Synthesis and in vitro evaluation of novel 1, 2, 4-triazole derivatives as antifungal agents

Article abstract of DOI:10.2174/157018010789869415

Despite the advances in medicine and the emergence of new antifungal agents, fungal infections remain a significant cause of morbidity and mortality. Azoles are widely used as antifungal agents. Azoles interfere with the conversion of lanosterol to ergosterol by inhibiting a fungal cytochrome P450enzyme, lanosterol 14α-demethylase. Resistance to azoles, particularly fluconazole, is emerging to Candida albicans, after long-term suppressive therapy. Thus, there is an urgent need for newer potent antifungals to combat resistance developed against widely used azoles. In present work, we report synthesis of novel triazole derivatives of 7-hydroxy-4-methylcoumarin using various substituted aromatic aldehydes and evaluated for their in vitro fungicidal activity against Candida albicans at various concentrations to obtain minimum inhibitory concentration (MIC).

Full text of DOI:10.2174/157018010789869415

46
Letters in Drug Design & Discovery, 2010, 7, 46-49
Synthesis and In Vitro Evaluation of Novel 1, 2, 4-Triazole Derivatives as Antifungal
Agents
Ganesh R. Kokil*,a, Prarthana V. Rewatkarb, Sandeep Gosainc, Saurabh Aggarwalc, Arunima Vermac, Atin
Kalrac and Suresh Thareja*,c
aDepartment of Pharmaceutical Chemistry, Sinhgad Institute of Pharmaceutical Sciences, Lonavala – 410401,India
bDepartment of Pharmaceutical Chemistry, Shrimati Kashibai Navale College of Pharmacy, Pune – 411048,India
cDepartment of Pharmaceutical Chemistry, GVM College of Pharmacy, Sonipat – 131001, India
Received July 22, 2009: Revised August 15, 2009: Accepted August 22, 2009
Abstract: Despite the advances in medicine and the emergence of new antifungal agents, fungal infections remain a significant cause of
morbidity and mortality. Azoles are widely used as antifungal agents. Azoles interfere with the conversion of lanosterol to ergosterol by
inhibiting a fungal cytochrome P450enzyme, lanosterol 14ꢀ-demethylase. Resistance to azoles, particularly fluconazole, is emerging to
Candida albicans, after long-term suppressive therapy. Thus, there is an urgent need for newer potent antifungals to combat resistance
developed against widely used azoles. In present work, we report synthesis of novel triazole derivatives of 7-hydroxy-4-methylcoumarin
using various substituted aromatic aldehydes and evaluated for their in vitro fungicidal activity against Candida albicans at various con-
centrations to obtain minimum inhibitory concentration (MIC).
Keyword: Azole, Antifungal, Minimum inhibitory concentration, Coumarin, Triazole.
INTRODUCTION
tions [12]. Treatments for these infections are still limited to a few
agents. Various azole antifungal agents ketoconazole, fluconazole,
voriconazole and itraconazole (Fig. 1), have been developed so far
for clinical use. However, the clinical values of these agents have
been limited by their relatively high risks of toxicity, the emergence
of drug resistance, pharmacokinetic deficiencies, and/or insuffi-
ciencies in their antifungal activities. Resistance to azoles, particu-
larly fluconazole, is emerging to Candida albicans, after long-term
suppressive therapy was observed [7]. There is an urgent need for
newer potent antifungals to combat resistance developed against
widely used azoles. Thus, much effort to develop novel antifungal
agents which are more safe and efficacious is still being made.
Fungal infections remain a significant cause of morbidity and
mortality despite advances in medicinal chemistry. Antifungal drug
discovery has identified three classes of natural products (griseo-
fulvin [1], polyenes [2] and echinocandins [3]) and four classes of
synthetic chemicals (azoles [4], allylamines [5], flucytosine [6] and
phenylmorpholines [7]) with clinical value against fungal infec-
tions. The azoles class of antifungal agent is chemically either an
imidazole or a triazole group joined to an asymmetric carbon atom
as their functional pharmacophore. They all work by blocking the
active site of an enzyme variously known as lanosterol 14ꢀ-
demethylase or cytochrome P450DM [8]. The affinity for P450 and
the activity of the azole antifungals is not only determined by the
affinity of the nitrogen for the heme iron, but also by that of the N-l
substituent for the apoprotein moiety of P450 [9]. This affinity for
the apoprotein not only determines the activity of the azole antifun-
gal, but also its selectivity. The remaining part of the azole antifun-
gal fits in the similar way like lanosterol in hydrophobic groove by
interacting with Met-313and the P-methyl group of Thr-318 [10].
More than any other antifungal class, the azoles have been steadily
refined and improved upon over the course of almost 50 years. The
earliest azole for clinical use, chlormidazole, was really not a very
good pharmaceutical due to its toxicity, but the ease with which
variants on the chlormidazole chemical structure could be synthe-
sized and tested led to steady progress with azole antifungal agents
[11].
Coumarins are also known to show the antifungal activity.
Naturally occurring angelicin (furanocoumarin) (Fig. 2) and its
various synthetic derivatives were already reported to have good
antifungal activity [13].
Mouri et al. reported fifty-three new 3-(2-diethylaminoethyl)-4-
methyl-7-substituted coumarins [14] which were synthesized by
four different routes utilizing commercially available 3-(2-
diethylaminoethyl)-7-hydroxy-4-methylcoumarin
hydrochloride.
Their antifungal activities were measured against phytopathologic
fungi, Botrytis cinerea. Satyanarayana et al. reported the synthesis
and antifungal screening of new schiff base 2-[(4-methyl-2-oxo-2H-
chromen-7-yl)oxy]-N'-(substitutedmethylene) aceto hydrazides
were under conventional and microwave conditions [15].
In the present work, we have used chemical hybridization ap-
proach and combined triazole moiety with coumarin. Coumarin and
triazole derivatives have been considered to be an ideal requirement
for exhibiting wide spectrum of antifungal activity. Thus it was
considered of interest to synthesize novel coumarin derivatives
having triazole moiety attached through a spacer.
For the treatment of opportunistic fungal infections, the devel-
opment of new potent and broad-spectrum antifungal agents is an
important challenge for modern medicine, with a potent, broad
spectrum of antifungal activity, good pharmacokinetics, and excel-
lent bioavailability. It has been reported that serious infections
caused by fungi are an increasing problem because of factors such
as intensive care practices, human immunodeficiency virus infec-
tions, organ transplantation, and other immunosuppressive condi-
EXPERIMENTAL
Materials and Method
*Address correspondence to these authors at the Gat No. 309 / 310, Off Mumbai –
Pune Expressway, Kusgoan (Bk.), Lonavala, Tal. Maval, Dist. Pune, Maharashtra,
410401, India; Tel: +91-9096272981; E-mail: ganesh.kokil@gmail.com
All chemicals and solvents were obtained from commercial
sources and purified using standard procedures whenever required.
All melting points were recorded on Veego-540 melting point appa-
ratus and are uncorrected. The structures of the compounds were
GVM College of Pharmacy, Murthal Road, Sonipat, 131001, India; Tel: +91-
9216236234; E-mail: suresh_mph@yahoo.co.in
1570-1808/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Synthesis and In Vitro Evaluation of Novel 1, 2, 4-Triazole Derivatives
Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1 47
Cl
Cl
CH3
O
CH3
O
O
N
N
O
N
N
Ketoconazole
N
N
O
O
N
N
O
N
N
N
O
Cl
N
Itraconazole
Cl
F
N
N
F
N
F
CH3
N
HO
F
N
N
OH
F
N
N
N
N
N
Fluconazole
Voriconazole
Fig. (1). Various azoles clinically used for treatment of fungal infection.
1
confirmed by IR and HNMR spectra. IR spectra were recorded on
JASCO V500 spectrometer using KBr pellets. 1HNMR spectra were
recorded on a Varian Mercury YH-300 MHz and using tetramethyl-
silane (TMS) as internal standard. Splitting patterns are designated
as follows: s, singlet; d, doublet; t, triplet; m, multiplet; b, broad.
Elemental analysis has been carried out using Perkin–Elmer 2400
elemental analyzer. Thin layer chromatography (TLC) was per-
formed on pre-coated aluminium sheets coated with Silica Gel 60
F254, 0.2 mm thickness.
Characterization Data
A) 7-hydroxy-4-methyl-coumarin [7-hydroxy-4-methyl-2H-
chromen-2-one] (A)
Yield: 89%; m. p.: 183-185˚C; TLC [benzene: ethyl acetate:: 4
: 1] Rf : 0.45
IR (KBr; cm-1): 3499, 3104, 2818, 1670, 1605, 1275. 1H NMR
peaks (ꢀ, ppm, CDCl3): 3.92 (bs, 1H, Ar-OH), 7.43(d, 1H, Ar- H ),
6.82(d, 1H, Ar- H ) , 6.75(s, 1H, Ar- H ), 6.03 (s, 1H, HC-C=O),
2.38 (s, 3H, CH3). Anal.: Calcd. For C10H8O3. C(68.18), H (4.58),
O (27.25). Found: C (68.92), H (4.71), O (27.04).
O
O
B) 7-(3-chloropropoxy)-4-methyl-2H-chromen-2-one (B)
O
Yield: 82%; m. p.: 145-147˚C; TLC [benzene: ethyl acetate:: 4
: 1] Rf : 0.58
Fig. (2). Furanocoumarin.
IR (KBr; cm-1): 3093, 2959, 2887, 1678, 1611, 1293, 706. 1H
NMR peaks (ꢀ, ppm, DMSO-d6): 7.53(d, 1H, Ar- H ), 6.88(d, 1H,
Ar- H ) , 6.80(s, 1H, Ar- H ), 6.09 (s, 1H, HC-C=O), 4.17 (t, 2H,
CH2-O) ,3.62 (t, 2H, CH2-Cl), 2.36 (s, 3H, CH3). 2.32 (m, 2H,
CH2). Anal.: Calcd. for C13H13ClO3. C (61.79), H (5.19), O (18.99).
Found: C (61.95), H (5.57), O (18.72).
Chemistry
In the first step, commercially available resorcinol was stirred
with ethylacetoacetate in presence of conc. H2SO4 to form 7-
hydroxy-4-methylcoumarin (A) [16,17]. 7-hydroxy-4-methylco-
umarin (A) obtained from first step was refluxed with 1-bromo-3-
chloropropane in presence of anhydrous potassium carbonate for
twelve hours to afford 7-(3-chloropropoxy)-4-methyl-2H-chromen-
2-one (B) which was condensed with 1,2,4-triazole to give 7-(3-
(1H-1,2,4-triazol-1-yl)propoxy)-4-methyl-2H-chromen-2-one (C).
Condensation of 7-(3-(1H-1,2,4-triazol-1-yl)propoxy)-4-methyl-
2H-chromen-2-one with various substituted aldehyde in presence of
glacial acetic acid to afford final products D-1 to D-5. The synthetic
pathways have been illustrated in Scheme 1.
C) 7-(3-(1H-1, 2, 4-triazol-1-yl) propoxy)-4-methyl-2H-chromen-
2-one(C)
Yield: 79%; m. p.: 122-124˚C; TLC [benzene: ethyl acetate:: 4
: 1] Rf : 0.41
IR (KBr; cm-1): 3064, 2849, 1678, 1601, 1326, 1274. 1H NMR
peaks (ꢀ, ppm, DMSO-d6): 7.88(s, 2H, HC=N), 7.53(d, 1H, Ar- H
), 6.91(d, 1H, Ar- H ) , 6.85(s, 1H, Ar- H ), 6.10 (s, 1H, HC-C=O),
4.27 (t, 2H, CH2-O), 4.17 (t, 2H, CH2-N) , 2.36 (s, 3H, CH3). 2.32

48 Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1
Kokil et al.
OH
CH3
Ethylacetoacetate
Conc.H2SO4
OH
HO
O
O
A
1-Bromo-3-chloropropane
K2CO3, Acetonitrile
CH3
CH3
1,2,4-Triazole
N
O
O
O
N
K2CO3, Acetonitrile
O
N
C
Cl
O
O
B
Glacial acetic acid
HC CH
OHC
R1
R1
N
N
O
R
O
O
N
D(1-5)
1 = H, OH, NO2, Cl, OCH3
Scheme 1. Synthesis of various 1, 2, 4-triazole derivatives.
(m, 2H, CH2). Anal.: Calcd. for C15H15N3O3. C (63.15), H (5.30), O
(16.82), N (14.73). Found: C (63.85), H (5.77), O (16.12), N
(14.52).
J=16.2Hz), 8.10 (d, 2H Ar-H ), 7.94 (s, 2H, HC=N), 7.51(d, 1H,
Ar- H ), 7.45 (d, 2H Ar-H ), 7.17(d,1H, RCH=CHAr, J=16.2Hz),
6.88(d, 1H, Ar- H ) , 6.76(s, 1H, Ar- H ), 6.05 (s, 1H, HC-C=O),
4.24 (t, 2H, CH2-O), 4.08 (t, 2H, CH2-N) , 2.23 (m, 2H, CH2). A-
nal.: Calcd. for C22H18N4O5. C (63.15), H (4.34), O (19.12), N
(13.39). Found: C (63.39), H (4.64), O (19.31), N (13.30).
D) (E)-7-(2-(1H-1, 2, 3-triazol-1-yl) propoxy)-4-styryl-2H-
chromen-2-one (D-1)
Yield: 76%; m. p.: 110-112˚C; TLC [chloroform: methanol:: 4 :
1] Rf : 0.54
G) (E)-7-(2-(1H-1, 2, 4-triazol-1-yl) propoxy)-4-(4-chlorostyryl)-
2H-chromen-2-one (D-4)
IR (KBr; cm-1): 3082, 2857, 1684, 1609, 1326, 1282. 1H NMR
peaks (ꢀ, ppm, DMSO-d6): 8.13(d,1H,CH=CHAr,J=15.9Hz), 7.92
(s, 2H, HC=N), 7.48(d, 1H, Ar- H ), 7.27 (d, 2H Ar-H ), 7.21 (m,
3H Ar-H )7.16 (d,1H, RCH=CHAr,J=15.9Hz), 6.87(d, 1H, Ar- H ) ,
6.82(s, 1H, Ar- H ), 6.10 (s, 1H, HC-C=O), 4.25 (t, 2H, CH2-O),
4.21 (t, 2H, CH2-N) , 2.31 (m, 2H, CH2). Anal.: Calcd. for
C22H19N3O3. C (70.76), H (5.13), O (12.85), N (11.25). Found: C
(71.25), H (5.51), O (12.72), N (10.89).
Yield: 77%; m. p.: 101-103˚C; TLC [chloroform: methanol:: 4 :
1] Rf : 0.48
IR (KBr; cm-1): 3086, 2892, 1682, 1609, 1324, 1274, 722. 1H
NMR peaks (ꢀ, ppm, DMSO-d6): 8.22(d,1H,CH=CHAr,J=
16.3Hz), 7.91 (s, 2H, HC=N), 7.49(d, 1H, Ar- H ), 7.32 (d, 2H Ar-
H ), 7.28 (d, 2H Ar-H ), 7.21(d,1H, RCH=CHAr,J=16.3Hz), 6.92(d,
1H, Ar- H ) , 6.79(s, 1H, Ar- H ), 6.09 (s, 1H, HC-C=O), 4.26 (t,
2H, CH2-O), 4.13 (t, 2H, CH2-N) , 2.27 (m, 2H, CH2). Anal.:
Calcd. for C22H18ClN3O3. C (64.79), H (4.45), O (11.77), N (10.30).
Found: C (64.98), H (4.57), O (11.72), N (10.55).
E) (E)-7-(2-(1H-1, 2, 3-triazol-1-yl) propoxy)-4-(4-hydroxystyryl)-
2H-chromen-2-one (D-2)
Yield: 81%; m. p: 98-100˚C; TLC [chloroform: methanol:: 4 :
1] Rf : 0.44
H) (E)-7-(2-(1H-1, 2, 4-triazol-1-yl) propoxy)-4-(4-methoxystyryl)-
2H-chromen-2-one (D-5)
IR (KBr; cm-1): 3420, 3084, 2892, 1684, 1610, 1326, 1274. 1H
NMR peaks (ꢀ, ppm, DMSO-d6): 8.19(d,1H,CH=CHAr,J=
15.7Hz), 7.96 (s, 2H, HC=N), 7.49(d, 1H, Ar- H ), 7.15(d,1H,
RCH=CHAr, J=15.7Hz), 7.10 (d, 2H Ar-H ), 6.89(d, 1H, Ar- H ) ,
6.78(s, 1H, Ar- H ), 6.62 (d, 2H Ar-H ), 6.05 (s, 1H, HC-C=O),
4.62 (bs, 1H, Ar-OH), 4.19 (t, 2H, CH2-O), 4.05 (t, 2H, CH2-N) ,
2.22 (m, 2H, CH2). Anal.: Calcd. for C22H19N3O4. C (67.86), H
(4.92), O (16.43), N (10.79). Found: C (67.39), H (4.78), O (16.76),
N (10.54).
Yield: 75%; m. p.: 113-115˚C; TLC [chloroform: methanol:: 4 :
1] Rf : 0.68
IR (KBr; cm-1): 3084, 2892, 1686, 1610, 1326, 1292. 1H NMR
peaks (ꢀ, ppm, DMSO-d6): 8.24(d,1H,CH=CHAr,J=16.1Hz), 7.95
(s, 2H, HC=N), 7.45(d, 1H, Ar- H ), 7.21 (d,1H, RCH=CHAr,
J=16.1Hz), 7.11 (d, 2H Ar-H ), 6.89(d, 1H, Ar- H ) , 6.77(s, 1H, Ar-
H ), 6.92(d, 2H, Ar- H ) , 6.03 (s, 1H, HC-C=O), 4.24 (t, 2H, CH2-
O), 4.05 (t, 2H, CH2-N) , 3.79(s, 3H, CH3-O) , 2.27 (m, 2H, CH2).
Anal.: Calcd. for C23H21N3O4. C (68.47), H (5.25), O (15.86), N
(10.42). Found: C (69.10), H (5.82), O (15.22), N (10.73).
F) (E)-7-(2-(1H-1, 2, 3-triazol-1-yl) propoxy)-4-(4-nitrostyryl)-2H-
chromen-2-one (D-3)
Yield: 84%; m. p.: 103-105˚C; TLC [chloroform: methanol:: 4 :
1] Rf : 0.46
In-Vitro Antifungal Activity
All the compounds were screened for their in vitro antifungal
activity against strain of Candida albicans ATCC 24433 (NCIM
3557) using tube dilution method [18] and the minimum inhibitory
IR (KBr; cm-1): 3084, 2872, 1682, 1610, 1354, 1326, 1276. 1H
NMR peaks (ꢀ, ppm, DMSO-d6): 8.24(d,1H,CH=CHAr,

Synthesis and In Vitro Evaluation of Novel 1, 2, 4-Triazole Derivatives
Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1 49
concentration was determined by visual comparison with the posi-
tive and negative control tubes. A stock solution of the compound
was prepared using dimethyl sulphoxide. To 2mL of sterile
Sabourauds dextrose broth taken in a test tube, 10 to 80 μL of the
stock solution was added, followed by a loopful of an authentic
culture of Candida albicans ATCC 24433 (NCIM 3557). This cor-
responds to a concentration range of 12.5, 25, 37.5, 50, 75, 100,
125, 150 and 200 μg/mL of the compounds. The tests were carried
out in duplicate. The tubes were incubated at 37(±1) °C and ob-
served for growth at the end of 24 and 48 hours [19]. The activity of
the compounds was determined by visual observation of the pres-
ence or absence of turbidity, used as a marker for indicating the
growth of the organism. Minimum inhibitory concentration (MIC)
was taken as the minimum concentration of the compound at which
the clarity of the medium in the tube was the same as the negative
control indicating complete inhibition of growth given in Table 1.
antifungal agents in the armamentarium against fungal infections.
We have combined triazole as well as coumarin moiety together as
both having antifungal activity in order to explore their antifungal
activity. All compounds showed moderate antifungal activity
against Candida albicans strain while compound D-3 showed activ-
ity comparable to ketoconazole. Present work may prove to be a
lead for the development of new agents against resistant strain for
the treatment of fungal infection.
ACKNOWLEDGEMENTS
We gratefully acknowledge Principal, Sinhgad Institute of
Pharmaceutical Sciences and Director, GVM College of Pharmacy
for providing necessary facilities to carry out research work
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Table 1.
In-Vitro Antifungal Activity
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N
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N
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MIC (μg/mL)
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RESULT AND DISCUSSION
We have successfully synthesized novel compounds using
combination of two functionalities active against various fungus
strains. Novels triazole derivative with coumarin moiety along with
different donor as well as acceptor functionalities were synthesized
and characterized using 1H-NMR, FT-IR and elemental analysis
and evaluated in vitro against Candida albicans using ketoconazole
as reference standard. All compounds except compound D-1 (MIC>
200(μg/mL) showed moderate antifungal activity while (D-3) with
nitro substituent at para-position showed antifungal activity
(MIC~12.5(μg/mL) comparable to that of ketoconazole.
[15]
[16]
[17]
[18]
[19]
CONCLUSION
Fungal infections remain a significant cause of morbidity and
mortality despite advances in medicine and the emergence of new