Ar). 13C NMR (DMSO-d6, 500MHz) δ: 172.8, 167.9 (2C = O), 142.8, 138.7, 137.3,
133.4, 133.2, 131.3, 129.8, 129.7, 129.1, 128.7, 126.9, 126.8 (aromatic carbons), 57.9, 38.4, 21.5
(aliphatic carbons). HRMS-ESI (m/z): 424.1142 (M+H), calculated, 424.1140.
3-(1H-indol-2-yl)-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]propanoic acid
(9c). Yield (0.4609 g, 99.74%), appearance, white powder, mp, 108.60–108.90˚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, 1160 (SO2N), 1128, 1073, 1027 (C-N, C-O). 1H NMR
(DMSO-d6, 500MHz) δ: 10.73 (s, 1H, NH of indole), 7.91 (t, J = 7.45 Hz, 3H, ArH), 7.58 (t,
J = 7.45 Hz, 2H, ArH), 7.45 (m, 5H, ArH), 7.25 (t, J = 8.60 Hz, 1H, ArH), 7.13 (d, J = 8.05 Hz,
1H, ArH), 7.01 (t, J = 7.45 Hz, 1H, ArH), 6.88 (t, J = 7.45 Hz, 1H, ArH), 3.84 (dd, J = 7.45, 8.05
Hz, 1H, ArH), 3.01 (dd, J = 6.30, 6.30 Hz, 1H, CHa of CH2), 2.80 (dd, J = 8.05, 8.00 Hz, 1H,
CHb of CH2), 2.28 (s, 3H, CH3-Ar). 13C NMR (DMSO-d6, 500MHz) δ: 173.2, 167.8 (2C = O),
142.7, 138.5, 136.6, 133.4, 131.3, 129.8, 129.7, 129.1, 127.4, 126.8, 124.5, 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, 480.2139.
4-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]pentanoic acid (9d).
Yield (0.3889 g, 99.92%), appearance, white powder, mp, 98.90–99.60˚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 (C = C), 1327, 1292 (2S = O), 1161, 1128 (SO2N), 1091, 1073, 1027
(C-N, C-O). 1H NMR (DMSO-d6, 500MHz) δ: 7.91 (t, J = 6.90 Hz, 3H, ArH), 7.59 (m, 2H,
ArH), 7.46 (t, J = 8.00 Hz, 3H, ArH), 7.31 (d, J = 8.00 Hz, 1H, ArH), 3.59 (dd, J = 8.05, 8.55 Hz,
1H, CH-CO2H), 1.52 (m, 1H, CH), 1.33 (m, 2H, CH2), 0.76 (d, J = 6.30 Hz, 3H, CH3), 0.65 (d,
J = 6.30 Hz, 3H, CH3). 13C NMR (DMSO-d6, 500MHz) 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 (ali-
phatic carbons). HRMS-ESI (m/z): 390.2354 (M+H), calculated, 390.2358.
3-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]pentanoic acid (9e).
Yield (0.3890 g, 99.95%), mp, 98.40–99.90˚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,
500MHz) δ: 7.89 (m, 3H, ArH), 7.59 (m, 2H, ArH), 7.46 (t, J = 8.00 Hz, 3H, ArH), 7.30 (d,
J = 8.00 Hz, 1H, ArH), 3.49 (d, J = 2.3 Hz, 1H, CH-CO2H), 2.33 (s, 3H, CH3-Ar), 1.61 (m, 1H,
CH), 1.31 (m, 1H, CHa of CH2), 1.05 (m, 1H, CHb of CH2), 0.72 (dt, J = 6.30, 6.90 Hz, 6H,
2CH3). 13C NMR (DMSO-d6, 500MHz) δ: 172.7, 167.8 (2C = O), 142.9, 138.9, 133.4, 131.3,
129.8, 129.4, 129.1, 127.1 (aromatic carbons), 60.5, 37.5, 24.9, 21.5, 15.9, 11.4 (aliphatic car-
bons). HRMS-ESI (m/z): 388.0894 (M-H), calculated, 388.0896.
3-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]butanoic acid acid
(9f). Yield (0.372 g, 99.20%), appearance, white powder, mp, 99.90–100.20˚C, 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, 1161 (SO2N), 1127, 1087, 1073 (C-N, C-O). 1H NMR
(DMSO-d6, 500MHz) δ: 7.91 (d, J = 7.45 Hz, 2H, ArH), 7.59 (m, 4H, ArH), 7.45 (t, J = 8.00 Hz,
2H, ArH), 7.30 (d, J = 8.00 Hz), 3.45 (d, J = 4.60 Hz, 1H, CH-CO2H), 1.88 (m, 1H, CH), 0.77
(m, 6H, CH3). 13C NMR (DMSO-d6, 500MHz) δ: 172.7, 167.9 (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 car-
bons). HRMS-ESI (m/z): 375.1148 (M+), calculated, 375.1140.
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Synthesis of new anti-trypanosomal agents
2-[N-(benzenesulfonyl)-1-phenylformamido]acetic acid (9i). Yield (0.2999 g, 93.92%),
appearance, white needles, mp, 121.60–121.90˚C, FTIR (KBr, cm-1): 3073, 3011 (C-H aro-
matic), 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,
400MHz) δ: 7.90 (t, J = 8.20 Hz, 4H, ArH), 7.57 (m, 2H, ArH), 7.45 (t, J = 7.80 Hz, 4H, ArH),
3.54 (s, 2H, CH2). 13C NMR (DMSO-d6, 400MHz) δ: 174.7, 167.9 (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): 320.0516 (M+H), calculated, 320.0514.
2-[N-(benzenesulphonyl)-1-phenylformamido]-3-phenylpropanoic acid (9j). Yield
(0.4090 g, 99.90%), appearance, white powder, mp, 94.10–94.70˚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 (C = C), 1376, 1348 (2S = O), 1170, 1108 (SO2N), 1094, 1073, 1027,
1000 (C-N, C-O). 1H NMR (DMSO-d6, 400MHz) δ: 7.91 (d, J = 8.00 Hz, 4H, ArH), 7.58 (t,
J = 7.45 Hz, 2H, ArH), 7.52 (t, J = 8.00 Hz, 1H, ArH), 7.45 (m, 4H, ArH), 7.39 (t, J = 8.00 Hz,
1H, ArH), 7.15 (m, 2H, ArH), 7.08 (d, J = 6.30 Hz, 1H, ArH), 3.84 (t, J = 5.75 Hz, 1H,
CH-COOH), 2.90 (dd, J = 5.70, 5.70 Hz, 1H, CHa of CH2), 2.67 (dd, J = 9.15, 9.15 Hz, 1H, CHb
of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 172.8, 167.8 (2C = O), 141.5, 137.3, 133.4, 132.6,
131.3, 129.8, 129.7, 129.4, 129.1, 128.7, 127.1, 126.8 (twelve aromatic carbons), 57.9, 38.3 (ali-
phatic carbons). HRMS-ESI (m/z): 410.0988 (M+H), calculated 410.0983.
2-[N-(benzenesulfonyl)-1-phenylformamido]-3-(1H-indol-2-yl)propanoic acid (9k).
Yield (0.4480 g, 99.89%), appearance, white powder, mp, 110.90–111.20˚C, 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, 1454, 1425 (C = C), 1339, 1292 (2S = O), 1162, 1129 (SO2N),
1083, 1027 (C-O, C-N). 1H NMR (DMSO-d6, 500MHz) δ: 10.79 (s, 1H, NH), 7.91 (m, 3H,
ArH), 7.57 (m, 2H, ArH), 7.46 (m, 3H, ArH), 7.35 (t, J = 7.45 Hz, 2H, ArH), 7.26 (m, 2H,
ArH), 7.01 (t, J = 6.85 Hz, 2H, ArH), 6.90 (t, J = 7.45 Hz, 1H, ArH), 3.87 (dd, J = 7.45, 8.05 Hz,
1H, CH-COOH), 3.02 (dd, J = 6.85, 6.30 Hz, 1H, CHa of CH2), 2.82 (dd, J = 7.45, 7.45 Hz, 1H,
CHb of CH2). 13C NMR (DMSO-d6, 500MHz) 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, 124.5, 121.4, 118.9, 118.4, 111.9, 109.4 (sixteen
aromatic carbons), 57.2, 28.8 (aromatic carbons). HRMS-ESI (m/z): 449.1096 (M+H), calcu-
lated, 449.1093.
2-[N-(benzenesulfonyl)-1-phenylformamido]-4-methylpentanoic acid (9l). Yield
(0.3659 g, 97.86%), appearance, white powder, mp, 90.40–90.60˚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 (2S = O), 1186, 1128 (SO2N), 1093, 1074, 1027 (C-N, C-O). 1H NMR
(DMSO-d6, 500MHz) δ: 7.91 (t, J = 8.60 Hz, 3H, ArH), 7.74 (d, J = 7.45 Hz, 1H, ArH), 7.58 (m,
2H, ArH), 7.52 (t, J = 8.05 Hz, ArH), 7.46 (t, J = 8.00 Hz, 3H, ArH), 3.61 (m, 1H, CH-COOH),
1.49 (m, 1H, CH), 1.34 (m, 2H, CH2), 0.72 (m, 6H, CH3). 13C NMR (DMSO-d6, 400MHz) 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 car-
bons), 54.5, 41.4, 24.3, 23.1, 21.5 (five aliphatic carbons). HRMS-ESI (m/z): 376.1143 (M+H),
calculated, 376.1140.
2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methylpentanoic acid (9m). Yield
(0.3750 g, 99.89%), appearance, white powder, mp, 91.40–91.90˚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 (C = C), 1327, 1293 (2S = O), 1169, 1129 (SO2N), 1092, 1074, 1027
(C-N, C-O). 1H NMR (DMSO-d6, 500MHz) δ: 7.89 (d, J = 7.15 Hz, 2H, ArH), 7.72 (d, J = 7.15
Hz, 1H, ArH), 7.55 (m, 2H, ArH), 7.47 (m, 5H, ArH), 3.50 (t, J = 6.30 Hz, 1H, CH-COOH),
1.59 (m, 1H, CH), 1.28 (m, 1H, CHa, CH2), 1.03 (m, 1H, CHb, CH2), 0.72 (d, J = 6.90 Hz, 3H,
CH3-CH), 0.67 (t, J = 7.45 Hz, 3H, CH3-CH2). 13C NMR (DMSO-d6, 500MHz) δ: 172.7, 167.9
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Synthesis of new anti-trypanosomal agents
(2C = O), 141.5, 133.4, 132.8, 131.2, 129.8, 129.4, 129.1, 126.9 (eight aromatic carbons), 60.6,
37.4, 24.9, 15.8, 11.3 (five aliphatic carbons). HRMS-ESI (m/z): 376.1141 (M+H), calculated,
376.1140.
2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methylpentanoic acid (9n). Yield
(0.3050 g, 84.37%), appearance, white powder, 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 (C = C), 1327, 1293 (2S = O), 1169, 1129 (SO2N), 1128, 1093, 1074 (C-O,
C-N). 1H NMR (DMSO-d6, 500MHz) δ: 7.91 (m, 3H, ArH), 7.74 (t, J = 7.45 Hz, 1H, ArH),
7.57 (m, 2H, ArH), 7.51 (d, J = 7.45 Hz, 1H, ArH), 7.46 (m, 3H, ArH), 3.49 (d, J = 6.30 Hz,
1H, CH-COOH), 1.88 (m, 1H, CH), 0.75 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 500MHz) δ:
172.7, 167.9 (2C = O), 141.7, 133.4, 132.8, 131.3, 129.8, 129.4, 129.1, 127.0 (eight aromatic car-
bons), 61.8, 30.9, 19.5, 18.4 (aliphatic carbons). HRMS-ESI (m/z): 360.0984 (M-H), calculated,
360.0983.
2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]acetic acid (9q). Yield (0.2126 g,
58.36%), appearance, white powder, mp, 135.00–135.60˚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), 1527, 1454 (N-O), 1327, 1290 (2S = O), 1181, 1163 (SO2N), 1128, 1106, 1074
(C-N, C-O). 1H NMR (DMSO-d6, 500MHz) δ: 8.36 (d, 8.60 Hz, 2H, ArH), 8.01 (d, J = 8.60 Hz,
2H, ArH), 7.91 (d, J = 6.85 Hz, 2H, ArH), 7.58 (t, J = 7.45 Hz, 1H, ArH), 7.47 (t, J = 8.05 Hz,
2H, ArH), 3.67 (s, 2H, CH2). 13C NMR (DMSO-d6, 500MHz) δ: 170.7, 167.9 (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, 363.0251.
2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-3-phenylpropanoic acid (9r).
Yield (0.4545 g, 100%), appearance, white powder, mp, 122.50–122.90˚C, 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-O). 1H NMR (DMSO-d6, 400MHz) δ: 8.16 (m, 2H,
ArH), 7.90 (t, J = 7.36 Hz, 2H, ArH), 7.70 (m, 2H, ArH), 7.59 (m, 1H, ArH), 7.46 (m, 2H,
ArH), 7.07 (m, 5H, ArH), 3.92 (m, 1H, CH-CO2H), 2.95 (dd, J = 4.60, 4.56 Hz, 1H, CHa of
CH2), 2.65 (dd, J = 10.08, 10.08 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6, 400MHz) δ:
172.7, 167.9 (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, 455.1932.
3-(1H-indol-2-yl)-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]propanoic acid
(9s). Yield (0.4932 g, 99.64%), appearance, white powder, mp, 153.30–153.70˚C, 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 (N-O), 1327, 1292 (2S = O), 1179, 1167 (SO2N), 1129,
1092, 1073, 1027 (C-N, C-O). 1H NMR (DMSO-d6, 400MHz) δ: 10.68 (s, 1H, NH of indole),
7.91 (m, 3H, ArH), 7.84 (m, 1H, ArH), 7.58 (m, 2H, ArH), 7.46 (m, 3H, ArH), 7.22 (d, J = 7.80
Hz, 1H, ArH), 7.03 (d, J = 7.80 Hz, 1H, ArH), 6.98 (d, J = 2.32 Hz, 1H, ArH), 6.84 (m, 2H,
ArH), 3.88 (m, 1H, CH-COOH), 3.03 (dd, J = 4.12, 4.12 Hz, 1H, CHa of CH2), 2.77 (dd,
J = 10.08, 10.56 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 173.3, 167.8
(2C = O), 148.9, 144.7, 138.9, 136.5, 133.4, 132.9, 131.3, 129.8, 129.1, 127.4, 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): 494.0945 (M+H), calculated 494.0943.
3-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]pentanoic acid (9t).
Yield (0.4201 g, 99.93%), appearance, white powder, 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
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Synthesis of new anti-trypanosomal agents
(SO2N), 1105, 1073, 1027, 1012 (C-N, C-O). 1H NMR (DMSO-d6, 400MHz) δ: 8.34 (d, J = 8.68
Hz, 2H, ArH), 7.98 (d, J = 8.72 Hz, 2H, ArH), 7.90 (t, J = 7.32 Hz, 2H, ArH), 7.57 (t, J = 7.32
Hz, 1H, ArH), 7.46 (t, J = 7.72 Hz, 2H, ArH), 3.60 (d, J = 2.28 Hz, CH-COOH), 1.67 (m, 1H,
CH), 1.31 (m, 1H, CHa of CH2), 1.12 (m, 1H, CHb of CH2), 0.74 (m, 6H, 2CH3). 13C NMR
(DMSO-d6, 400MHz) 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.
4-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]pentanoic acid (9u).
Yield (0.4204 g, 100%), appearance, white powder, mp, 116.30–116.60˚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, 400MHz) δ: 8.35 (d, J = 8.72 Hz, 2H, ArH), 7.97 (d, J = 9.16 Hz,
2H, ArH), 7.90 (t, J = 6.88 Hz, 2H, ArH), 7.58 (t, J = 7.36 Hz, 1H, ArH), 7.46 (m, 2H, ArH),
3.73 (t, J = 5.48 Hz, 1H, CH-COOH), 1.55 (m, 1H, CHa of CH2), 1.38 (m, 1H, CHb of CH2),
0.79 (d, J = 6.44 Hz, 3H, CH3), 0.70 (d, J = 6.40 Hz, 3H, CH3). 13C NMR (DMSO-d6, 400MHz)
δ: 173.4, 167.9 (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.
3-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]butanoic acid (9v).
Yield (0.4063 g, 99.98%), appearance, white powder, mp, 116.10–117.20˚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, 1013, 1000 (C-N, C-O). 1H NMR (DMSO-d6, 400MHz)
δ: 8.34 (d, J = 9.16 Hz, 2H, ArH), 7.95 (d, J = 8.72 Hz, 2H, ArH), 7.90 (t, J = 6.88 Hz,
2H, ArH), 7.58 (t, J = 7.32 Hz, 2H, ArH), 7.45 (m, 2H, ArH), 3.57 (d, J = 2.76Hz, 1H,
CH-COOH), 1.94 (m, 1H, CH), 0.77 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400MHz) δ:
172.4, 167.9 (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, 405.0731.
Boric acid catalysed direct amidation of unactivated carboxylic acid and
3-aminoquinoline
To a suspension of N-benzoyl-substituted-benzenesulphonamides (9a-f, i-n, q-v, 7g-h, o-p
and w-x) (1.0 mmol) (1.0 mmol) in dry toluene (40 mL) equipped with Dean-Stark apparatus
for azeotropic removal of water, was added 3-aminoquinoline (1.0 mmol) and boric acid (0.1
mmol) at room temperature and refluxed for 8 h. Upon completion (as monitored by TLC),
the amide products were precipitated out from the reaction mixture by adding 40 mL n-hex-
ane. The carboxamides 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-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)acetamide
(11a). Yield (0.4489 g, 99.43%), brownish oil, FTIR (KBr, cm-1): 3390 (NH), 3059 (C-H aro-
matic), 1702, 1688 (C = O), 1627 (C = N), 1602, 1584, 1493, 1451 (C = C), 1351, 1317 (2S = O),
1158, 1120 (SO2N), 1094, 1071, 1026, 1001 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.44 (s,
1H, NH), 7.91 (d, J = 7.76 Hz, 3H, ArH), 7.74 (d, J = 8.24 Hz, 1H, ArH), 7.64 (d, J = 7.80 Hz,
1H, ArH), 7.55 (t, J = 6.40 Hz, 3H, ArH), 7.43 (m, 3H, ArH), 7.27 (m, 3H, ArH), 7.12 (m, 1H,
ArH), 3.54 (s, 2H, CH2), 2.28 (m, 3H, CH3). 13C NMR (DMSO-d6, 500MHz) δ: 170.8, 167.9
(C = O), 143.8, 143.2, 142.9, 141.4, 138.3, 133.4, 131.3, 130.0, 129.8, 129.4, 129.1, 128.9, 128.7,
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Synthesis of new anti-trypanosomal agents
127.5, 127.0, 126.1, 125.8, 124.6, 112.3 (nineteen aromatic carbons), 44.3, 21.4 (two aliphatic
carbons). HRMS-ESI (m/z): 460.1265 (M+H), calculated, 460.1263.
2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-3-phenyl-N-(quinolin-3-yl)pro-
panamide (11b). Yield (0.5401 g, 98.34%), brownish oil, FTIR (KBr, cm-1): 3452 (NH), 3021
(C-H aromatic), 1682, 1659 (C = O), 1630 (C = N), 1601, 1497 (C = C), 1385, 1301 (2S = O),
1156, 1143 (SO2N), 1092 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.40 (s, 1H, ArH), 8.13 (d,
J = 9.16 Hz, 1H, ArH), 7.91 (d, J = 7.32 Hz, 1H, ArH), 7.72 (d, J = 8.24 Hz, 1H, ArH), 7.55 (t,
J = 6.88 Hz, 1H, ArH), 7.44 (m, 3H, ArH), 7.30 (m, 3H, ArH), 7.16 (m, 5H, ArH), 7.08 (m,
4H, ArH), 6.55 (s, 1H, NH), 3.81 (m, 1H, CH-C = O), 2.88 (dd, J = 5.52, 5.96 Hz, 1H, CHa of
CH2), 2.65 (dd, J = 9.16, 9.20 Hz, 1H, CHb of CH2), 2.26 (m, 3H, CH3). 13C NMR (DMSO-d6,
400MHz) δ: 172.8, 167.9 (C = O), 143.9, 142.9, 142.8, 141.4, 138.7, 137.9, 137.3, 133.4, 129.9,
129.8, 129.7, 129.4, 128.9, 128.7, 128.7, 126.9, 126.8, 126.1, 125.8, 124.4, 112.0 (twenty one aro-
matic carbons), 57.9, 38.4, 21.5 (three aliphatic carbons). HRMS-ESI (m/z): 548.1169 (M-H),
calculated, 548.1165.
3-(1H-indol-2-yl)-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-N-(quinolin-
3-yl)propanamide (11c). Yield (0.5792 g, 98.47%), appearance, brown powder, mp, 88.10–
88.80˚C, FTIR (KBr, cm-1): 3413, 3373 (2NH), 3058 (C-H aromatic), 2922 (C-H aliphatic),
1702, 1698 (C = O), 1622 (C = N), 1597, 1494, 1457 (C = C), 1353, 1319 (2S = O), 1185, 1157
(SO2N), 1091, 1011 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 10.74 (s, 1H, NH of indole), 8.40
(s, 1H, ArH), 8.08 (d, J = 8.24 Hz, 1H, ArH), 7.91 (d, J = 6.88 Hz, 1H, ArH), 7.72 (d, J = 8.28
Hz, 1H, ArH), 7.56 (m, 1H, ArH), 7.44 (m, 3H, ArH), 7.26 (m, 5H, ArH), 7.11 (m, 4H, ArH),
7.01 (m, 2H, ArH), 6.87 (t, J = 7.32 Hz, 1H, ArH), 3.83 (m, 1H, CH-C = O), 3.01 (dd, J = 6.44,
6.40 Hz, 1H, CHa of CH2), 2.79 (dd, J = 7.80, 7.76 Hz, 1H, CHb of CH2), 2.26 (m, 3H, CH3).
13C NMR (DMSO-d6, 400MHz) δ: 173.2, 163.9 (C = O), 143.9, 142.9, 142.7, 141.5, 138.5,
136.6, 129.9, 129.8, 129.6, 129.4, 129.0, 128.7, 127.4, 126.9, 126.8, 126.1, 125.8, 124.5, 124.4,
121.3, 118.8, 118.3, 111.9, 111.8, 109.4 (twenty five aromatic carbons), 57.1, 28.8, 21.5 (three
aliphatic carbons). HRMS-ESI (m/z): 588.1834 (M+), calculated, 588.1831.
4-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)pen-
tanamide (11d). Yield (0.5010 g, 97.24%), brownish oil, FTIR (KBr, cm-1): 3359 (NH), 3063
(C-H aromatic), 2957, 2871 (C-H aliphatic), 1700, 1692 (C = O), 1626 (C = N), 1602, 1584,
1495, 1452 (C = C), 1353, 1317 (2S = O), 1292, 1160 (SO2N), 1094, 1072, 1026 (C-N). 1H NMR
(DMSO-d6, 400MHz) δ: 8.45 (s, 1H, ArH), 8.02 (d, J = 8.72 Hz, 1H, ArH), 7.92 (t, J = 6.88 Hz,
1H, ArH), 7.75 (d, J = 8.28 Hz, 1H, ArH), 7.62 (d, J = 8.24 Hz, 1H, ArH), 7.57 (d, J = 8.24 Hz,
1H, ArH), 7.45 (t, J = 7.80 Hz, 1H, ArH), 7.31 (m, 2H, ArH), 7.19 (m, 3H, ArH), 7.11 (m, 5H,
ArH), 6.53 (s, 1H, NH), 3.61 (t, J = 5.96 Hz, 1H, CH-C = O), 1.35 (m, 1H, CH), 1.20 (m, 2H,
CH2), 0.79 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400MHz) δ: 173.8, 167.9 (C = O), 143.5,
143.0, 142.9, 141.0, 138.9, 137.9, 133.4, 130.0, 129.9, 129.8, 129.4, 129.2, 129.1, 128.9, 128.7,
128.4, 127.1, 126.1, 125.8, 124.6, 112.5 (twenty one aromatic carbons), 54.5, 34.7, 23.1, 21.6,
14.5 (five aliphatic carbons). HRMS-ESI (m/z): 514.0101 (M-H), calculated, 514.0109.
3-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl) pen-
tanamide (11e). Yield (0.4998 g, 97.01%), brownish oil, FTIR (KBr, cm-1): 3363 (NH), 3063
(C-H aromatic), 2962, 2931, 2876 (C-H aliphatic), 1704, 1675 (C = O), 1627 (C = N), 1585,
1493, 1451 (C = C), 1317, 1304 (2S = O), 1258, 1159 (SO2N), 1094, 1071, 1025 (C-N). 1H NMR
(DMSO-d6, 400MHz) δ: 8.41 (s, 1H, ArH), 7.91 (m, 3H, ArH), 7.72 (d, J = 8.24 Hz, 1H, ArH),
7.58 (m, 3H, ArH), 745 (m, 2H, ArH), 7.30 (m, 3H, ArH), 7.12 (m, 2H, ArH), 3.48 (d, J = 5.96
Hz, 1H, CH-C = O), 2.31 (s, 3H, CH3-Ar), 1.60 (m, 1H, CH), 1.32 (m, 1H, CHa of CH2), 1.04
(m, 1H, CHb of CH2), 0.70 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400MHz) δ: 172.7, 167.9
(C = O), 143.8, 142.9, 142.9, 141.3, 138.8, 133.4, 131.3, 130.0, 129.8, 129.4, 129.1, 128.9, 127.1,
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Synthesis of new anti-trypanosomal agents
126.9, 126.1, 124.5, 112.2 (seventeen aromatic carbons), 60.5, 37.4, 24.9, 21.5, 15.9, 11.4 (six ali-
phatic carbons). HRMS-ESI (m/z): 515.1889 (M+), calculated 515.1879.
3-Methyl-2-[N-(4-methylbenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)
butanamide (11f). Yield (0.4979 g, 99.34%), brownish oil, FTIR (KBr, cm-1): 3390 (NH),
3059 (C-H aromatic), 2965 (C-H aliphatic), 1704, 1668 (C = O), 1632 (C = N), 1603, 1493,
1451 (C = C), 1317, 1300 (2S = O), 1166, 1134 (SO2N), 1093, 1071, 1043, 1019 (C-N). 1H NMR
(DMSO-d6, 400MHz) δ: 8.43 (s, 1H, ArH), 7.88 (t, J = 8.24 Hz, 2H, ArH), 7.75 (d, J = 8.24 Hz,
2H, ArH), 7.58 (m, 3H, ArH), 7.45 (t, J = 7.80 Hz, 1H, ArH), 7.33 (m, 5H, ArH), 7.18 (d,
J = 2.32 Hz, 2H, ArH), 6.50 (s, 1H, NH), 3.78 (d, J = 3.20 Hz, 1H, CH-C = O), 2.28 (m, 3H,
CH3-Ar), 1.87 (m, 1H, CH), 0.76 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400MHz) δ: 172.7,
167.9 (C = O), 159.3, 143.0, 142.9, 140.4, 138.9, 133.4, 131.3, 130.1, 129.8, 129.8, 129.1, 128.2,
127.3, 127.1, 126.2, 124.9, 113.1 (sixteen aromatic carbons), 61.7, 30.9, 21.5, 19.5, 18.4 (five ali-
phatic carbons). HRMS-ESI (m/z): 500.1604 (M-H), calculated, 500.1606.
4-Hydroxy-1-(4-methylbenzenesulfonyl)-N-(quinolin-3-yl)pyrrolidine-2-carboxamide
(11g). Yield (0.4111 g, 100%), brownish oil, FTIR (KBr, cm-1): 3437 (OH), 3398 (NH), 2926
(C-H aliphatic), 1728 (C = O), 1631 (C = N), 1597, 1496, 1403 (C = C), 1332, 1305 (2S = O),
1198, 1156 (SO2N), 1092, 1013 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.39 (s, 1H, ArH),
7.72 (d, J = 8.24 Hz, 1H, ArH), 7.64 (d, J = 8.24 Hz, 2H, ArH), 7.55 (d, J = 8.24 Hz, 1H, ArH),
7.28 (m, 2H, ArH), 4.17 (s, 1H, OH), 4.01 (t, J = 4.24 Hz, 1H, CH-C = O), 3.41 (m, 1H, CH-
OH), 3.04 (d, J = 5.32 Hz, 2H, CH2N), 2.35 (s, 3H, CH3), 1.90 (m, 2H, CH2). 13C NMR
(DMSO-d6, 400MHz) δ: 173.8 (C = O), 143.9, 143.7, 134.9, 130.1, 129.4, 129.0, 128.7, 127.9,
126.9, 126.1, 125.9, 124.4, 111.9 (thirteen aromatic carbons), 68.9, 60.2, 56.8, 21.5 (four ali-
phatic carbons). HRMS-ESI (m/z): 411.1323 (M+H), calculated, 411.328.
1-(4-Methylbenzenesulfonyl)-N-(quinolin-3-yl)pyrrolidine-2-carboxamide (11h).
Yield (0.3949 g, 99.95%), brownish oil, FTIR (KBr, cm-1): 3435 (NH), 2979 (C-H aliphatic),
1700 (C = O), 1626 (C = N), 1602, 1597, 1498, 1440 (C = C), 1338, 1304 (2S = O), 1197, 1158
(SO2N), 1094, 1013 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.44 (s, 1H, ArH), 7.73 (d,
J = 8.24 Hz, 1H, ArH), 7.66 (d, J = 8.24 Hz, 2H, ArH), 7.55 (d, J = 7.76 Hz, 1H, ArH), 7.31
(m, 3H, ArH), 7.14 (m, 2H, ArH), 4.04 (t, J = 4.56 Hz, 1H, CH-C = O), 3.29 (m, 1H, CHa of
CH2N), 3.07 (m, 1H, CHb of CH2N), 2.33 (s, 3H, CH3), 1.76 (m, 3H), 1.47 (m, 1H, CH). 13
C
NMR (DMSO-d6, 400MHz) δ: 173.7 (C = O), 143.6, 142.9, 141.1, 135.1, 130.4, 129.4, 128.7,
127.7, 127.1, 126.1, 125.8, 124.6, 112.4 (thirteen aromatic carbons), 60.9, 48.9, 30.9, 24.8, 21.5
(five aliphatic carbons). HRMS-ESI (m/z): 395.1307 (M+), calculated, 395.1304.
2-[N-(benzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)acetamide (11i). Yield
(0.4001 g, 89.89%), brownish oil, FTIR (KBr, cm-1): 3391 (NH), 3071 (C-H aromatic), 2835
(C-H aliphatic), 1688 (C = O), 1688 (C = O), 1623 (C = N), 1603, 1453, 1424 (C = C), 1350,
1325 (2S = O), 1187, 1129 (SO2N), 1072, 1026 (C-N). 1H NMR (DMSO-d6, 500MHz) δ: 8.44
(s, 1H, ArH), 7.93 (d, J = 8.05 Hz, 3H, ArH), 7.74 (d, J = 8.10 Hz, 1H, ArH), 7.56 (t, J = 8.10
Hz, 2H, ArH), 7.46 (t, J = J = 8.05 Hz, 3H, ArH), 7.30 (m, 2H, ArH), 7.20 (t, J = 8.05 Hz, 2H,
ArH), 7.11 (m, 2H, ArH), 2.25 (s, 3H, CH3). 13C NMR (DMSO-d6, 500MHz) δ: 167.9, 163.8
(C = O), 143.9, 142.9, 141.5, 137.9, 133.4, 131.3, 130.0, 129.8, 129.5, 129.4, 129.3, 129.1, 129.0,
128.7, 127.7, 126.9, 126.1, 125.8, 124.6, 124.4 (twenty aromatic carbons), 21.6 (aliphatic car-
bons). HRMS-ESI (m/z): 445.1112 (M+), calculated, 445.1096.
2-[N-(benzenesulfonyl)-1-phenylformamido]-3-phenyl-N-(quinolin-3-yl)propanamide
(11j). Yield (0.5300 g, 98.95%), appearance, white powder, 112.70–112.90˚C, FTIR (KBr,
cm-1): 3389 (NH), 3066 (C-H aromatic), 1692, 1673 (C = O), 1623 (C = N), 1601, 1467
(C = C), 1343, 1321 (2S = O), 1178, 1154 (SO2N), 1092, 1053 (C-N). 1H NMR (DMSO-d6,
400MHz) δ: 8.47 (d, J = 2.72 Hz, 1H, ArH), 8.27 (d, J = 8.72 Hz, 1H, ArH), 7.79 (d, J = 8.24 Hz,
2H, ArH), 7.61 (m, 1H, ArH), 7.55 (m, 2H, ArH), 7.48 (m, 2H, ArH), 7.38 (t, J = 8.24 Hz, 3H,
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Synthesis of new anti-trypanosomal agents
ArH), 7.33 (m, 1H, ArH), 7.31 (m, 1H, ArH), 7.23 (m, 1H, ArH), 7.16 (m, 5H, ArH), 7.08 (m,
2H, ArH), 3.87 (m, 1H, CH-C = O), 2.92 (dd, J = 5.48, 5.52 Hz, 1H, CHa of CH2), 2.69 (dd,
J = 9.16, 9.20 Hz, 1H, CHa of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 172.8, 167.9 (C = O),
142.8, 140.1, 137.7, 137.2, 133.4, 132.7, 131.3, 130.1, 129.8, 129.7, 129.4, 129.1, 128.7, 128.5,
127.9, 127.4, 127.1, 126.7, 126.2, 125.8, 125.1, 113.5 (twenty one aromatic carbons), 57.9, 38.4
(two aliphatic carbons). HRMS-ESI (m/z): 535.1667 (M+), calculated, 535.1666.
2-[N-(benzenesulfonyl)-1-phenylformamido]-3-(1H-indol-2-yl)-N-(quinolin-3-yl)pro-
panamide (11k). Yield (0.5701 g, 99.22%), appearance, white powder, mp, 73.50–73.80˚C,
FTIR (KBr, cm-1): 3412, 3369 (2NH), 3002 (C-H aromatic), 2984 (C-H aliphatic), 1701, 1689
(C = O), 1622 (C = N), 1601, 1587, 1453 (C = C), 1342, 1309 (2S = O), 1185, 1134 (SO2N),
1089, 1045 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 10.76 (s, 1H, NH), 8.39 (d, J = 2.72 Hz,
1H, ArH), 8.18 (s, 1H, ArH), 7.71 (d, J = 8.24 Hz, 1H, ArH), 7.55 (m, 3H, ArH), 7.47 (m, 2H,
ArH), 7.31 (m, 6H, ArH), 7.09 (d, J = 2.76 Hz, 1H, ArH), 7.01 (m, 2H, ArH), 6.90 (t, J = 7.34
Hz, 1H, ArH), 3.86 (m, 1H, CH-C = O), 3.02 (dd, J = 6.88, 6.44 Hz, 1H, CHa of CH2), 2.81 (dd,
J = 7.80, 7.80 Hz, 1H, CHb of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 173.1, 167.1 (C = O),
151.2 143.9, 142.9, 141.4, 136.6, 133.9, 133.5, 132.6, 130.0, 129.9, 129.8, 129.4, 129.2, 129.0,
128.7, 127.5, 126.9, 126.7, 126.1, 124.4, 121.4, 118.9, 118.4, 111.9, 109.4 (twenty five aromatic
carbons), 57.2, 28.8 (two aliphatic carbons). HRMS-ESI (m/z): 573.2795 (M-H), calculated,
573.2796.
2-[N-(benzenesulfonyl)-1-phenylformamido]-4-methyl-N-(quinolin-3-yl)pentanamide
(11l). Yield (0.4912 g, 98.00%), appearance, white powder, 132.40–132.80˚C, FTIR (KBr,
cm-1): 3362 (NH), 3062 (C-H aromatic), 2958 (C-H aliphatic), 1704, 1687 (C = O), 1628
(NO2), 1603, 1450 (C = C), 1353, 1315 (2S = O), 1260, 1163 (SO2N), 1094, 1071, 1025 (C-N).
1H NMR (DMSO-d6, 400MHz) δ: 8.40 (s, 1H, ArH), 8.11 (d, J = 8.72 Hz, 2H, ArH), 7.91 (d,
J = 6.84 Hz, 2H, ArH), 7.71 (d, J = 1.84 Hz, 3H, ArH), 7.51 (m, 5H, ArH), 7.31 (m, 3H, ArH),
3.59 (m, 1H, CH-C = O), 1.50 (m, 1H, CH), 1.32 (m, 2H, CH2), 0.71 (m, 6H, CH3). 13C NMR
(DMSO-d6, 400MHz) δ: 173.8, 162.7 (C = O), 143.9, 142.9, 141.6, 141.4, 138.7, 134.3, 133.4,
132.8, 129.8, 129.5, 129.1, 128.9, 126.9, 126.1, 124.4, 112.0, 100.0 (seventeen aromatic carbons),
54.5, 41.4, 24.4, 23.1 (four aliphatic carbons). HRMS-ESI (m/z): 500.1563 (M-H), calculated,
500.1568.
2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl-N-(quinolin-3-yl)pentanamide
(11m). Yield (0.4514 g, 90.06%), appearance, brown powder, 145.10–145.30˚C, FTIR (KBr,
cm-1): 3361 (NH), 3062 (C-H aromatic), 2933, 2877 (C-H aliphatic), 1704, 1687 (C = O), 1627
(C = N), 1603, 1584, 1500, 1449 (C = C), 1353, 1315 (2S = O), 1259, 1162 (SO2N), 1093, 1071,
1025 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.42 (d, J = 2.76 Hz, 1H, ArH), 7.91 (m, 2H,
ArH), 7.74 (m, 2H, ArH), 7.51 (m, 5H, ArH), 7.29 (m, 3H, ArH), 7.19 (t, J = 7.32 Hz, 1H,
ArH), 7.09 (m, 2H, ArH), 3.52 (d, J = 2.76 Hz, 1H, CH-C = O), 1.61 (m, 1H, CH), 1.30 (m, 1H,
CHa of CH2), 1.04 (m, 1H, CHb of CH2), 0.71 (m, 6H, 2CH3). 13C NMR (DMSO-d6, 400MHz)
δ: 172.7, 167.9 (C = O), 143.8, 142.9, 141.7, 141.4, 133.4, 132.8, 131.3, 130.0, 129.8, 129.4, 129.1,
128.9, 128.7, 127.0, 126.9, 126.1, 125.8, 124.5, 112.1 (nineteen aromatic carbons), 60.6, 37.4,
24.9, 15.9, 11.4 (five aliphatic carbons). HRMS-ESI (m/z): 501.1742 (M+), calculated, 501.1742.
2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl-N-(quinolin-3-yl)butanamide
(11n). Yield (0.4511 g, 92.59%), brownish oil, FTIR (KBr, cm-1): 3361 (NH), 3063 (C-H aro-
matic), 2966 (C-H aliphatic), 1703, 1664 (C = O), 1627 (C = N), 1603, 1584, 1498, 1450
(C = C), 1353, 1316 (2S = O), 1273, 1164 (SO2N), 1094, 1071, 1025, 1000 (C-N). 1H NMR
(DMSO-d6, 400MHz) δ: 8.46 (s, 1H, ArH), 8.01 (m, 3H, ArH), 7.76 (t, J = 8.05 Hz, 2H, ArH),
7.50 (m, 5H, ArH), 7.30 (m, 3H, ArH), 7.19 (t, J = 8.05 Hz, 1H, ArH), 7.10 (m, 2H, ArH),
3.51 (d, J = 6.44 Hz, 1H, CH-C = O), 1.92 (m, 1H, CH), 0.76 (m, 6H, 2CH3). 13C NMR
(DMSO-d6, 400MHz) δ: 172.8, 167.9 (C = O), 143.9, 142.9, 141.7, 141.5, 137.9, 133.4, 131.3,
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Synthesis of new anti-trypanosomal agents
129.8, 129.4, 129.4, 129.1, 128.9, 128.7, 127.0, 126.9, 126.1, 125.8, 124.5 (eighteen aromatic car-
bons), 61.8, 30.9, 19.5, 18.3 (four aliphatic carbons). HRMS-ESI (m/z): 486.1435 (M-H), calcu-
lated, 486.1437.
1-(Benzenesulfonyl)-4-hydroxy-N-(quinolin-3-yl)pyrrolidine-2-carboxamide (11o).
Yield (0.3970 g, 99.89%), brownish oil, FTIR (KBr, cm-1): 3416 (OH), 3365 (NH), 3065 (C-H
aromatic), 2974, 2879 (C-H aliphatic), 1701 (C = O), 1618 (C = N), 1601, 1447 (C = C), 1384,
1332 (2S = O), 1172, 1157 (SO2N), 1092, 1045 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.42
(s, 1H, ArH), 7.75 (m, 3H, ArH), 7.60 (m, 4H, ArH), 7.25 (m, 2H, ArH), 7.11 (s, 1H, ArH),
6.69 (s, 1H, NH), 4.18 (s, 1H, OH), 4.05 (t, J = 7.80 Hz, 1H, CH-C = O), 3.43 (m, 1H, CH-OH),
3.10 (d, J = 5.24 Hz, 2H, CH2N), 1.92 (m, 2H, CH2). 13C NMR (DMSO-d6, 400MHz) δ: 173.8
(C = O), 143.9, 141.5, 137.8, 133.5, 129.6, 129.4, 128.9, 128.7, 127.9, 126.9, 126.1, 125.8, 124.5,
112.1 (thirteen aromatic carbons), 68.9, 60.2, 56.9, 23.0 (four aliphatic carbons). HRMS-ESI
(m/z): 398.1172 (M+H), calculated, 398.1176.
1-(Benzenesulfonyl)-N-(quinolin-3-yl)pyrrolidine-2-carboxamide (11p). Yield (0.3813
g, 99.98%), brownish oil, FTIR (KBr, cm-1): 3417 (NH), 3063 (C-H aromatic), 2978, 2877 (C-H
aliphatic), 1725 (C = O), 1619 (C = N), 1499, 1446 (C = C), 1384, 1339 (2S = O), 1198, 1160
(SO2N), 1094, 1072, 1016 (C-N). 1H NMR (DMSO-d6, 500MHz) δ: 8.41 (s, 1H, ArH), 7.79 (t,
J = 6.85 Hz, 2H, ArH), 7.73 (d, J = 8.00 Hz, 1H, ArH), 7.66 (t, J = 7.45 Hz, 1H, ArH), 7.58 (m,
3H, ArH), 7.30 (m, 1H, ArH), 7.21 (t, J = 7.45 Hz, 1H, ArH), 7.11 (m, 1H, ArH), 6.50 (s, 1H,
NH), 4.07 (m, 1H, CH-C = O), 3.33 (m, 1H, CHa of CH2N), 3.12 (m, 1H, CHb of CH2N), 1.81
(m, 3H), 1.52 (m, 1H, CH).13C NMR (DMSO-d6, 500MHz) δ: 173.7 (C = O), 143.8, 142.9,
141.3, 138.0, 133.6, 129.9, 129.4, 128.9, 128.7, 127.6, 127.0, 126.1, 125.9, 124.5, 112.2 (fifteen
aromatic carbons), 60.9, 48.9, 30.9, 24.8 (four aliphatic carbons). HRMS-ESI (m/z): 399.2098
(M+NH4), calculated, 399.2096.
2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)acetamide
(11q). Yield (0.4889 g, 99.76%), appearance, white powder, mp, 102.80–102.90˚C, FTIR
(KBr, cm-1): 3377 (NH), 3091 (C-N aromatic), 1745, 1672 (C = O), 1619 (C = N), 1601, 1437
(C = C), 1527 (NO2), 1350, 1306 (2S = O), 1256, 1161 (SO2N), 1092 (C-N). 1H NMR (DMSO-
d6, 400MHz) δ: 8.70 (d, J = 9.16 Hz, 1H, ArH), 8.44 (m, 2H, ArH), 8.13 (m, 2H, ArH), 7.91
(m, 2H, ArH), 7.73 (m, 2H, ArH), 7.59 (m, 1H, ArH), 7.45 (m, 1H, ArH), 7.35 (m, 1H, ArH),
7.22 (m, 2H, ArH), 7.07 (m, 2H, ArH), 3.13 (s, 2H, CH2). 13C NMR (DMSO-d6, 400MHz) δ:
172.7, 167.9 (C = O), 147.1, 143.1, 142.7, 139.9, 130.1, 129.8, 129.7, 129.4, 129.1, 128.7, 128.6,
128.2, 127.8, 127.4, 126.2, 125.2, 124.7 (seventeen aromatic carbons), 58.2 (aliphatic carbons).
HRMS-ESI (m/z): 490.1714 (M+), calculated, 490.1718.
2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-3-phenyl-N-(quinolin-3-yl)propa-
namide (11r). Yield (0.5529 g, 95.48%), brownish oil, FTIR (KBr, cm-1): 3359 (NH), 3063
(C-H aromatic), 1705, 1697 (C = O), 1602 (C = N), 1584, 1499, 1451 (C = C), 1350, 1315
(2S = O), 1165, 1118 (SO2N), 1088, 1071, 1025 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.44
(m, 1H, ArH), 8.33 (m, 1H, ArH), 8.15 (d, J = 9.16 Hz, 1H, ArH), 8.02 (d, J = 9.16 Hz, 1H,
ArH), 7.91 (m, 3H, ArH), 7.72 (t, J = 7.32 Hz, 2H, ArH), 7.56 (m, 2H, ArH), 7.45 (m, 3H,
ArH), 7.30 (m, 3H, ArH), 7.12 (d, J = 6.58 Hz, 2H, ArH), 7.07 (m, 1H, ArH), 3.95 (m, 1H,
CH-C = O), 2.96 (dd, J = 5.04, 5.04 Hz, 1H, CHa of CH2), 2.68 (dd, J = 10.08, 10.08 Hz, 1H,
CHb of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 172.7, 167.9 (C = O), 143.8, 142.9, 141.3,
137.2, 133.4, 131.3, 130.0, 129.8, 129.7, 129.4, 129.1, 128.9, 128.7, 128.6, 128.2, 126.9, 126.9,
126.1, 124.9, 124.7, 124.5, 112.2 (twenty one aromatic carbons), 58.2, 38.1 (two aliphatic car-
bons). HRMS-ESI (m/z): 597.1860 (M+NH4), calculated, 597.1864.
3-(1H-indol-2-yl)-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-N-(quinolin-
3-yl) propanamide (11s). Yield (0.6089 g, 98.34%), appearance, white powder, 147.70–
147.90˚C, FTIR (KBr, cm-1): 3416, 3387 (NH), 3076 (C-H aromatic), 1710, 1684 (C = O), 1627
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Synthesis of new anti-trypanosomal agents
(C = N), 1607 (C = C), 1527 (NO2), 1350, 1312 (2S = O), 1164, 1142 (SO2N), 1093 (C-N). 1H
NMR (DMSO-d6, 400MHz) δ: 10.69 (s, 1H, NH indole), 8.61 (d, J = 8.24 Hz, 1H, ArH), 8.41
(s, 1H, ArH), 8.05 (s, 1H, ArH), 7.87 (m, 2H, ArH), 7.72 (d, J = 8.24 Hz, 1H, ArH), 7.55 (d,
J = 7.76 Hz, 1H, ArH), 7.46 (d, J = 8.68 Hz, 3H, ArH), 7.26 (m, 4H, ArH), 7.12 (m, 1H, ArH),
7.04 (d, J = 8.24 Hz, 1H, ArH), 6.99 (m, 1H, ArH), 6.84 (m, 3H, ArH), 6.48 (s, 1H, NH), 3.88
(m, 1H, CH-C = O), 3.03 (dd, J = 4.56, 4.12 Hz, 1H, CHa of CH2), 2.78 (dd, J = 10.52, 10.08 Hz,
1H, CHb of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 173.3, 164.1 (C = O), 158.1, 148.9, 148.4,
146.4, 143.8, 142.9, 141.3, 136.5, 130.0, 129.8, 129.4, 128.9, 128.7, 127.4, 126.9, 126.1, 124.9,
124.4, 123.8, 121.2, 118.8, 118.2, 112.1, 111.7, 109.2 (twenty four aromatic carbons), 57.1, 28.4
(two aliphatic carbons). HRMS-ESI (m/z): 637.1603 (M+NH4), calculated, 637.1609.
4-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)penta-
namide (11t). Yield (0.5401 g, 98.88%), brownish oil, FTIR (KBr, cm-1): 3388 (NH), 3065
(C-H aromatic), 2955 (C-H aliphatic), 1701, 1688 (C = O), 1631 (C = N), 1604, 1452 (C = C),
1524 (NO2), 1353, 1315 (2S = O), 1172, 1123 (SO2N), 1018 (C-N). 1H NMR (DMSO-d6,
500MHz) δ: 8.54 (d, J = 8.60 Hz, 1H, ArH), 8.43 (s, 1H, NH), 8.35 (d, J = 9.15 Hz, 2H, ArH),
8.01 (d, J = 6.90 Hz, 2H, ArH), 7.73 (d, J = 8.05 Hz, 2H, ArH), 7.57 (m, 3H, ArH), 7.46 (t,
J = 7.45 Hz, 3H, ArH), 7.30 (m, 3H, ArH), 7.20 (t, J = 7.45 Hz, 1H, ArH), 7.11 (m, 3H, ArH),
3.73 (t, J = 5.70 Hz, 1H, CH-C = O), 1.57 (m, 1H, CH), 1.40 (m, 2H, CH2), 0.76 (m, 6H,
2CH3). 13C NMR (DMSO-d6, 500MHz) δ: 173.4, 167.9 (C = O), 147.3, 143.9, 142.9, 141.4,
137.9, 133.4, 131.3, 130.0, 129.8, 129.4, 129.1, 128.9, 128.7, 128.7, 126.9, 126.1, 125.8, 124.8,
124.4, 112.1 (twenty aromatic carbons), 54.7, 24.5, 23.1, 21.6, 21.4 (five aliphatic carbons).
HRMS-ESI (m/z): 547.0836 (M+H), calculated, 547.0839.
3-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)penta-
namide (11u). Yield (0.5392 g, 98.72%), brownish oil, FTIR (KBr, cm-1): 3345 (NH), 3066
(C-H aromatic), 2959, 2876 (C-H aliphatic), 1695, 1689 (C = O), 1603 (C = N), 1584, 1451
(C = C), 1530 (NO2), 1350, 1314 (2S = O), 1172, 1137 (SO2N), 1092, 1070, 1025 (C-N). 1H
NMR (DMSO-d6, 400MHz) δ: 8.33 (m, 2H, ArH), 8.01 (m, 1H, ArH), 7.91 (m, 2H, ArH), 7.73
(d, J = 8.24 Hz, 1H, ArH), 7.57 (m, 2H, ArH), 7.45 (m, 3H, ArH), 7.31 (m, 2H, ArH), 7.19 (m,
1H, ArH), 7.09 (m, 2H, ArH), 3.62 (d, J = 3.20 Hz, 1H, CH-C = O), 1.70 (m, 1H, CH), 1.32
(m, 1H, CHa of CH2), 1.06 (m, 1H, CHb of CH2), 0.76 (m, 6H, 2CH3). 13C NMR (DMSO-d6,
400MHz) δ: 172.4, 167.9 (C = O), 149.9, 147.2, 143.6, 141.1, 137.9, 133.4, 131.3, 130.0, 129.8,
129.4, 129.1, 128.7, 127.1, 126.1, 125.8, 124.8, 124.6, 112.4 (seventeen aromatic carbons), 60.9,
37.3, 24.8, 15.9, 11.4 (five aliphatic carbons). HRMS-ESI (m/z): 546.1582 (M+), calculated,
546.1573.
3-Methyl-2-[N-(4-nitrobenzenesulfonyl)-1-phenylformamido]-N-(quinolin-3-yl)buta-
namide (11v). Yield (0.5294 g, 99.39%), brownish oil, FTIR (KBr, cm-1): 3391 (NH), 3069
(C-H aromatic), 2961 (C-H aliphatic), 1687 (C = O), 1629 (C = N), 1604, 1584, 1452 (C = C),
1529 (NO2), 1351, 1316 (2S = O), 1174 (SO2N), 1093, 1071, 1026 (C-N). 1H NMR (DMSO-d6,
400MHz) δ: 8.34 (m, 2H, ArH), 8.01 (d, J = 8.72 Hz, 1H, ArH), 7.94 (m, 3H, ArH), 7.74 (d,
J = 8.28 Hz, 1H, ArH), 7.56 (m, 2H, ArH), 7.44 (t, J = 7.80 Hz, 3H, ArH), 7.30 (m, 2H, ArH),
7.13 (m, 3H, ArH), 3.61 (d, J = 5.96 Hz, 1H, CH-C = O), 2.00 (m, 1H, CH), 0.81 (m, 6H,
2CH3). 13C NMR (DMSO-d6, 400MHz) δ: 172.5, 167.9 (C = O), 149.9, 147.3, 143.7, 142.9,
141.2, 137.9, 133.3, 131.3, 130.0, 129.8, 129.4, 129.1, 128.8, 128.7, 127.0, 126.1, 125.8, 124.7,
124.5, 112.4 (twenty aromatic carbons), 61.9, 30.8, 19.6, 18.2 (four aliphatic carbons).
HRMS-ESI (m/z): 533.1702 (M+H), calculated, 533.1709.
4-Hydroxy-1-(4-nitrobenzenesulfonyl)-N-(quinolin-3-yl)pyrrolidine-2-carboxamide
(11w). Yield (0.4421 g, 100%), appearance, white powder, mp, 80.20–80.90˚C, FTIR (KBr,
cm-1): 3428 (OH), 3332 (NH), 3054 (C-H aromatic), 2945, 2876 (C-H aliphatic), 1687 (C = O),
1641 (C = N), 1609, 1572, 1471, 1435 (C = C), 1534 (NO2), 1347, 1290 (2S = O), 1190, 1129
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Synthesis of new anti-trypanosomal agents
(SO2N), 1019 (C-N). 1H NMR (DMSO-d6, 400MHz) δ: 8.36 (d, J = 8.68 Hz, 2H, ArH), 8.02 (d,
J = 8.72 Hz, 2H, ArH), 7.72 (d, J = 8.24 Hz, 1H, ArH), 7.56 (d, J = 7.80 Hz, 1H, ArH), 7.31 (m,
2H, ArH), 7.11 (m, 1H, ArH), 7.03 (s, 1H, ArH), 6.48 (s, 1H, NH), 4.17 (s, 1H, OH), 4.10 (t,
J = 3.96 Hz, 1H, CH-C = O), 3.44 (m, 1H, OH), 3.19 (d, J = 5.45 Hz, 2H, CH2N), 2.01 (m, 1H,
CHa of CH2), 1.90 (m, 1H, CHb of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 173.5 (C = O),
150.3, 143.9, 143.6, 142.9, 129.9, 129.5, 129.0, 126.9, 126.1, 124.8, 124.5, 118.7, 112.0 (thirteen
aromatic carbons), 69.0, 60.5, 57.1, 29.1 (four aliphatic carbons). HRMS-ESI (m/z): 441.0871
(M-H), calculated, 441.0872.
1-(4-Nitrobenzenesulfonyl)-N-(quinolin-3-yl)pyrrolidine-2-carboxamide (11x). Yield
(0.4201 g, 98.59%), appearance, white powder, mp, 89.20–90.10˚C, FTIR (KBr, cm-1): 3367
(NH), 3104 (C-H aromatic), 2981 (C-H aliphatic), 1691 (C = O), 1623 (C = N), 1607, 1499,
1473 (C = C), 1529 (NO2), 1350, 1304 (2S = O), 1199, 1163 (SO2N), 1106, 1011 (C-N). 1H NMR
(DMSO-d6, 500MHz) δ: 8.39 (t, J = 8.60 Hz, 2H, ArH), 8.06 (d, J = 9.15 Hz, 2H, ArH), 7.72 (d,
J = 8.60 Hz, 1H, ArH), 7.55 (d, J = 8.00 Hz, 1H, ArH), 7.31 (m, 2H, ArH), 7.21 (t, J = 7.45 Hz,
1H, ArH), 7.11 (m, 1H, ArH), 4.18 (dd, J = 4.00, 4.00 Hz, 1H, CH-C = O), 3.37 (m, 1H, CHa of
CH2N), 3.21 (m, 1H, CHb of CH2N), 1.96 (m, 1H, CH of CH2), 1.81 (m, 2H, CH2), 1.63 (m, 1H,
CH of CH2). 13C NMR (DMSO-d6, 400MHz) δ: 173.4 (C = O), 150.4, 143.9, 142.9, 141.6, 130.0,
129.2, 129.1, 128.7, 126.9, 126.0, 125.1, 124.4, 111.9 (thirteen aromatic carbons), 61.1, 48.9, 30.9,
24.7 (four aliphatic carbons). HRMS-ESI (m/z): 427.1075 (M+H), calculated, 427.1077.
Pharmacokinetic prediction
The drug-likeness was predicted using online quantitative estimation of drug-likeness tools.
The prediction was based on the calculated logP, topological polar surface area (TPSA), hydro-
gen bond donors (HBD), hydrogen bond acceptor (HBA), number of acid (NA), molecular
weight (MW), number of rotatable bonds (NRB) and percentage absorption (ABS). The pre-
diction tool was accessed from crdd.osdd.net/oscadd/qed/submit_virtual.php, molinspiration
and druglito.
In vitro antitrypanosomal activities
In vitro antitrypanosomal activities against T. b. gambiense strain was described by Otoguro
et al [25]. In brief, T. b. gambiense strain was cultured in IMDM with various supplements and
10% heat-inactivated FBS at 37˚C, under 5.0% CO2/95% air according to the method of Baltz
et al [26]. Ninety five mL of the trypanosomes suspension (2.0–2.5104 trypanosomes/mL for
strain GUTat 3.1) was seeded in a 96-well microplate, and 5.0 mL of a test compound solution
(dissolved in 5.0% dimethylsulfoxide) was added followed by incubation for 72 h (long incuba-
tion-low inoculation test: LILIT). Ten mL of the fluorescent dye Alamar Blue was added to
each well. After incubation for 3–6 h, the resulting solution was read at 528/20 nm excitation
wavelength and 590/35 nm emission wavelength by a FLx800 fluorescent plate reader (Bio-Tek
Instrument, Inc. Vermont, USA). Data were transferred into a spreadsheet program (Excel).
The IC50 values were determined using fluorescent plate reader software (KC-4, Bio-Tek). Suc-
cessive subcultures were done in 24-well tissue culture plates under the same conditions.
Determination of LD50 for the active anti-inflammatory compounds
Male mice were divided into various groups and test compounds were administered in various
doses intraperitoneally. Following treatments, the animals were observed for up to 4 h contin-
uously and were then kept under observation for 72 h. All behavioral changes and deaths dur-
ing the observation periods were recorded. The percentage of death at each dose level was then
calculated, converted to probits and the LD50 (μM/kg) values were calculated [27]. To observe
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Synthesis of new anti-trypanosomal agents
the health status of the mice, they were monitored 4 times a day. Humane endpoints were used
when the animal shows sign of weight loss, weakness accompanied by inability to get food,
complete anorexia and convulsion for 24 h. For the purpose of ameliorating the suffering of
the dying mice, CO2 euthanasia was applied. All the dead mice were disposed in bio-safety
containers in accordance with local standard protocols. The mortality rate in each group was
calculated according to the formula:
Mortality rateð%Þ ¼ ðthe number of dead mice=the number of mice in the groupÞ Â 100:
Results and discussion
To assess the effect of electron density, we decided to study several benzenesulphonamides
bearing electron- rich and deficient substituents (Figs 2 and 3). In the first step, the substituted
benzenesulphonamides (7a-x) were synthesized by the reaction of substituted benzenesulpho-
nyl chlorides (5a-c) with amino acids (6a-h) in the presence of sodium carbonate as base (Fig
2). The N-benzoylated derivatives (9a-f, 9i-n and 9q-v) were obtained by the reaction of the
appropriate benzenesulphonamides (7a-x) with benzoyl chloride (8) in the presence of sodium
hydroxide (Fig 2). Boric acid catalysed amidation of the carboxylic acid end of the N-benzoy-
lated derivatives (9a-f, 9i-n and 9q-v) and 3-aminoquinoline (10) afforded the corresponding
carboxamide derivatives (11a-f, 11i-n and 11q-v) (Fig 2). In addition to the N-benzoylated
derivatives, the proline and 4-hydroxyproline derivatives of substituted benzenesulphona-
mides (7g, h, o, p, w and x) were also reacted with 3-aminoquinoline in the same manner to
afford the carboxamide sulphonamide derivatives 11g, h, o, p, w and x. The carboxamides
were crystallized in their analytical grade using n-hexane. The synthesized compounds were
characterized by various spectroscopic techniques like FTIR, 1H NMR, 13C NMR and high res-
olution mass spectroscopy (HRMS). The presence of a sharp bands between 3448–3415 cm-1,
3385–3248 cm-1 and 1753–1699 cm-1 assigned to OH of carboxylic acid, NH and C = O respec-
tively were indicative of successful formation of compounds 7a-x. The disappearance of the
N-H band at 3385–3248 cm-1 in the N-benzoylated derivatives coupled with the appearance of
an additional band at 1685–1689 cm-1 is diagnostic of the successful N-benzoylation of the
substituted benzenesulphonamides. In the 1H NMR spectra of the N-benzoylated derivatives,
the disappearance of the NH peak and the appearance of additional aromatic peaks having five
protons were indicative of successful coupling. In the 13C NMR, the appearance of four addi-
tional aromatic carbons and a peak at 167 ppm were diagnostic of successful N-benzoylation.
The IR of all the new carboxamides showed a sharp band between 3452–3359 cm-1 and
1632–1622 cm-1 corresponding to the NH and C = N band respectively. In the 1H NMR, the
singlet appearing between 8.46–8.40 ppm in the derivatives corresponds to the one aromatic
proton of 3-aminoquinoline group; the peak at 6.54–6.50 ppm corresponds to the singlet peak
of the NH group in the carboxamide derivatives. In the 13C NMR spectra, the appearance of
additional nine aromatic peaks corresponds to the nine carbons of the 3-aminoquinoline.
These spectral characterizations, in addition to the HRMS-ESI spectra which showed the
molecular ion peaks of the compounds, were supportive of the successful formation of the
final products. The aromatic and aliphatic protons and carbons appeared at the predicted
range using BioDraw.
In vitro antitrypanosomal activities and structure-activity relationship
The results of the in vitro antitrypanosomal activities (Fig 4), revealed that compounds 11f,
11g, 11h, 11n, 11o, 11p, 11v, 11w and 11x had IC50 values of 3, 2, 5, 1, 3, 4, 1, 2, 3 nM respec-
tively which in exception of compounds 11h and 11p were 2-fold, 3-fold, 5-fold, 2-fold, 5-fold,
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Synthesis of new anti-trypanosomal agents
Fig 2. Synthesis of 3-aminoquinoline derivatives of benzenesulphonamides. A structural representation of the synthesis of
benzenesulphonamides.
https://doi.org/10.1371/journal.pone.0191234.g002
3-fold and 2-fold more active than melarsoprol (IC50 5 nM). These derivatives with good
antitrypanosomal activity against T. b. gambiense could serve either as a replacement to melar-
soprol and pentamidine where there is record of toxicity or as a new entrant to HAT chemo-
therapy. The L-valine, L-hydroxyproline and L-proline derivatives were the most active
compounds in each of the series. The 4-nitrobenzenesulphonamide derivatives were found to
be more active than the unsubstituted benzenesulphonamide and 4-methylbenzenesulphona-
mide derivatives. The p-nitrobenzenesulphonamides were the most active derivatives followed
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Synthesis of new anti-trypanosomal agents
Fig 3. Structures of the new derivatives. A structural representation of the new derivatives.
https://doi.org/10.1371/journal.pone.0191234.g003
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Synthesis of new anti-trypanosomal agents
Fig 4. In vitro antitrypanosomal activities. A table of value representing the in vitro antitrypanosomal activities.
https://doi.org/10.1371/journal.pone.0191234.g004
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Synthesis of new anti-trypanosomal agents
by the p-toluenesulphonamides and then the benzenesulphonamides. These findings under-
scores the importance of a substituent at the para position of the benzene ring in the antitrypa-
nosomal activity. In general, the effect of the substituents on the benzene ring followed the
trend NO2>CH3>H. The effect of the amino acid residue showed that the L-valine derivatives
(11f, 11n and 11v) had better activity than the L-leucine (11d, 11l and 11t), L-isoleucine (11e,
11m and 11u) and glycine (11a, 11i and 11q) derivatives. This shows that the chain length of a
substituent at the β-carbon contributes significantly to biological activity. The effect of the
presence of a substituent at the β-carbon was shown by the biological activity of the L-leucine,
L-isoleucine and L-valine derivatives which were better than the glycine derivatives that lacked
substitution at the β-carbon. Among the aromatic amino acids, the L-tryptophan (11c, 11k
and 11s) were more active than the L-phenylalanine (11b, 11j and 11r), this may not be
unconnected with the presence of nitrogen on the ring. The L-4-hydroxyproline (11g, 11o and
11w) were more active than their corresponding L-prolines (11h, 11p and 11x) which high-
lights the importance of the hydroxyl group on biological activity of the molecules.
The LD50 values showed that the most promising hits in exception of the p-nitrobenzene-
sulphonamide derivatives (11v-x) had better toxicity profile than melarsoprol and as such may
likely not have the toxicity problems associated with melarsoprol and other antitrypanosomal
agents currently in use. Compound 11h was the safest hit with LD50 of 18.02 μM/kg. The p-
toluenesulphonamide derivatives (11f-h) were the safest derivatives followed by the benzene-
sulphonamide derivatives (11n-p).
In silico calculation of the pharmacokinetics properties (ADME-T) and
drug-likeness
Drug-likeness describes an integrated equilibrium between multiple molecular properties and
structural features that define whether a particular compound is comparable to known drugs.
Lipinski’s rule of 5 (ro5) is among the most common principle applied to evaluate drug-like-
ness properties of a compound [28]. Verber’s criteria have also been applied extensively to
evaluate oral bioavailability of compounds [29]. These properties measure hydrophilicity, elec-
tronic distribution, hydrogen bonding capability, molecule size and flexibility that would affect
molecules behaviours in a living system. The behavior predicted includes bioavailability, trans-
port properties, affinity to proteins reactivity and toxicity [30].
A computational studies of all the carboxamides 11a-x using DrugLiTo and MedChem
Designer 3.0 software was carried out to determine the Lipinski’s molecular properties, the
blood-brain barrier likeness, and the number of rotatable bonds (NRB), together with the
topological polar surface area (TPSA; a sum of polar atoms surfaces, a descriptor for drug
absorption, penetrability and bioavailability) and the percentage of absorption (ABS %) calcu-
lated as (ABS % = 109–0.345×TPSA) [31].
The results of the pharmacokinetics prediction (Fig 5) revealed that all the tested com-
pounds in exception of compound 11c complied with ro5 where LogP values ranged between
-0.154 and 4.650 (ꢀ 5), MW range 381–619 (ꢀ 500 but one violation is permissible for ro5),
HBA range 4–6 (ꢀ10), HBD range 1–2 (ꢀ5), suggesting that these compounds would not
be expected to cause oral bioavailability problems. Compound 11c needs derivatization to
improve on its oral bioavailability profile. In exception of compounds 11r-11u (NRB = 11), all
the compounds showed NRB values range 5–10 (ꢀ10), indicating acceptable molecular flexi-
bility with consequent expected good permeability and oral bioavailability. Additionally, all
the compounds evaluated showed TPSA range 75.19–135.40 Å2 (ꢀ140 Å2), showing good
permeability and transport of the compounds in the cellular plasma membrane. Furthermore,
all the tested compounds exhibited a considerable %ABS range 62.29–83.06% which is a
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Synthesis of new anti-trypanosomal agents
Fig 5. Pharmacokinetic properties in vitro antitrypanosomal activities. A table of value repreenting the in vitro antitrypanosomal activities.
https://doi.org/10.1371/journal.pone.0191234.g005
designation of good bioavailability upon oral administration. Finally, since sleeping sickness
occurs when single-cell trypanosome parasites spread from to brain over the blood-brain bar-
rier, the BBB likeness of the compounds were evaluated. All the evaluated compounds showed
NA values 0 (0), HBA range 4–6 (<10) and MW range 381–619 (<500), indicating that
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Synthesis of new anti-trypanosomal agents
compounds 11b-11e, 11j-11k and 11r-11v cannot cross the blood-brain barrier and as such
would not succeed in the treatment of second stage of human African trypanosomiasis. It is
important to note that the more active derivatives in the in vitro antitrypanosomal activities
study (11f-h, 11n-p and 11v-x) had fascinating pharmacokinetics properties.
Conclusion
Despite the fact that over 100,000 death annually is attributed to trypanosome, there is cur-
rently no new drug for the treatment of trypanosome. Although eflornithine was introduced
in the 90’s, it was found to be ineffective against T. b. rhodesiense. The development of resis-
tance species to existing antitrypanosomal agent is quite worrisome. We have presented an
efficient, eco-friendly, highly yielding and versatile direct amidation procedure for unactivated
carboxylic acids bearing benzenesulphonamides. Beside the synthetic procedure reported, the
compounds were found to possess fascinating antitrypanosomal activities against T. b. gam-
biense. Some of these derivatives reported herein was found to be more active than melarso-
prol. The novel compounds showed satisfactory predicted physico-chemical properties
including oral bioavaiability, permeability and transport properties.
Supporting information
S1 File. 1H and 13C spectra of the new derivatives.
(DOC)
Acknowledgments
Authors are thankful to Prof. Sandeep Verma of the Department of Chemistry, Indian Insti-
tute of Technology, Kanpur for providing the facilities for synthesis and spectral characteriza-
tion. We are also thankful to the department of biological science and bioengineering IIT,
Kanpur for helping in the in silico analysis. We are also thankful to the department of Veteri-
nary Parasitology and Entomology, University of Nigeria, Nsukka for the in vitro antitrypano-
somal activities study.
Author Contributions
Conceptualization: David Izuchukwu Ugwu, Uchechukwu Chris Okoro.
Data curation: David Izuchukwu Ugwu, Narendra Kumar Mishra.
Formal analysis: David Izuchukwu Ugwu, Narendra Kumar Mishra.
Funding acquisition: David Izuchukwu Ugwu.
Investigation: David Izuchukwu Ugwu.
Methodology: David Izuchukwu Ugwu, Uchechukwu Chris Okoro, Narendra Kumar Mishra.
Project administration: David Izuchukwu Ugwu, Uchechukwu Chris Okoro.
Resources: David Izuchukwu Ugwu.
Software: David Izuchukwu Ugwu, Narendra Kumar Mishra.
Supervision: David Izuchukwu Ugwu, Uchechukwu Chris Okoro.
Validation: David Izuchukwu Ugwu.
Visualization: David Izuchukwu Ugwu.
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Synthesis of new anti-trypanosomal agents
Writing – original draft: David Izuchukwu Ugwu.
Writing – review & editing: David Izuchukwu Ugwu, Uchechukwu Chris Okoro.
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