Synthesis of xylitan derivatives and preliminary evaluation of in vitro trypanocidal activity

Article abstract of DOI:10.3390/molecules21101342

A series of novel xylitan derivatives derived from xylitol were synthesized using operationally simple procedures. A xylitan acetonide was the key intermediate used to prepare benzoate, arylsulfonate esters and 1,2,3-Triazole derivatives of xylitan. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as positive control against T. cruzi and cytotoxicity was determined in mammalian L929 cells. The arylsulfonate xylitan derivative bearing a nitro group displayed the best activity of all the compounds tested, and was slightly more potent than the reference drug benznidazole. The importance of the isopropylidene ketal moiety was established and the greater lipophilicity of these compounds suggests enhancement in cell penetration.

Full text of DOI:10.3390/molecules21101342

molecules
Article
Synthesis of Xylitan Derivatives and Preliminary
Evaluation of in Vitro Trypanocidal Activity
Paula Regina Elias 1, Gleicekelly Silva Coelho 1, Viviane Flores Xavier 1,2
,
Policarpo Ademar Sales Junior 2, Alvaro José Romanha 2, Silvane Maria Fonseca Murta 2,
Claudia Martins Carneiro 3, Nilton Soares Camilo 4, Flaviane Francisco Hilário 1
and Jason Guy Taylor 1,
*
1
Chemistry Department, ICEB, Federal University of Ouro Preto, Campus Universitário Morro do Cruzeiro,
35400-000 Ouro Preto, MG, Brazil; paulaelias23@yahoo.com.br (P.R.E.); silvagleicekelly@gmail.com (G.S.C.);
vivifxavier@yahoo.com.br (V.F.X.); flavianehilario@iceb.ufop.br (F.F.H.)
Centro de Pesquisas René Rachou, A Fundação Oswaldo Cruz/FIOCRUZ, 30190-002 Belo Horizonte, MG,
Brazil; policarpoasjunior@cpqrr.fiocruz.br (P.A.S.J.); romanha@cpqrr.fiocruz.br (A.J.R.);
silvane@cpqrr.fiocruz.br (S.M.F.M.)
Immunopathology Laboratory, NUPEB, Federal University of Ouro Preto,
Campus Universitário Morro do Cruzeiro, 35400-000 Ouro Preto-MG, Brazil;
claudiamartinscarneiro@gmail.com
2
3
4
Instituto de Química, Universidade Estadual de Campinas, C.P. 6154, CEP. 13084-971 Campinas, SP, Brazil;
soares7@yahoo.com
*
Correspondence: jason@iceb.ufop.br; Tel.: +55-31-3559-1707
Academic Editor: Maria Emília de Sousa
Received: 4 September 2016; Accepted: 30 September 2016; Published: 10 October 2016
Abstract: A series of novel xylitan derivatives derived from xylitol were synthesized using
operationally simple procedures. A xylitan acetonide was the key intermediate used to prepare
benzoate, arylsulfonate esters and 1,2,3-triazole derivatives of xylitan. These compounds were
evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote
forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as positive control
against T. cruzi and cytotoxicity was determined in mammalian L929 cells. The arylsulfonate xylitan
derivative bearing a nitro group displayed the best activity of all the compounds tested, and was
slightly more potent than the reference drug benznidazole. The importance of the isopropylidene
ketal moiety was established and the greater lipophilicity of these compounds suggests enhancement
in cell penetration.
Keywords: xylitan; xylitol; anhydropentitol; amastigote; trypomastigote; in vitro; chagas disease
1. Introduction
The protozoan hemoflagellate Trypanosoma cruzi is the etiologic agent responsible for Chagas
disease [1]. This disease is endemic to 21 Latin American countries [2,3] and almost half of those infected
either have or will develop cardiomyopathy, digestive megasyndromes, or both [
4]. This “neglected
disease” is currently treated in Brazil with benznidazole, but unfortunately, this drug causes many
significant side effects such as edema, fever, rash, agranulocytosis and neurotoxicity. Furthermore, the
therapeutic effectiveness of benznidazole is dependent on the type of T. cruzi strain [5]. Nifurtimox
has also been used to treat Chagas disease but due to the side effects of nifurtimox being more severe
than benznidazole and its lower efficacy, the commercialization of nifurtimox was suspended in Brazil,
Argentina, Chile and Uruguay in the 1980s. A number of studies focused on the synthesis and in vitro
activity of biologically active compounds against T. cruzi have been reported in the literature. In vitro
bioassays using the epimastigote form present in the midgut vector have been used as screening method
Molecules 2016, 21, 1342; doi:10.3390/molecules21101342
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for the evaluation of anti T. cruzi activity [6–9]. Intracellular amastigotes forms of T. cruzi have been
targeted in recent studies due to the fact that they are present in the vertebrate host during the acute
and chronic phases of the disease [10 12]. Compounds presenting promising in vitro activities against
trypomastigote forms of the parasite have also been reported [13 15]. However, in vitro assays that allow
–
–
the direct analysis of compounds on T. cruzi-infected cell lineages whilst monitoring simultaneously the
effects on both amastigotes and trypomastigotes in just one system, are seldom employed in the discovery
phase. This is particularly relevant for studies that seek to evaluate the parasite forms that are relevant
to human infection. Following the guidelines suggested by the Fiocruz Program for Research and
Technological Development on Chagas Disease Initiative, the whole cell-based screening methodology
was utilized in the present study [16]. Soares and co-workers demonstrated that ribonucleosides were
promising molecular scaffolds for the development of T. cruzi inhibitors [15] and their results motivated
us to investigate anhydropentitol derivatives for therapy of parasitic diseases. Xylitol is a five-carbon
sugar alcohol that has commercial uses in medicine and dietary applications as an alternative sweetener
for diabetic persons. Xylitol can be converted to (
an acid catalyzed cyclisation reaction (Scheme 1) [17].
±
)-xylitan (also known as 1,4-anhydro-D/L-xylitol) via
Scheme 1. Synthesis of (±)-xylitan from xylitol.
Synthetic efforts directed towards the preparation of xylitan derivatives have been scarce but
some reports documenting the synthesis of these molecules have been described in the scientific
literature [18–22]. Although many 1,4-anhydro-alditols have been extensively studied for their
applications to treat infectious diseases, xylitan derivatives have been largely underexplored chemical
frameworks for the development of bioactive compounds. In order to meet the deficit in new drug
candidates for Chagas disease, we have prepared 22 xylitan derivatives and tested them against both
amastigote and trypomastigote forms of T. cruzi in vitro.
2. Materials and Methods
All commercial reagents were used as received. Arylazides were prepared from the corresponding
anilines following literature procedures [23]. Anhydrous solvents were purchased from Sigma Aldrich
(St. Louis, MO, USA). Flash column chromatography was performed using silica gel 200–400 Mesh.
TLC analyses were performed using silica gel plates, using ultraviolet light (254 nm), phosphomolybdic
acid or vanillin solution for visualization. Melting points are uncorrected and were recorded on a Buchi
B-540 apparatus (Zurich, Switzerland). For NMR data, the chemical shifts are reported in
δ (ppm)
referenced to residual solvent protons and 13C signals in deuterated chloroform. Coupling constants
(J) are expressed in hertz (Hz). Infrared spectra were obtained on a Thermo Scientific Nicolet 380 FT-IR
apparatus (600–4000 cm−1, Nicolet Instrument Corp., Madison, WI, USA) using attenuated total
reflection (ATR). Mass spectra were obtained by GC-MS, Shimadzu QP-2010 Plus model (Shimadzu,
Kyoto, Japan). SMILES notations of the xylitan derivatives were inputted into the online Molinspiration
software (software version v2015.01) and only bioactive compounds were subjected to molecular
properties prediction by Molinspiration software [24].
2.1. Synthesis of 3,5-O-Isopropylidene-1,4-xylitan (2)
To a round bottom flask (1000 mL) equipped with stir bar was added xylitan (100 g), anhydrous
copper sulfate (100 g) and dry acetone (500 mL) at room temperature under an atmosphere of nitrogen.
Concentrated sulfuric acid (0.3 mL) was added to the heterogeneous mixture and the system was kept

Molecules 2016, 21, 1342
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under stirring at room temperature for 12 h. After this period, the reaction mixture was filtered through
a sintered glass funnel. The organic phase was neutralized with an excess of calcium hydroxide, and
filtered again on a sintered glass funnel. The mixture was then concentrated in vacuo to yield a viscous
liquid. Purification was performed by column chromatography on flash silica gel eluting with ethyl
acetate to afford xylitan-acetonide (
±
)-
2
(80%) as a white solid, m.p. 68–70 ◦C. 1H-NMR (250 MHz,
CDCl3):
δ
4.17–4.23 (m, 3H), 3.88–4.07 (m, 3H), 3.72 (d, J = 8.3 Hz, 1H), 2.96 (bs, OH), 1.41 (s, 3H),
1.33 (s, 3H); 13C-NMR (62.5 MHz, CDCl3): δ 97.4, 76.6, 75.4, 74.4, 72.0, 60.6, 28.5, 19.3.
2.2. Synthesis of (±)-3,5-O-Phenylboronate-1,4-xylitan (3)
In a round bottom flask equipped with stir bar and reflux condenser, xylitol (20 g; 131 mmol)
and an aqueous solution of sulphuric acid (5.60 mL, 5% v/v) were added. The mixture was heated at
135 ◦C with stirring for 45 min. Upon cooling, xylitan was obtained as a viscous pale yellow liquid
(16.40 g; 82%) and used in the next step without further purification. In a two necked round bottom
flask equipped with stir bar, a Dean-Stark apparatus, a Liebig condenser and an addition funnel with
pressure equalizing side arm, phenylboronic acid (0.874 g; 7.16 mmol) and 80 mL of benzene were
added. A solution of xylitan
1
(0.800 g; 5.97 mmol) in 20 mL of methanol was added dropwise by
◦
◦
addition funnel at 80 C. Upon complete addition of xylitan, the temperature was raised to 100 C and
allowed to stir for 1 h. Finally, the reaction was allowed to cool to room temperature, the excess of
benzene was removed under reduced pressure and the resulting liquid residue was triturated with
a mixture of ethyl acetate and hexane (1:4) to afford compound (
±
)-3 as a white solid in 47% yield.
m.p. 103–104 ◦C; Rf = 0.48 (ethyl acetate/hexane, 2:3); IR (cm−1): 3441, 1595, 1448, 1310; 1H-NMR
(500 MHz, CDCl3):
δ 1.91 (brs, 1H), 3.80 (d, 1H, J = 10 Hz), 4.22–4.51 (m, 6H), 7.34 (t, 1H, J = 7.5 Hz),
7.43 (t, 2H, J = 7.5 Hz), 7.78 (d, 2H, J = 10 Hz); 13C-NMR (125 MHz, CDCl3):
127.5, 130.9, 133.8, 134.4; EI m/z (%): 57 (40%), 149 (100%).
δ 61.2, 74.5, 74.6, 77.0, 77.4,
2.3. Synthesis of Benzoate Esters (±)-4a–g
A general procedure is as follows: xylitan acetonide ( )-2 (3 mmol) and a benzoyl chloride
±
(3 mmol) or phthalic anhydride (3 mmol) were stirred in CH2Cl2 (5 mL) and pyridine (2 mL) at 0 ◦C
for 0.5 h and then allowed to warm to room temperature. Stirring was continued for a further 16 h
at room temperature. Upon completion, the reaction mixture was taken up into a separatory funnel
containing a mixture of CH2Cl2 (15 mL) and a saturated aqueous solution of sodium bicarbonate
(20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated
in vacuo and the crude product was purified by flash chromatography.
(
±
)-2-Benzoyl-3,5-O-isopropylidene-1,4-xylitan (4a): Product obtained as a white solid in 58% yield. m.p.
80–82 ◦C; Rf = 0.15 (ethyl acetate/hexane 2:8); IR (cm−1): 1725, 1449, 1263, 1174, 1102, 924, 782, 710;
1H-NMR (300 MHz, CDCl3):
1.41 (s, 3H), 1.46 (s, 3H), 3.96–4.48 (m, 6H), 5.39 (d, 1H, J = 3 Hz), 7.43
(t, 2H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5 Hz), 8.01 (d, 2H, J = 6 Hz); 13C-NMR (75 MHz, CDCl3):
19.4, 28.7,
δ
δ
60.6, 72.3, 72.6, 73.5, 79.3, 97.8, 129.6, 129.8, 133.5, 165.5; EI m/z (%): 177 (30%), 105 (100%), 77 (40%),
69 (50%).
(
±
)-2-(4-Methoxybenzoyl)-3,5-O-isopropylidene-1,4-xylitan (4b): Product obtained as a white solid in 25%
yield. m.p. 102–104 ◦C; Rf = 0.48 (ethyl acetate/hexanes 2:8); IR (cm−1): 1699, 1592, 1449, 862, 756;
1H-NMR (300 MHz, CDCl3):
1.33 (s, 3H), 1.38 (s, 3H), 3.76–4.37 (m, 7H), 6.82 (d, 2H, J = 9 Hz), 7.87
(d, 2H, J = 9 Hz); 13C-NMR (75 MHz, CDCl3):
19.1, 28.5, 55.3, 60.3, 72.0, 72.4, 73.3, 78.8, 97.5, 113.5,
121.7, 131.6, 163.6, 165.0; EI m/z (%): 207 (30%), 135 (100%), 101 (60%).
δ
δ
(
±
)-2-(3,4,5-Trimethoxybenzoyl)-3,5-O-isopropylidene-1,4-xylitan (4c): Product obtained as a white solid in
12% yield. m.p. 120–122 ◦C; Rf = 0.45 (ethyl acetate/hexanes 2:8); IR (cm−1): 2989, 2945, 1699, 1592,
1449, 1227, 995, 862, 756; 1H-NMR (300 MHz, CDCl3):
1.44 (s, 3H), 1.49 (s, 3H), 3.92–4.51 (m, 15H),
5.40 (s, 1H), 7.29 (s, 2H); 13C-NMR (75 MHz, CDCl3):
19.5, 28.7, 56.4, 60.6, 61.1, 72.3, 72.7, 73.5, 79.5,
97.9, 107.1, 124.5, 142.8, 153.1, 165.3; EI m/z (%): 167 (25%), 95 (100%), 68 (60%).
δ
δ

Molecules 2016, 21, 1342
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( )-2-(3-Nitrobenzoyl)-3,5-O-isopropylidene-1,4-xylitan (4d): Product obtained as a white solid in 63%
±
◦
yield. m.p. 110–111 C; Rf = 0.30 (ethyl acetate/hexane 2:8); IR (cm−1): 2882, 1716, 1610, 1520, 969, 827,
719; 1H-NMR (300 MHz, CDCl3):
1.40 (s, 3H), 1.46 (s, 3H), 3.96–4.48 (m, 6H), 5.40 (d, 1H, J = 3 Hz),
7.66 (t, 1H, J = 9 Hz), 8.33 (d, 1H, J = 9 Hz), 8.41 (d, 1H, J = 9 Hz), 8.78 (s, 1H); 13C-NMR (75 MHz,
CDCl3): 19.4, 28.6, 60.5, 72.1, 72.7, 73.4, 80.3, 97.9, 124.6, 127.9, 129.9, 131.3, 135.4, 148.4, 163.5; EI m/z
(%): 104 (30%), 81 (100%).
δ
δ
(
±
)-2-(4-Chlorobenzoy◦l)-3,5-O-isopropylidene-1,4-xylitan (4e): Product obtained as a white solid in 54%
yield. m.p. 198–199 C; Rf = 0.48 (ethyl acetate/hexane 2:8); IR (cm−1): 1681, 1583, 1414, 916, 844,
800, 765, 684; 1H-NMR (300 MHz, CDCl3):
J = 9 Hz), 7.94 (d, 2H, J = 9 Hz); 13C-NMR (75 MHz, CDCl3):
113.6, 121.7, 131.7, 163.6, 165.1; EI m/z (%): 313 (1%), 91 (100%), 68 (90%).
δ
1.25 (s, 3H), 1.41 (s, 3H), 3.95–5.38 (m, 7H), 7.41 (d, 2H,
19.4, 28.7, 60.6, 72.3, 72.6, 73.5, 79.3, 97.8,
δ
(
±
)-2-(4-Methylbenzoyl)-3,5-O-isopropylidene-1,4-xylitan (4f): Product obtained as a white solid in 55%
yield. m.p. 85–87 ◦C; Rf = 0.25 (ethyl acetate/hexane 2:8); IR (cm−1): 2971, 1708, 1111, 969, 827, 746,
666; 1H-NMR (300 MHz, CDCl3):
1.41 (s, 3H), 1.46 (s, 3H), 2.40 (s, 3H), 3.95–4.48 (m, 6H), 5.37 (d, 1H,
J = 6 Hz), 7.23 (d, 2H, J = 9 Hz), 7.90 (d, 2H, J = 9 Hz); 13C-NMR (75 MHz, CDCl3):
19.8, 22.2, 29.2, 61.0,
δ
δ
72.8, 73.1, 73.1, 79.6, 98.2, 127.3, 129.7, 130.2, 144.7, 166.1; EI m/z (%): 119 (100%), 91 (30%), 81 (30%),
69 (40%).
(
±
)-2-(2-Carboxybenzoyl)-3,5-O-isopropylidene-1,4-xylitan (4g): Product obtained as a pale yellow liquid
in 35% yield. Rf = 0.46 (ethyl acetate/hexane 2:8); 1H-NMR (300 MHz, CDCl3):
1.40 (s, 3H), 1.45
(s, 3H), 3.77–4.10 (m, 6H), 4.40–4.58 (m, 1H), 5.37 (d, 1H, J = 3Hz), 7.55–7.58 (m, 2H), 7.70–7.77 (m, 2H);
13C-NMR (75 MHz, CDCl3):
19.5, 28.7, 60.6, 71.8, 72.6, 73.2, 80.1, 97.8, 129.2, 131.6, 166.4, 167.0. EI m/z
δ
δ
(%): 69 (80%), 81 (70%), 98 (30%), 149 (100%), 211 (40%), 282 (42%).
2.4. Synthesis of Arylsulfonate Esters (±)-5a–g
A general procedure is as follows: xylitan acetonide ( )-2 (5 mmol), the appropriate arylsulfonyl
±
chloride (10 mmol), 4-Dimethylaminopyridine (DMAP) (5 mol %) and CH2Cl2 (10 mL) were stirred
together in round bottom flask at room temperature for 12 h. Next, the reaction mixture was taken up
into a separatory funnel containing a mixture of CH2Cl2 (15 mL) and a saturated aqueous solution of
sodium bicarbonate (20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered, concentrated in vacuo and the crude product was purified by flash chromatography.
(
±
)-2-Benzenesulfonyl-3,5-O-isopropylidene-1,4-xylitan (5a): Product obtained as a white solid in 74%
yield. m.p. 62–64 ◦C; Rf = 0.19 (ethyl acetate/hexane 6:4); IR (cm−1): 1440, 1356, 910, 826, 756, 684;
1H-NMR (300 MHz, CDCl3):
1.31 (s, 3H), 1.35 (s, 3H), 3.76–4.04 (m, 4H), 4.20 (dd, 1H, J = 9 Hz,
J = 3 Hz), 4.33 (s, 1H); 4.86 (d, 1H, J = 6 Hz), 7.54–7.70 (m, 3H), 7.90 (d, 2H, J = 9 Hz); 13C-NMR (75 MHz,
CDCl3): 19.3, 28.6, 60.3, 71.6, 72.1, 73.5, 84.6, 97.8, 127.9, 129.5, 134.3, 136.4; EI m/z (%): 299 (20%),
141 (30%), 81 (80%), 69 (100%), 59 (40%).
δ
δ
( )-2-(4-Methylbenzenesulfonyl)-3,5-O-isopropylidene-1,4-xylitan (5b): Product obtained as a white solid
±
in 73% yield. m.p. 82–85 ◦C; Rf = 0.48 (ethyl acetate/hexanes 6:4); IR (cm−1): 3004, 2912, 1592, 1355,
1188, 1099, 1050, 894, 809, 778, 667; 1H-NMR (300 MHz, CDCl3): 1.33 (s, 3H), 1.38 (s, 3H), 2.45 (s, 3H),
3.76 4.05 (m, 4H), 4.20 (dd, 1H, J = 7.5 Hz, J = 4.5 Hz), 4.35 (s, 1H), 4.84 (d, 1H, J = 3 Hz), 7.36 (d, 2H,
J = 6 Hz), 7.79 (d, 2H, J = 6 Hz); 13C-NMR (75 MHz, CDCl3): 19.3, 21.8, 28.6, 60.4, 71.7, 72.2, 73.6, 84.5,
97.9, 128.0, 130.2, 133.4, 145.5; EI m/z (%): 312 (20%), 155 (60%), 91 (70%), 81 (60%), 68 (100%).
(
±
)-2-(4-Chlorobenzenesulfonyl)-3,5-O-isopropylidene-1,4-xylitan (5c): Product obtained as a white solid
in 47% yield. m.p. 74–75 ◦C; Rf = 0.37 (ethyl acetate/hexane 2:8); IR (cm−1): 2909, 1699, 1574, 1485,
1360, 889, 800; 1H-NMR (300 MHz, CDCl3):
1.33 (s, 3H), 1.39 (s, 3H), 3.78–4.05 (m, 4H), 4.24 (dd, 1H,
J = 7.5 Hz, J = 3 Hz), 4.36 (s, 1H), 4.86 (d, 1H, J = 3 Hz), 7.55 (d, 2H, J = 6 Hz), 7.85 (d, 2H, J = 6 Hz);
δ

Molecules 2016, 21, 1342
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13C-NMR (75 MHz, CDCl3):
δ
19.3, 28.6, 60.3, 71.6, 72.2, 73.6, 84.9, 97.9, 129.4, 129.9, 134.8, 141.1; EI m/z
(%): 333 (20%), 175 (30%), 111 (30%), 69 (100%), 59 (60%).
)-2-(4-Fluorobenzenesulfonyl)-3,5-O-isopropylidene-1,4-xylitan (5d): Product obtained as a pale yellow
liquid in 67% yield. Rf = 0.24 (ethyl acetate/hexanes 3:7); IR (cm−1): 2918, 1699, 1592, 1502, 1369, 1114,
1102, 960, 898, 844; 1H-NMR (300 MHz, CDCl3):
1.27 (s, 3H), 1.33 (s, 3H), 3.73–4.00 (m, 4H), 4.18 (dd,
1H, J = 7.5 Hz, J = 4.5 Hz), 4.31 (s, 1H), 4.82 (d, 1H, J = 3 Hz), 7.21(t, 2H, J = 7.5 Hz), 7.87–7.92 (m, 2H);
13C-NMR (75 MHz, CDCl3):
19.2, 28.4, 60.1, 71.4, 72.0, 73.4, 84.7, 97.7, 116.8 (d, C-F, J = 23.2 Hz), 130.7
(
±
δ
δ
(d, C-F, J = 9.7 Hz), 132.3 (d, C-F, J = 3Hz), 165.9 (d, C-F, J = 255.7 Hz); EI m/z (%): 317 (20%), 159 (30%),
95 (40%), 69 (100%).
(
±
)-2-(4-Methoxybenzenesulfonyl)-3,5-O-isopropylidene-1,4-xylitan (5e): Product obtained as a pale yellow
liquid in 19% yield. Rf = 0.45 (ethyl acetate/hexane 3:7); IR (cm−1): 1601, 1502, 1369, 898, 809; 1H-NMR
(300 MHz, CDCl3): 1.31 (s, 3H), 1.36 (s, 3H), 3.75–4.33 (m, 10H), 4.80 (s, 1H), 7.00 (d, 2H, J = 6 Hz),
7.82 (d, 2H, J = 6 Hz); 13C-NMR (75 MHz, CDCl3):
19.7, 29.0, 56.3, 60.8 72.1, 72.5, 74.0, 84.7, 98.2,
115.1, 128.0, 130.6, 164.6; EI m/z (%): 328 (50%), 188 (70%), 171 (100%), 107(30%), 81 (70%), 59 (60%).
δ
δ
(
±
)-2-(4-Nitrobenzenesulfonyl)-3,5-O-isopropylidene-1,4-xylitan (5f): Product obtained as a white solid in
60% yield. m.p. 116–118 ◦C; Rf = 0.52 (ethyl acetate/hexanes 2:8); IR (cm−1): 3117, 1602, 1529, 1356,
1314, 1193, 1099, 1039, 894, 732, 686; 1H-NMR (300 MHz, CDCl3):
1.34 (s, 3H), 1.40 (s, 3H), 3.82–4.07
δ
(m, 4H), 4.27 (dd, 1H, J = 3 Hz, J = 6 Hz), 4.40 (d, 1H, J = 3 Hz), 4.95 (d, 1H, J = 3 Hz), 8.12 (d, 2H,
J = 9 Hz), 8.42 (d, 2H, J = 9 Hz); 13C-NMR (75 MHz, CDCl3):
124.8, 129.3, 142.1, 151.1; EI m/z (%): 344 (10%), 69 (100%).
δ 19.5, 28.6, 60.3, 71.6, 72.3, 73.6, 85.7, 98.1,
(
±
)-2-(8-Quinolinesulfonyl)-3,5-O-isopropylidene-1,4-xylitan (5g): Product obtained as a white solid in
32% yield. m.p. 129–131 ◦C; Rf = 0.24 (ethyl acetate/hexanes 4:6); IR (cm−1): 2997, 2934, 2904, 1561,
1499, 1455, 1362, 1278, 1176, 1088, 910, 840, 797, 743, 668; 1H-NMR (300 MHz, CDCl3):
1.34 (s, 3H),
δ
1.36 (s, 3H), 3.84–4.04 (m, 4H), 4.28 (d, 1H, J = 3 Hz), 4.46 (s, 1H), 5.52 (s, 1H), 7.54–7.67 (m, 2H), 8.13 (d,
1H, J = 4, 5 Hz), 8.27 (d, 1H, J = 6 Hz), 8.50 (d, 1H, J = 6 Hz), 9.08 (s, 1H); 13C-NMR (75 MHz, CDCl3):
δ
19.7, 29.1, 60.9, 72.4, 72.6, 74.3, 86.6, 98.2, 123.0, 125.9, 129.5, 133.7, 134.7, 135.5, 137.1, 144.2, 152.3;
EI m/z (%): 210 (50%), 192 (20%), 129 (100%), 101 (20%), 81 (20%), 59 (20%).
2.5. Synthesis of (±)-2-Benzyl-3,5-O-isopropylidene-1,4-xylitan (6)
Xylitan acetonide ( )-2 (5 mmol) dissolved in anhydrous THF (15 mL) was added to sodium
±
hydride (6 mmol) at 0 ◦C under an inert atmosphere of nitrogen. The mixture was stirred for 10 min
and benzyl bromide (6 mmol) was added slowly to the mixture, allowed to warm to room temperature
and left to stir for a further 24 h. Distilled water (15 mL) was added to quench the reaction and the
organic product was extracted from the aqueous phase with ethyl acetate (2
×
20 mL) in a separatory
funnel. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated
in vacuo and the crude product was purified by flash chromatography to afford a pale yellow liquid
in 15% yield. Rf = 0.31 (ethyl acetate/hexane 2:8); 1H-NMR (300 MHz, CDCl3):
δ
1.37 (s, 3H), 1.44
(s, 3H), 3.86–4.33 (m, 7H), 4.57 (s, 2H), 7.33 (s, 5H); 13C-NMR (75 MHz, CDCl3):
δ 19.4, 28.8, 60.8, 71.7,
72.1, 72.4, 73.5, 84.2, 97.5, 127.7, 127.1, 128.6; EI m/z (%): 264 (10%), 249 (60%), 157 (30%), 91 (100%),
77 (10%).
2.6. Synthesis of (±)-2-(4-Methylbenzenosulfonyl)-1,4-xylitan (7)
To a round bottom flask equipped with stir bar was added ( )-5b (0.3 mmol), CH2Cl2 (5 mL) and
±
TFA (0.9 mL). The reaction was stirred for 1 h at room temperature and after this time, the solvent
was removed under reduced pressure and the resultant liquid residue was transferred directly to a
column and purified by flash chromatography. Upon purification, compound (
a transparent liquid in 15% yield. Rf = 0.55 (ethyl acetate/hexane 3:7); 1H-NMR (300 MHz, CDCl3):
2.46 (s, 3H), 3.83–4.23 (m, 5H), 4.41 (s, 1H), 4.81 (s, 1H), 7.36 (d, 2H, J = 9 Hz), 7.79 (d, 2H, J = 9 Hz);
±
)-7 was obtained as
δ

Molecules 2016, 21, 1342
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13C-NMR (75 MHz, CDCl3):
δ
21.4, 61.2, 70.6, 78.6, 85.1, 109.7, 127.6, 129.8, 132.8, 145.1; EI m/z (%):
91 (100%), 81 (80%), 68 (80%).
2.7. Synthesis of (±)-3,5-Isopropylidene-1,4-anidro-2-deoxy-pent-1-enitol (9)
Xylitan-acetonide ( )- (2.4 g, 13.9 mmol), anhydrous CH2Cl2 (20 mL) and triethylamine (5.8 mL,
41.7 mmol), were stirred in a round bottom flask under an atmosphere of nitrogen at
10 ◦C. Next,
±
2
−
methanesulfonyl chloride (2.2 mL, 27.7 mmol), was added dropwise by addition funnel and the
mixture was allowed to stir at room temperature for 2 h. The reaction was quenched by the addition of
distilled water (20 mL) and then taken up into a separatory funnel. The organic layer was washed
with HCl (1 M, 10 mL), saturated solution of Na2CO3 (20 mL) and finally the organic layer was
evaporated under reduced pressure to afford ( as a light brown solid in 92% yield. An analyti◦cal
±
)-
8
sample of ( )-8 was obtained by recrystallization with EtOAc/Hex. White solid, m.p. 93–94 C.
±
Rf = 0.75 (ethyl acetate/hexane 3:7); IR (cm−1): 2999, 2934, 1349, 1179, 1095, 1042; 1H-NMR (400 MHz,
CDCl3): 1.35 (s, 3H), 1.43 (s, 3H), 3.05 (s, 3H), 3.88–4.09 (m, 4H), 4.35 (dd, 1H, J = 12 Hz, J = 8 Hz),
4.48 (s, 1H), 5.03 (d, 1H, J = 4 Hz); 13C-NMR (100 MHz, CDCl3):
19.3, 28.5, 38.5, 60.3, 71.8, 72.1,
73.5, 83.7, 97.8; EI m/z (%): 81 (90%), 69 (100%), 59 (60%), 57 (40%). Compound ( )- (4 mmol)
δ
δ
±
8
was stirred in 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (10 mL) at 150 ◦C for 45 min then cooled to
room temperature and extracted with water (30 mL) and ethyl acetate (40 mL) in a seperatory funnel.
The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated in
vacuo and the crude product was purified by flash chromatography to provide a viscous pale yellow
liquid in 56% yield Rf = 0.36 (Hexane/EtOAc, 5:1) after visualization by vanillin; 1H-NMR (250 MHz,
CDCl3):
δ 6.67 (d, J = 2.8 Hz, 1H), 5.17 (t, J = 2.5 Hz, 1H), 4.93 (dd, J = 2.8, 6.5 Hz, 1H), 4.37 (dd, J = 6.0,
12.5 Hz, 1H), 4.06 (dd, J = 6.0, 12.0 Hz, 1H), 3.87 (dd, J = 6.5, 12.0 Hz, 1H), 1.41 (s, 3H), 1.38 (s, 3H));
EI m/z (%) = 81 (100%), 68 (35%).
2.8. Synthesis of (±)-2-Propargyl-3,5-O-isopropylidene-1,4-xylitan (10)
To a round bottom flask equipped with stir bar and 4 Å molecular sieves (1 g), was added xylitan
acetonide ( )-2 (3.2 mmol), sodium tert-butoxide (6.3 mmol) and acetonitrile (35 mL). The solution
±
was cooled to 0 ◦C and a solution of propargyl chloride (3.2 mmol in 7 mL of CH3CN) was added
dropwise by addition funnel. Upon addition of propargyl chloride, the solution was allowed to warm
to room temperature and stirred for a further 12 h. Next, the solution was filtered to remove the
molecular sieves and the filtrate was taken up into a separatory funnel containing distilled water
(20 mL). The product was extracted from the aqueous phase with ethyl acetate (3
×
20 mL) and the
organic phase extractions were combined, washed with brine, dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. The crude product was purified by flash chromatography to furnish a
(
)-10 as a transparent liquid in 86% yield. Rf = 0.36 (ethyl acetate/hexane 1:9); 1H-NMR (300 MHz,
±
CDCl3):
δ δ 19.3,
1.34 (s, 3H), 1.42 (s, 3H), 2.45 (s, 1H), 3.80–4.31 (m, 8H); 13C-NMR (75 MHz, CDCl3):
28.7, 56.9, 60.6, 71.8, 72.3, 73.2, 75.1, 79.3, 83.8, 97.6; EI m/z (%): 197 (30%), 101 (65%), 82 (100%).
2.9. Synthesis of Triazoles 11a–d
To a one necked round bottom flask equipped with stir bar was added freshly prepared arylazide
(2.7 mmol), a solution of CuSO4 5H2O (0.44 mmol in 3 mL of H2O) and a solution of sodium ascorbate
(0.56 mmol in 3 mL of H2O). The mixture was stirred vigorously and a solution of ( )-10 (1.4 mmol in
6 mL of CH2Cl2) was added dropwise and allowed to stir at room temperature for 24 h. The reaction
mixture was transferred to a separatory funnel and extracted with CH2Cl2 (2 25 mL). The organic
·
±
×
layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated in vacuo and the
crude product was purified by flash chromatography.

Molecules 2016, 21, 1342
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( )-2-[(1’-(4-Methoxyphenyl)-2-O-metil-1H-1,2,3-triazol]-3,5-O-isopropylidene-1,4-xylitan (11a): Product
±
obtained as a light brown solid in 85% yield. m.p. 106–108 ◦C; Rf = 0.29 (ethyl acetate/hexane 2:8);
1
IR (cm−1): 2936, 1494, 1201, 1102, 1031, 969, 836, 746; H-NMR (300 MHz, CDCl3):
δ 1.35 (s, 3H),
1.43 (s, 3H), 3.84–4.37 (m, 7H), 4.74 (s, 2H), 6.99 (d, 2H, J = 9 Hz), 7.58 (d, 2H, J = 9 Hz), 7.88 (s, 1H);
13C-NMR (75 MHz, CDCl3):
19.4, 28.8, 55.7, 60.7, 63.1, 72.0, 72.3, 73.2, 84.4, 97.6, 114.8, 121.1, 122.3,
130.4, 144.1 159.9; EI m/z (%): 361 (1%), 167 (25%), 149 (100%), 57 (60%).
δ
( )-2-[(1’-(4-Chlorophenyl)-2-O-metil-1H-1,2,3-triazol]-3,5-O-isopropylidene-1,4-xylitan (11b): Product
±
◦
obtained as a white solid in 41% yield. m.p. 134–136 C; Rf = 0.52 (ethyl acetate/hexane 1:9); IR (cm−1):
3007, 2909, 1520, 1449, 1272, 1209, 1111, 1040, 978, 827; 1H-NMR (300 MHz, CDCl3):
1.37 (s, 3H), 1.45
(s, 3H), 3.86–4.38 (m, 7H), 4.77 (s, 2H), 7.48–7.52 (m, 2H), 7.66–7.70 (m, 2H), 7.95 (s, 1H); 13C-NMR
(75 MHz, CDCl3): 19.5, 28.7, 60.7, 63.2; 72.0, 72.5, 73.3, 83.9, 84.7, 97.5, 120.7, 121.7, 129.1, 134.7, 135.4;
EI m/z (%): 167 (30%), 149 (80%), 71 (60%), 57 (100%).
δ
δ
(
±
)-2-[(1’-(2-Acylphenyl)-2-O-metil-1H-1,2,3-triazol]-◦3,5-O-isopropylidene-1,4-xylitan (11c): Product
obtained as a white solid in 29% yield. m.p. 135–136 C; Rf = 0.29 (ethyl acetate/hexane 2:8); IR (cm−1):
2900, 1502, 1440, 960, 809, 756; 1H-NMR (400 MHz, CDCl3):
3.75–4.39 (m, 7H), 4.78 (s, 2H), 7.86 (d, 2H, J = 8 Hz), 8.05 (s, 1H), 8.12 (d, 2H, J = 8 Hz); 13C-NMR
(100 MHz, CDCl3): 19.9, 27.1, 29.1, 61.0, 63.5, 72.3, 72.8, 73.7, 85.0, 98.0, 120.5, 121.0, 130.6, 137.4, 140.4,
146.3, 196.1; EI m/z (%): 207 (50%), 73 (100%).
δ 1.37 (s, 3H), 1.45 (s, 3H), 2.65 (s, 3H),
δ
( )-2-[(1’-(3,4-Dimethylphenyl)-2-O-metil-1H-1,2,3-triazol]-3,5-O-isopropylidene-1,4-xylitan (11d): Product
±
◦
obtained as a white solid in 34% yield. m.p. 110–111 C; Rf = 0.13 (ethyl acetate/hexane 2:8); IR (cm−1):
2936, 1601, 1440, 1378, 1201, 1066, 960, 827, 756; 1H-NMR (400 MHz, DMSO):
1.23 (s, 3H), 1.39 (s, 3H),
2.28 (s, 3H), 2.31 (s, 3H), 3.68–4.07 (m, 6H), 4.39 (m, 1H), 4.68 (s, 2H); 7.33–7.41 (m, 2H), 7.59 (d, 1H,
J = 4 Hz), 8.74 (s, 1H); 13C-NMR (100 MHz, DMSO):
19.1, 19.6, 28.8, 60.1, 62.1, 71.4, 71.9, 72.7, 83.7,
δ
δ
96.9, 117.5, 121.1, 122.3, 130.7, 134.7, 137.2, 138.3, 144.8; EI m/z (%): 202 (40%), 158 (100%), 145 (51%),
105 (70%).
2.10. Anti-Trypanosoma cruzi Activity Assay
The in vitro anti-T. cruzi activity was evaluated on L929 cells (mouse fibroblasts) infected with
Tulahuen strain of the parasite expressing the Escherichia coli β-galactosidase as reporter gene according
to the method described previously [16]. Briefly, for the bioassay, 4000 L929 cells were added to each
well of a 96-well microtiter plate. After an overnight incubation, 40,000 trypomastigotes were added to
the cells and incubated for 2 h. Then the medium containing extracellular parasites was replaced with
200
For IC50 determination, the cells were exposed to each synthesized compound at serial decreasing
dilutions and the plate was incubated for 96 h. After this period, 50 L of 500 M chlorophenol red
µL of fresh medium and the plate was incubated for an additional 48 h to establish the infection.
µ
µ
beta-D-galactopyranoside (CPRG) in 0.5% Nonidet P40 was added to each well, and the plate was
incubated for 16–20 h, after which the absorbance at 570 nm was measured. Controls with uninfected
cells, untreated infected cells, infected cells treated with benznidazole at 3.8 µM (positive control) or
DMSO 1% were used. The results were expressed as the percentage of T. cruzi growth inhibition in
compound-tested cells as compared to the infected cells and untreated cells. The IC50 values were
calculated by linear interpolation. Quadruplicates were run in the same plate, and the experiments
were repeated at least once.

Molecules 2016, 21, 1342
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3. Results and Discussion
3.1. Chemistry
Heating xylitol in the presence of a strong mineral acid, sulfuric acid, with concomitant removal
of water yields a mixture of ( )-xylitan and ( )-1,4-anhydroarabinitol in a ratio of 12:1, as determined
by integration of the 1H-NMR signals. The key intermediate for the preparation of the target molecules
was obtained by exploitation of the cis diol for the introduction of an isopropylidene ketal. ( )-Xylitan
acetonide was obtained in gram quantities by reacting ( )- with acetone in the presence of CuSO4
at room temperature (Scheme 2). As expected, only ( )-xylitan containing two contiguous hydroxyls
disposed in a cis configuration reacts to form ( )- . This allows for easy separation of the desired
product from the unreacted ( )-1,4-anhydroarabinitol by column chromatography. In a similar fashion,
the boronate ester ( )- was obtained by reacting ( )-xylitan with phenylboronic acid in refluxing
benzene. Intermediate ( )- is a novel compound and could be potentially modified at the phenyl
ring or substituted with other groups by employing substituted phenylboronic acids.
±
±
±
2
±
1
±
±
2
±
±
3
±
1
±
3
OH
OH
OH
HO
HO
HO
HO
O
i)
and
O
O
O
O
1,4-anhydroarabinitol
1
2
OH
HO
OH
OH
HO
HO
O
ii)
B(OH)2
B
and
O
+
O
HO
O
O
1,4-anhydroarabinitol
1
3
Scheme 2. Synthetic route for the preparation of (
acetone, room temperature, 18 h, 75% yield; (ii) methanol–benzene, Dean-Stark, 1 h, reflux, 47%.
±
)-xylitan acetonide
2
and boronate ester
3
: (i) CuSO4,
Next, the free hydroxyl group of (
arylsulfonyl chlorides to provide a range structurally related analogues, (
either electron donating or withdrawing groups (Scheme 3). Phthalic anhydride was reacted with (
in pyridine at room temperature to afford ( )-4g. A sulfonyl quinoline derivative ( )-5g was also
obtained in good yield using the standard procedure (Scheme 3). In order to discern the importance
±
)-
2
was reacted with substituted benzoyl chlorides and
)- and ( )- , containing
)-
±
4
±
5
±
2
±
±
of the carbonyl ester for anti T. cruzi activity, compound (
synthesized by alkylation of (±)-2 with benzyl bromide.
±
)-
6
, the ether equivalent of ( )-4a was
±
O
O
SOCl2
COCl
O
O
S
O
R
O
i)
ii)
R
O
R
O
O
OH
O
O
O
O
O
O
4a-f
SO2Cl
5a-f
CO2H
R
O
O
O
N
N
O
O
O
S
2
ii)
i)
O
O
O
O
O
4g
O
5g
O
OH
O
O
O
Br
iii)
+
O
O
O
O
2
6
Scheme 3. Synthetic route for the preparation of (
±
)-xylitan acetonide derivatives: (i) pyridine, CH2Cl2,
rt, 16 h, see Table 1; (ii) pyridine, 4-Dimethylaminopyridine (DMAP) (5 mol %), CH2Cl2, rt, 16 h, see
◦
Table 1; (iii) NaH, THF, 0 C–room temperature, 24 h, 15%.

Molecules 2016, 21, 1342
9 of 13
Table 1. Product yields for compounds 4a–g and 5a–g.
Compound
R
Yield (%)
(±)-4a
(±)-4b
(±)-4c
(±)-4d
(±)-4e
(±)-4f
(±)-4g
(±)-5a
(±)-5b
(±)-5c
(±)-5d
(±)-5e
(±)-5f
(±)-5g
H
4-OCH3
3,4,5-(OCH3)3
3-NO2
4-Cl
58
25
12
63
54
55
35
74
73
47
67
19
60
32
4-CH3
2-CO2H
H
CH3
Cl
F
OCH3
NO2
Quinoline
In order to evaluate the importance of the isopropylidene ketal for anti T. cruzi activity,
deprotection of ( )-5b was carried out using TFA to liberate the cis diol which furnished compound
(±)-7 (Scheme 4).
±
O
S
O
S
O
O
O
O
i)
CH3
O
HO
HO
O
O
O
CH3
7
5b
Scheme 4. Deprotection of (±)-5b: (i) TFA, CH2Cl2, 0.5 h, room temperature, 15%.
Xylitan acetonide (
Unfortunately, compound (
anilines and azides. Thus, all attempts at introducing other functionalities at the C-2 position with
inversion of configuration were unsuccessful. In contrast, when ( )- was treated with a sterically
hindered base such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at elevated temperatures (150 ◦C),
±
)-
2
±
was mesylated smoothly to provide (
)-8 was unreactive towards nucleophilic substitution with phenols,
±
)-8 in good yield (Scheme 5).
±
8
an elimination reaction ensued that provided the corresponding glycal (
modest yield (56%).
±
)-9 (Scheme 5), albeit, in only
OH
OMs
O
O
O
ii)
i)
O
O
O
O
O
O
2
9
8
◦
Scheme 5. Synthesis of glycal (
[5.4.0]undec-7-ene (DBU), 0.5 h, 150 C, 56%.
±
)-
9
: (i) CH3SO2Cl, CH2Cl2, Et3N, 2 h, 0 C, 96%; (ii) 1,8-Diazabicyclo
◦
Andrade and co-workers reported the biological evaluation of 1,2,3-triazole-based analogues of
benznidazole [24] and their promising results inspired us to incorporate a pendant triazole moiety
into xylitan acetonide (
was carried out and the resulting ether (
cycloaddition reaction to provide the desired triazoles (±)-11 in modest yields (Scheme 6).
±
)-
2
. To achieve this goal, the alkylation of (
±
)-2 with propargyl chloride
±
)-10 was subsequently coupled to aromatic azides via a

Molecules 2016, 21, 1342
10 of 13
N3
ii)
O
O
N
O
O
Cl
R
N
2
N
i)
O
O
O
O
10
11a-d
R
◦
Scheme 6. Synthesis of xylitan-triazole compounds ( )-11a–d: (i) t-BuONa, CH3CN, 0 C, 12 h, 86%;
±
(ii) CuSO4·5H2O, NaAsc, EtOH/H2O, room temperature, see Table 2.
Table 2. Product yields for compounds 11a–d.
Compound
R
Yield (%)
11a
11b
11c
11d
4-OCH3
4-Cl
4-COCH3
3,4-(CH3)2
85
41
29
34
Compounds ( )-3–
11 are novel and were characterized by mass spectrometry, FT-IR 1H- and
±
13C-NMR spectroscopy.
3.2. Biology
The antiprotozoal activity of compounds ( )-2–11 were evaluated in vitro against trypomastigote
±
and amastigote forms of T. cruzi using the method described by Romanha et al. [16]. Benznidazole
was used as positive control against T. cruzi and cytotoxicity was determined in mammalian L929
cells (Table 3). Our reference compound provided an IC50 of 3.8
of 625 and was used as a benchmark value for assessing the potency and selectivity of the xylitan
derivatives. With these targets in mind, only those compounds that exhibited IC50 < 10 M were further
evaluated for their cytotoxicity. Many of the compounds described herein were inactive at the tested
concentrations. Amongst the carboxylic acid esters ( )-4a , only ( )-4e which contains a chloro
µM and gave a selectivity index (SI)
µ
±
–
g
±
substituent at the para position, demonstrated significant trypanocidal activity, but was almost four
times less potent than benznidazole. The arylsulfonate esters were in general more active than their
carboxylic acid ester counterparts and compounds (
values in the range of 2.7 to 29.5 M. Notably, compounds containing electron withdrawing groups
demonstrated greatest activity amongst the compounds tested (NO2 > F > CH3). In order to evaluate
the importance of the ketal group for trypanocidal activity, compound ( )- was prepared and tested.
The deprotected compound was essentially inactive unlike compound ( )-5b and so the decision was
taken to maintain the isopropylidene ketal group. The calculated Log P of compound ( )- was found
to be 1.15 whereas in comparison, ( )-5b was 2.09. It is unclear at this stage if the isopropylidene
ketal enhances potency or merely renders the xylitan derivatives more lipophilic and thus favouring
greater penetration into the parasite. The stand out lead compound was xylitan derivative ( )-5f
±
)-5b, (
±
)-5d, (
±
)-5f and (
±
)-5g displayed IC50
µ
±
5
±
±
7
±
±
which contains a nitro group. This novel compound was slightly more active than the positive control
and moderately selective (SI = 13). The physicochemical drug descriptors of the molecular properties
for the synthesized compounds were calculated by Molinspiration software (Table 3). The partition
coefficient (LogP: octanol/water partition coefficient) describes the equilibrium distribution between
two liquid phases such as octanol and water and the total polar surface area (TPSA) is a measure of
the extent of the molecules exposed polar area. Although there were no linear correlations between
molecular hydrophobicity and bioactivity, all Log P values for the bioactive compounds were found to
be less than 5 which satisfies Lipinski’s rule of five and suggests potentially good permeability across
cell membranes. Interestingly, compound ( )-5f presented the highest TPSA value which is below
±
the limit of 140 Å2 (Lipinski’s rule of five); based on the TPSA value alone, it would be expected to
perform the poorest at permeating cell membranes. The presence of the nitro group may therefore

Molecules 2016, 21, 1342
11 of 13
be important for enhancing a protein-ligand interaction at a specific target that is responsible for its
greater potency in vitro. Given the promising results described by the group of Andrade [25], we were
surprised to find that triazoles (±)-11a–d were inactive against T. cruzi.
Table 3. In vitro trypanocidal activity, cytotoxicity and selectivity index (SI) of bioactive xylitan derivatives.
TPSA (Å2)
Compound
R
Trypanocide IC50 (µM)
Cytotoxicity CC50 (µM)
SI
Log P
(±)-4e
(±)-4g
(±)-5b
(±)-5d
(±)-5f
(±)-5g
4-Cl
2-CO2H
4-CH3
4-F
4-NO2
Quinoline
15.6 (± 2.2)
324.0 (± 54)
16.4 (± 2.2)
6.6 (± 2.2)
2.7 (± 2.2)
29.2 (± 3.0)
ND
ND
ND
13.3
35.9
ND
-
-
-
2
13
-
3.22
1.73
2.09
1.80
1.60
1.60
54.01
91.31
71.08
71.08
116.90
83.97
Benznidazole
-
3.8
2381
625
-
-
IC50: 50% inhibitory concentration. ND: not determined. CC50: 50% cytotoxic concentration. SI: selectivity
index calculated from CC50/IC50. TPSA: total polar surface area.
4. Conclusions
In conclusion, although the potency of many of the xylitan derivatives was less active than the
positive control, potency was enhanced by the inclusion of halogens, nitro group or a quinoline moiety.
In one case, the xylitan derivative ( )-5f was slightly more potent than benznidazole. The xylitan
±
framework and other anhydropentitols may assist in crossing biologic membranes and in penetrating
into the parasite.
Acknowledgments: This work was supported by the Brazilian funding agency Fundação de Amparo à Pesquisa
do Estado de Minas Gerais (FAPEMIG) under research grant project code APQ-00356-13 and the Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq) under research grant project code 473461/2013-7.
Authors gratefully acknowledge the generous financial support from the Universidade Federal de Ouro Preto,
FAPEMIG and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). This work is a
collaboration research project of members of the Rede Mineira de Química (RQ-MG) supported by FAPEMIG
(Project: CEX-RED-00010-14). The authors thank the Program for Technological Development of Tools for
Health-PDTIS-FIOCRUZ for use of its facilities.
Author Contributions: P.R.E., G.S.C. and N.S.C. carried out the synthesis of the xylitan derivatives; P.A.S.J., V.F.X.,
A.J.R. and S.M.F.M. evaluated the biological activity against T. cruzi; J.G.T., F.F.H. and C.M.C. conceived and
designed the experiments and analyzed the data, J.G.T. wrote the paper. All authors read and approved the
final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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