Synthesis and biological activity of new triazole compounds

Article abstract of DOI:10.2174/157018010789869352

Six new N,N-bis(1,2,4-triazol-1-ylmethyl)amines have been prepared in one step by condensation of 1-(hydroxymethyl)triazole with a series of amines. These reactions were carried out in refluxed CH₃CN for 4 hours. The products were recuperated with excellent and good yields (75-89.5%). Compounds (3a-f) were screened for their antifungal activity against the budding yeast Saccharomyces cerevisiae and their antibacterial activity against Escherichia coli.

Full text of DOI:10.2174/157018010789869352

Letters in Drug Design & Discovery, 2010, 7, 41-45
41
Synthesis and Biological Activity of New Triazole Compounds
Hanane Al Bay1, Bouchra Quaddouri2, Abdelkarim Guaadaoui2, Rachid Touzani1,3, Nour-Eddine Benchat1,
Abdellah Hamal2, Mustafa Taleb4, Mohammed Bellaoui*,2,3 and Sghir El Kadiri*,1
1Laboratoire de Chimie Appliquée et Environnement, Département de Chimie, Faculté des Sciences, Université Mohamed Premier,
BP 524, 60 000 Oujda, Morocco
2Laboratoire de Génétique et Biotechnologies, Département de Biologie, Faculté des Sciences, Université Mohamed Premier, Oujda,
60000, Morocco
3Faculté Pluridisciplinaire de Nador, Université Mohamed Premier, BP300, Selouane 62700, Nador, Morocco
4Département de Chimie, Faculté des Sciences, DEM, Fès, Morocco
Received: May 03, 2009; Revised: August 06, 2009; Accepted: August 06, 2009
Abstract: Six new N,N-bis(1,2,4-triazol-1-ylmethyl)amines have been prepared in one step by condensation of 1-
(hydroxymethyl)triazole with a series of amines. These reactions were carried out in refluxed CH3CN for 4 hours. The products were re-
cuperated with excellent and good yields (75-89.5%). Compounds (3a-f) were screened for their antifungal activity against the budding
yeast Saccharomyces cerevisiae and their antibacterial activity against Escherichia coli.
Keywords: Synthesis, Antifungal activity, Antibacterial activity, Tridentate ligand, Nitrogen-rich and Triazole.
1. INTRODUCTION
these new ligands and their reactivity is strongly dependent on the
electronic richness of the nitrogen atoms and on the steric hindrance
of the substituents [10]. Thus it seems crucial to synthesise a diver-
sity of this type of tridentate ligands (Scheme 1). One of our re-
search interests is the synthesis of new tridentate nitrogen donor
compounds which have biological activities such as antifungal [11]
and anticancer [12]. In addition, we are very interested in the study
of their catalytic activities such as isomerisation [13] and oxidation
reaction [14]. To our knowledge the 1,2,4-triazole unit has never
been incorporated into a tridentate symmetrical structure type (-N-
CH2-N- junction) or screened for biological activities. We report
here an easy and facile synthesis of six new N,N-bis(1,2,4-triazolyl-
1-ylmethyl)amines containing new bulky alkyl, aromatic, amino
acid groups at the central nitrogen atom with diverse substituents
and their antifungal and antibacterial biological activities.
The chemistry of nitrogen containing multipodal molecules is
attracting current interest for the building of polynuclear metal
complexes, as a model for bioinorganic chemistry, materials sci-
ence, transport and activation of small molecules, as well as for the
discovery of new catalyst precursors [1, 4]. For example, polypyra-
zolyl compounds have been used as mimics of active sites in copper
oxidase [5]. The triazolyl ring seems to play a key role as antifungal
drugs, for example, fluconazole I is effective against oropharyngeal
and esophageal candidiasis [6, 7], although fosfluconazole II is less
active than I in vitro but has similar efficacy clinical profile in ani-
mal models and patients [8, 9] (Fig. 1).
2. RESULTS AND DISCUSSION
2.1. Synthesis
The synthesis of N,N-bis(1,2,4-triazol-1-ylmethyl)amines 3a-f
as outlined in Scheme 1 was carried out by refluxing one equivalent
of an amines 2a-f and two equivalent of 1-(hydroxymethyl)-1,2,4-
triazole 1 in CH3CN for 4 hours.
The electronic effect of the substituents R (alkyl group or aryl
group) as an electro-donating or electro-accepting group represents
only one way to modify the coordination properties of donor sites
from the triazolyl rings. The nature of the substituents R, particu-
larly the electronic effect of alkyl versus aryl group R, and the steric
hindrance of R are also important factors. Thus, six bulky amines
2a-f, differently substituted in ortho, meta and para position, were
condensed with the precursors 1 [15] (Scheme 1). The electronic
impact of the different groups R is visible on the chemical shift in
proton and carbone NMR of the methylene bridge between the
central nitrogen atom and the triazolyl rings as well as on the two –
CH triazolique. As expected the hydrogen atoms of the triazolyl
rings are more strongly influenced by the nature of R according to
the observed values for 3e 8.00; 8.22 ppm (amino acid); 3a 7.75;
8.17 ppm (phenyl with attracting group on para and ortho) and for
3f 7.84; 8.18 ppm (alkyl group). Compounds 3d-e show two une-
quivalent methylene groups with partially overlapping signals as a
consequence of the chiral carbon centre. The methylene proton
Fig. (1).
Meanwhile, these compound derivatives have been involved in
several types of chelating ligands, classified as a - 6 and 8 - electron
donating tridentate ligands with two N-donor sites of triazolyl rings
and one N-donor site of amine. The property behaviour of
*Address correspondence to this author at the Laboratoire de Chimie Appliquée et
Environnement, Département de Chimie, Faculté des Sciences, Université Mohamed
Premier, BP 524, 60 000 Oujda, Morocco; E-mail: elkadiri_sghir@yahoo.fr;
bmbellaoui@gmail.com
1570-1808/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

42 Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1
Al Bay et al.
N
Br
N
N
N
N
N
N
N
Br
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
3a
3f
Br
NH2
N
3b
H2N
Br
NH2
2a
2f
N
N
2b
N
N
O
HO
1
H2N
H2N
OH
N
N
N
N
N
N
N
N
2c
2e
N
NH2
O
HO
N
N
N
NH2
N
N
N
NH2
N
2d
N
N
N
N
O
N
N
HO
N
HO
N
N
N
N
N
O
N
N
N
N
N
N
N
3e
3c
3d
Reaction conditions: one equivalent of amine 2a-f plus two equivalents of 1 in reflux CH3CN during 4 hours.
Scheme 1. Synthesis of N,N-bis(1,2,4-triazol-1-ylmethyl)amines 3a-f.
1
Table 1. Chemical shift in H NMR and 13C NMR of the methylene bridge between the central nitrogen atom and the triazolyl rings and the -CH
triazolic
1H NMR ꢀ en ppm (H
1H NMR ꢀ en
13C NMR ꢀ en
13C NMR ꢀ en ppm (C triazol)
Compounds
Yield
triazol)
ppm (N-CH2-N)
ppm (N-CH2-N)
3a
3b
3c
3d
3e
3f
77.2%
89.5%
85%
5.84
5.62
54.69
71.51
7.75; 8.17
7.99; 8.10
7.99; 8.68
7.95; 8.56.
8.00; 8.22
7.84; 8.17
141.72; 146.97
144.41; 151.98
144.64; 152.06
144.37;151.85
146.80; 151.98
143.57; 151.82
5.94
64.59
84.5%
81%
5.36
64.63
5.31; 5.65
5.06
67.36; 71.96
66.16
86%
resonances changed with the variation of the nature of the substitu-
ent on amines, which agree with the literature reported [16-18]. The
methylene protons are diastereotopic in the chiral ligands and their
signals appear as AB systems with similar germinal coupling con-
stants of 14.7Hz (3d) and 13.6Hz (3e) (Table 1).
The variation of the proton and carbon’s shift of the methylene
groups (5.06 to 5.84) and (54.69 to 71.96) could be correlated to the
tuning of the electronic richness of these ligands. One can envis-
aged that with the new electro attracting and/or bulky substituents,
these six ligands have more potential for different coordination

Synthesis and Biological Activity of New Triazole Compounds
Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1 43
Table 2.
Antimicrobial Activity of the Compounds Evaluated
Against E. coli. (+): Active, (-): Not Active
Compound\Concentrations
1 mM
2 mM
3a
3b
3c
3d
3e
3f
-
-
-
-
-
-
-
-
+
+
+
+
behaviour than reported similar ligands [19] as well as on their
biological activities.
2.2. Antibacterial and Antifungal Activities
We first evaluated the compounds for their antibacterial activity
against E. coli as described in Materials and methods. Compounds
3a, 3b, 3c and 3d showed no antibacterial activity when they were
used at 1 mM. Even higher concentrations of these compounds (2
mM) did not inhibit growth (Table 2). Whereas, the presence of 1
mM of compound 3e or 3f in the culture prevented the growth of E.
coli cells, demonstrating that these compounds have antibacterial
activity against E. coli (Table 2).
Regarding the antifungal activity, compounds were tested for
toxicity against the budding yeast (Saccharomyces cerevisiae) cells.
Cells were cultured in the presence of 1 mM of each compound and
assayed for growth inhibition in liquid culture as described in Mate-
rials and methods. Compounds 3a and 3b were not toxic to yeast
cells, whereas compounds 3c and 3d showed weak antifungal activ-
ity (Fig. 2A). Interestingly, compounds 3e and 3f displayed strong
antifungal activity (Fig. 2A), consistent with their antibacterial
activity against E. coli. Further evaluation of 3e and 3f compounds
has demonstrated that compound 3e was more potent than com-
pound 3f. As a matter of fact, when these two compounds were
used at 0.5 mM, 3e was much more toxic than 3f to yeast cells after
longer incubation with the compound (Fig. 2B). Compound 3d,
which has an acidic function, had little anti-fungal activity when
used even at 1 mM, indicating that the acidic functional group of
compound 3e is not critical for the anti-fungal activity of this com-
pound. Similarly, 3d had no anti-bacterial activity when used at 2
mM, demonstrating that the acidic functional group of compound
3e is not important for the anti-bacterial activity of this compound.
Therefore, our results suggest that the bulky nature as well as the
flexibility of the alkyl group at the central nitrogen atom of the
triazole compound is important for the biological activity.
Fig. (2). Cultures of S. cerevisiae were grown in the presence of the com-
pounds. Optical density was measured every 2 hours to follow cell growth.
N,N-bis((1H-1,2,4-triazol-1-yl)methyl)-3,5-dibromopyridin-2-
amine 3a
White solid (77.2%), Mp = 190-192°C, 1H NMR (300MHz,
DMSO) ꢀ ppm: 8.17(s, 2H, CHtr); 8.03(s, 1H, CHAr); 7.80(d, 1H,
CHAr); 7.75(s, 2H, CHtr); 5,84(d, 4H, N-CH2-N). 13C NMR
(75MHz, DMSO)
ꢀ
ppm: 151.89(CHAr); 146.97(CHtr);
141.72(CHAr, CHtr); 108.94(C-Br); 104.78(C-Br); 54.69(N-CH2-N).
IR (KBr, ꢀ cm-1) : 3317(C-H); 1501(C=N); 1303(N-0); 1270 (C-N);
674(C-Br). MS (ES) (m/z) (%)
167.64(50.92); 265.04(40.74).
= 411.48(100); 245.60(99);
N,N-bis((1H-1,2,4-triazol-1-yl)methyl)-pyridin-4-amine 3b
White solid (89.5%), Mp = 148-150°C. 1H NMR (300MHz,
DMSO) ꢀ ppm: 8.68 (s, 2H, -CHtz) 8.10 (d, 2H, -CHar, J = 3.73 Hz);
7.99 (s, 2H, -CHtz), 6.77 (d, 2H, -CHar, J = 4.83 Hz); 5.62 (s, 4H, -
NCH2N-); 5.46 (s, 2H, Pyr-CH2N-). 13C NMR (75MHz, DMSO) ꢀ
ppm: 152.21 (-CHar); 151.98 (-CHtz); 150.18 (-CHar); 144.41 (-
CHtz); 108.57(-CHar); 71.51 (-NCH2N-); 55.98 (Pyr-CH2N-). IR
(KBr, ꢀ cm-1): 3258.4 (-CH); 1610 (-C=C); 1507 (-C=N); 1275 (C-
N); 1133; 995; 681. MS (ES) (m/z) (%) = 270.75(98); 189.77(73.4);
172.90(100).
3. EXPERIMENTAL SECTION
Melting point is uncorrected, proton NMR spectra of the com-
pounds dissolved in CDCl3, and DMSO were obtained with Bruker
300 spectrometer. Infrared spectra were recorded on a Perkin-Elmer
1310 spectrophotometer. Mass spectra were determined on a Mi-
cromass LCT, where tz refers to triazole and ar refers to aromatic
compounds).
N,N,N,N-tetrakis((1H-1,2,4-triazol-1-yl)methyl)benzene-1,4-
diamine 3c
3.1. General Procedure
White solid (85%), Mp = 179-181°C; 1H NMR (300MHz,
DMSO) ꢀ ppm: 8.68 (s, 4H, -CHtz); 7.99 (s, 4H, -CHtz); 7.08 (s, 4H,
Har); 5.94 (s, 8H, -N-CH2-N-). 13C NMR (75MHz, DMSO) ꢀ ppm:
152.06 (-N=Ctz); 144.64 (-N=Ctz); 138.56 (-CHar); 116.38 (-CHtz);
64.59 (-NCH2N-). IR (KBr, ꢀ cm-1): 3104 (-C-H); 3138; 2994; 1530
(-C=C-); 1505 (-C=N); 1265 (-C-N); 1196; 1130; 956; 801; 759;
A mixture of N-hydroxymethyl-1,2,4-triazole (10 mmol) and
amine (5 mmol) in acetonitrile (25 mL) was stirred and refluxed in
a closed vessel for 4 hours. Then the acetonitrile layer was dried
and treated with anhydrous MgSO4. After filtration the solvent was
removed under vacuum and the crude products were washed with
water, diethylether or dichloromethane wasthen dried. The products
were analysed as such:

44 Letters in Drug Design & Discovery, 2010, Vol. 7, No. 1
Al Bay et al.
684. MS (ES) (m/z) (%) = 432.66 (50); 340.96 (48); 282 (100);
268.98 (33).
4. CONCLUSION
In conclusion, we have synthesised new variety of tripodal
compounds bearing 1,2,4-triazolyl moiety with good to excellent
yields. Their biological activities have been performed; antifungal
against yeast cells of (Saccharomyces cerevisiae) and antibacterial
against (Escherichia coli). The structural and the electronic diver-
sity of these products affected their biological activities. Further
developments on this subject to understand their mechanistic inter-
actions are currently in progress.
2-(bis((1H-1,2,4-triazol-1-yl)methyl)amino)propanoic acid 3d
White solid (84.50%), Mp = 124-126°C. 1H NMR (300MHz,
DMSO) ꢀ ppm : 8.56(s, 2H, CHtr); 7.95(s, 2H, CHtr); 5.36(q, 4H,
N-CH2-N, J = 14.7 Hz); 3.92(q, 1H, CH); 1.30(d, 3H,CH3). 13C
NMR (75MHz, DMSO) ꢀ ppm:175.17(COOH); 151.85(CHtr);
144.37(CHtr); 64.63(N-CH2-N); 58.39(CH); 14.55(CH3). IR (KBr,
ꢀ cm-1): 3109(OH); 1509(C=N); 1275(C-N); 1138; 679. MS (ES)
(m/z) (%) =253.46(100); 175.84(34); 245.49(14.67); 167.73(3.6).
ACKNOWLEDGEMENTS
The authors would like to thank the Academy of Sciences for
the Developing World (TWAS) and “la Commission Universitaire
pour le Développement (CUD, Belgium)” for their support.
2,6-bis(bis((1H-1,2,4-triazol-1-yl)methyl)amino)hexanoic acid 3e
Oil yellow (81%), 1H NMR (300MHz, DMSO) ꢀ ppm: 8.22(s,
4H, -CHtr); 8.00(s, 4H, -CHtr)
5.65(s, 4H, N-CH2-N); 5.31(q, 4H, N-CH2-N, J = 13.6); 3.6(t,
1H, N-CH-COOH); 2.65(t, 2H, N-CH2-CH2); 1.5(m, 2H, CH-
CH2); 1.25(m, 4H, CH2-CH2-CH2-CH2). 13C NMR (75MHz,
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Synthesis and Biological Activity of New Triazole Compounds
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