Mendeleev Commun., 2018, 28, 195–197
Ar2
N
C
Table 1 Susceptibility of T. cruzi epimastigotes (Y strain) to azole-naftifine
analogues and Naftifine.a
CH
Me
N3
OH
Ar2
N
3a,b
iii
i, ii
EC50 /μMb
Compound
EC50 /μMb
N
Compound
Ar1
2a–j
1, 2: a Ar1 = Ph
N
Ar1
Me
Ar1
N
4a
4d
4n
25.36±4.89
22.11±3.46
29.96±8.67
4o
25.56±11.07
19.08±5.28
59.80±8.21
1a–j
4a–t
4h
3a, 4a–j Ar2 = 1-naphthyl
Naftifine
b Ar1 = 4-FC6H4
c Ar1 = 4-ClC6H4
d Ar1 = 4-BrC6H4
e Ar1 = 4-IC6H4
3b, 4k–t Ar2 = anthracen-9-yl
aValues are expressed as the mean ± standard deviation. The EC50 values for
the presented azole-naftifine analogues were statistically significant by t-test
(p < 0.05 were considered significant) in relation to the EC50 values obtained
for Naftifine.
4a,k Ar1 = Ph
4b,l Ar1 = 4-FC6H4
4c,m Ar1 = 4-ClC6H4
4d,n Ar1 = 4-BrC6H4
4e,o Ar1 = 4-IC6H4
4f,p Ar1 = 4-F3CC6H4
4g,q Ar1 = 4-F3COC6H4
4h,r Ar1 = 2,4-F2C6H3
4i,s Ar1 = 3,4-F2C6H3
4j,t Ar1 = 2,4,6-Cl3C6H2
f Ar1 = 4-F3CC6H4
g Ar1 = 4-F3COC6H4
h Ar1 = 2,4-F2C6H3
carbon atom of the triazole ring at d 146.0 ppm and the signal
related to the C–H bond of triazole moiety at d 122.0 ppm were
observed in all 13C NMR spectra. In addition, the high resolution
mass spectra of products 4 revealed the signal of m/z for the
expected ion [M+H]+ of these compounds.
i
Ar1 = 3,4-F2C6H3
j Ar1 = 2,4,6-Cl3C6H2
Scheme 1 Reagents and conditions: i, MsCl, Et3N, CH2Cl2, –50°C; ii, NaN3,
DMSO, room temperature; iii, CuSO4·5H2O (aq.), Na-ascorbate, CH2Cl2,
room temperature.
The structure of the azole-naftifine analogue 4e was confirmed
by X-ray analysis.† There is only one molecule of 4e in the
asymmetric unit (Figure 2), its molecular backbone is completely
twisted due to different degrees of rotation around its several
open-chain single bonds. The torsions on the bond bridging rings
and open-chain deviate markedly from the values expected for
a planar conformation (0° or 180°). For instance, the C(10)–
C(1)–C(11)–N(4) and C(6')–C(1')–C(7')–N(1) torsions on the
bonds connecting peripheral naphthalene and benzene rings to
the open-chain are –69(2)° and 23(2)°, respectively. The central
triazole ring is also bent relative to the open-chain, which can be
described by the N(3)–Ctriazole–C(12)–N(4) and C(1')–C(7')–N(1)–
CHtriazole torsions of –48(2)° and 90(2)°, respectively. As a result
of these rotations, naphthalene and benzene rings are not coplanar
to the triazole mean plane, forming angles of 49.5(5)° and 79.4(5)°
with it, respectively. Double bonds in the triazole ring were clearly
identified between CHtriazole and Ctriazole carbons [1.37(2) Å] and
between N(2) and N(3) nitrogen atoms [1.31(2) Å].
Next we turn our attention to the study of the anti-T. cruzi
properties of the twenty new azole-naftifine analogues synthesized.
To determine the effects on parasite survival, 106 ml–1 log-phase
epimastigotes (Y strain) were incubated in culture medium at 28°C
in the presence of different concentrations of the azole-naftifine
analogues 4 (0–100 mm). After 4 days, cell viability was determined
using a colorimetric assay (MTT).25 Four independent experiments
were performed in triplicate and naftifine was used as a positive
control. Among twenty, five test compounds had effect on T. cruzi
proliferation under the concentration of 100 mm (Table 1). Azole-
naftifine analogue 4h, which bears the same di-flurophenyl ring
of fluconazole was the most potent compound, being 3-fold
more potent than naftifine (Table 1). Azole-naftifine analogues
4a,d,n,o were roughly 2-fold more potent than naftifine. The
unprecedented antiproliferative effects against T. cruzi of these
azole-naftifine analogues seems promising for further exploration
of their molecular scaffold for developing drugs that are more
effective to fight T. cruzi.
to all mesylates.24 Since the obtained mesylates have shown some
tendency to decompose, the crude product was purified only by
washing with water and solvent removal. The prepared mesylates
readily underwent azidation with sodium azide in DMSO at room
temperature within 15 h24 (see Scheme 1). The desirable azides
2a–j were obtained in 70 to 99% yields in relation to starting alcohols
1a–j. The IR spectra of the isolated products showed the charac-
teristic azido group absorption band at 2080–2100 cm–1 which is
in agreement with reported data.24 With azides 2a–j in hand, we
next coupled them, without purification, with propargylamines
3a,b (diluted in CH2Cl2) in the presence of CuSO4·5H2O, sodium
ascorbate (diluted in water) at room temperature for 1–5 h, providing
the desired azole-naftifine analogues 4 in 55–98% yields (see
Scheme 1). In fact, azide–alkyne click reaction worked well for
a variety of substituents on the aromatic ring of azides 2a–j,
affording good to excellent yields of the desired azole-naftifine
analogues, except for reaction of azide 2i with propargylamine 3b
(55%). The structures of the azole-naftifine analogues 4 were
confirmed by spectroscopic and spectrometric analyses. Along
with the expected signals for the proposed structures for the azole-
naftifine analogues, the common signal for non-hydrogenated
CH3
C(2)
N(4)
C(12)
C(3)
Ctriazole
C(11)
N(3)
C(4)
CHtriazole
C(1)
C(10)
I(1)
C(5)
C(2')
C(1')
C(3')
N(1)
C(9)
C(8)
C(4')
C(5')
N(2)
C(6')
C(6)
C(7')
C(7)
Figure 2 The ORTEP-3 drawing of the azole-naftifine analogue 4e.
Ellipsoids are at 30% probability level and an arbitrary labeling of atoms
is displayed.
In summary, twenty novel azole-naftifine analogues were
synthesized in 52–95% overall yield in two steps from readily
accessible benzylic alcohols and propargylamines. The unique
results of this work are the first application of azide–alkyne click
reaction to obtain novel azole-naftifine analogues and the anti-
proliferative effects of such a class of compounds against T. cruzi.
Five of new compounds were disclosed as promising lead ones
to develop new anti-T. cruzi agents.
†
Crystal data for 4e. Crystals of C22H21IN4 (M = 468.33) are triclinic, space
group P1, at 293(2) K: a = 5.5291(4), b = 12.9638(9) and c = 15.4547(11) Å,
–
a = 70.88(3)°, b = 84.50(4)°, g = 77.72(5)°, V = 1022.3(3) Å3, Z = 2
(Z' = 1), dcalc = 1.521 g cm–3, m = 1.580 mm–1, 3.23° £ q £ 26.62°, 7101
reflections collected, 2639 unique [I > 2s(I)], F(000) = 468, number of
refined parameters 255. The refinement converged to GOF on F2 1.258,
final R factors were R1 = 0.0711 and wR2 = 0.2368 [for I > 2s(I)], R1 =
= 0.1003 and wR2 = 0.2491 (for all reflections). Largest diff. peak/hole:
1.641/–1.377 eÅ–3.
This work was supported by the Foundation for Research
Support of Minas Gerais, National Council for Scientific and
Technological Development, and Coordination for the Improve-
ment of Higher Education Personnel.
CCDC 1039072 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
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