Synthesis and antimicrobial activity of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines

Article abstract of DOI:10.1016/j.bmcl.2009.12.063

A series of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines (1) and (2) were synthesized and evaluated for their antimicrobial activity against three representative gram-positive bacteria and two fungi. The structure-activity relationship (SAR) demonstrates that the 3- or 4-fluorophenyl component attached directly to the triazine ring was essential for activity. Of these compounds, 14, 15, and 25 demonstrated significant activity against all selected organisms compared to control. These compounds were generally nontoxic and may prove useful as antimicrobial agents.

Full text of DOI:10.1016/j.bmcl.2009.12.063

Bioorganic & Medicinal Chemistry Letters 20 (2010) 945–949
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antimicrobial activity of 2-fluorophenyl-4,6-disubstituted
[1,3,5]triazines
*
Mona Saleh, Shaun Abbott, Valérie Perron, Caroline Lauzon, Christopher Penney, Boulos Zacharie
ProMetic BioSciences Inc., 500 Boulevard Cartier Ouest, Bureau 150, Laval, Québec, Canada H7V 5B7
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines (1) and (2) were synthesized and evaluated
for their antimicrobial activity against three representative gram-positive bacteria and two fungi. The
structure–activity relationship (SAR) demonstrates that the 3- or 4-fluorophenyl component attached
directly to the triazine ring was essential for activity. Of these compounds, 14, 15, and 25 demonstrated
significant activity against all selected organisms compared to control. These compounds were generally
nontoxic and may prove useful as antimicrobial agents.
Received 30 October 2009
Revised 10 December 2009
Accepted 15 December 2009
Available online 23 December 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Fluorophenyl triazines
Rigid alkyl amines
Drug resistance
Antimicrobial activity
The increasing incidence of infection caused by the rapid devel-
opment of bacterial resistance to most of the known antibiotics is a
serious health problem.1 While many factors may be responsible
for mutations in microbial genomes, it has been widely demon-
strated that the incorrect use of antibiotics can greatly increase
the development of resistant genotypes.2 As multidrug-resistant
bacterial strains proliferate, the necessity for effective therapy
has stimulated research into the design and synthesis of novel anti-
microbial molecules.
phenyl-4,6-disubstituted [1,3,5]triazines are reported as exempli-
fied by general structures 1 and 2.
R
R
HN
HN
N
N
N
N
F
R1
F
F
N
N
N
H
1
2
The chemistry of [1,3,5]triazine compounds has been studied
intensively and is the subject of many reviews.3 The triazine scaf-
fold has provided the basis for the design of biologically relevant
molecules with broad biomedical value as therapeutics. For exam-
ple, triazine compounds possess potent antiprotozoal,4 anticancer,5
antimalarial,6 and antiviral activity.7 Also, it was reported that
some of these compounds possess potent antimicrobial activity.8
The starting material for these compounds is cyanuric chloride.
This is an inexpensive commercially available reagent which
makes its use more attractive. Increased interest in this scaffold
lies in the different reactivities of the substituent chlorine atoms,
which are controlled by temperature.3 This allows sequential intro-
duction of various substituents into the [1,3,5]triazine ring. As part
of an effort towards the discovery of novel therapeutics for the
treatment of infectious diseases, a search was initiated to discover
small molecules that possess significant antimicrobial activity. In
this Letter, the synthesis and antimicrobial activities of 2-fluoro-
A number of in-house triazine derivatives were screened
against gram-positive and gram-negative bacteria, and against fun-
gi. Only compounds of general structure 3, exemplified by fluoro-
triazine derivatives 4–6, demonstrated weak activities.
HN
NH2
HN
NH2
F
N
N
N
N
R2
F
N
H
N
N
H
n
N
N
H
R3
3; R2 = F; R3 = OH, F; n = 0-2
4; R2 = 3-F; R3 = 4-OH; n = 2
5; R2 = 4-F; R3 = 4-OH; n = 2
6; R2 = 3-F; R3 = 3-F; n = 0
7
For example, as shown in Table 1, the minimum inhibitory
concentrations (MICs) for compound 5 varied between 32 and
128
lg/mL against gram-positive bacteria. Weak MICs were also
* Corresponding author.
E-mail address: b.zacharie@prometic.com (B. Zacharie).
demonstrated against gram-negative bacteria (64–128
lg/mL)
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.063

946
M. Saleh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 945–949
Table 1
Gram-positive antibacterial activity of compounds 5 and 7(MIC values are in lg/mL)
Entry
Bacterium
Phenotype
MIC compd 5
MIC compd 7
MIC ciprofloxacin
1
2
3
4
5
6
7
8
9
Enterococcus faecalis
Enterococcus faecium
128
128
64
128
32
64
64
64
64
8
4
8
8
2
4
8
8
8
>16
>16
>16
>16
0.12
>16
>16
1
VAN-R
VAN-R
M-R
CNS
CNS
Staphylococcus aureus
Staphylococcus aureus
Staphylococcus cohnii
Staphylococcus warneri
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pneumoniae
Propionibac-terium acnes
MSSE
MD-R
>16
0.5
10
32
16
Compounds 5 and 7 were tested in vitro by Anti-Infective services of Eurofins Medinet, Inc., Herndon, Virginia.
Key: MSSE: methicillin susceptible; M-R: methicillin resistant; VAN-R: vancomycin resistant; CNS: coagulase negative susceptible; MD-R: multidrug-resistant.
and against clinically-relevant fungi (128
l
g/mL). The next step
yield (>80%). The latter was treated with aminoalkyl or aralkyl
amines and base at room temperature to give the monochlorotri-
azine 9. This reaction proceeded in high yield (>85%) and is general
for different substituted alkyl amines. The next step was the for-
mation of the aryl–aryl bond between the triazine and the benzene
rings using the Suzuki cross-coupling reaction.11 Thus, treatment
of chloro-derivative 9 with ortho-, meta- or para-substituted fluor-
ophenylboronic acid in the presence of Pd(PPh3)4 and base gave the
final product 1 in respectable yields (>65%). This route is practical,
amenable to scale-up and offers a general procedure for the
preparation of a variety of analogues of 2-(fluorophenyl)-4,6-
disubstituted [1,3,5]triazines. A similar approach was applied to
synthesize diphenyl triazine derivatives 2. For example, the chloro
intermediate 8 was reacted with 2 equiv of fluorophenylboronic
acid under Suzuki condition to give the corresponding fluorotri-
azine products 2.
Compound 7 was selected as a lead structure upon which to de-
fine a structure–activity relationship for a 2-(fluorophenyl)-4,6-
disubstituted [1,3,5]triazine scaffold. Therefore, analogues were
synthesized in which different groups were introduced at positions
4 and 6 of the triazine ring. These compounds were evaluated
against three representative gram-positive bacteria: Staphylococcus
epidermidis (ATCC 155-U), Enterococcus faecium (ATCC 49624) and
Bacillus cereus (ATCC 13061). Since trisubstituted triazines have
been reported to possess antifungal activity,12 these molecules
were also tested against two fungi, that is, C. albicans (ATCC
10231) and Aspergillus niger (ATCC 16404). Table 2 summarizes
the results. Ten compounds (7, 12, 14, 15, 21, 24–27, and 30) dis-
played significant activity against the bacteria, comparable to
streptomycin control, whereas three triazine derivatives (14, 15,
and 24) displayed good activity against C. albicans, as compared
to amphotericin B control. Only, one compound 28 showed potent
activity against A. niger compared to the control. As shown in
Scheme 1, analogues of the lead compound 7 were synthesized
with variations in R (aminoalkyl or aralkyl groups) and R1 (4-
hydroxyphenethyl or aryl substituents), while maintaining the
third group as fluorophenyl. Table 2 illustrates the variation of
these substituents. Prior work10 indicated the importance of the
carbon chain length (n-pentyl) between the amine groups at the
R position. In fact, homologation of the chain with one carbon atom
(21) demonstrated moderate activity. In contrast, an increase in
chain length of two carbons (22) resulted in reduction of activity.
It was observed that good antibacterial activity was obtained with
the introduction of rigidity in the diamine fragment (R); for exam-
ple, isopentyl (24), cyclopentylmethyl (28), cyclohexyl methyl (27)
or benzyl amine (29) derivatives. However, 24–29 are inactive
against fungi except for amines 24 and 28 which respectively dem-
onstrate reasonable and significant activity against C. albicans and
A. niger compared to reference compounds. In general, it can be
was to synthesize analogues in an attempt to enhance the activities
of this class of compounds. The fluorophenyl portion appears to be
essential and activity declines upon substitution of triazine 3 with
other groups (R2 or R3 = H, CH3, Cl, NH2).9 One possible modifica-
tion is the introduction of rigidity on one side chain of the triazine
ring by linkage directly to the fluorophenyl fragment. As will be
seen from the subsequent SAR discussion, this was found to be a
preferred variation, since activity is dependent upon distance and
relative degrees of freedom at a particular position. An example
of this modification is presented by compound 7. This compound
displays weak activity against gram-negative bacteria (MIC values
16–32
trol. In addition, compound 7 exhibited moderate activity (MIC va-
lue 8 g/mL) against Candida albicans (fungal), as compared to
amphotericin B control (MIC 4 g/mL). However, the best results
(Table 1) were obtained against gram-positive bacteria (MIC values
(2–16 g/mL), where triazine 7 exhibited activity at least twofold
lg/mL) which is eightfold higher than the ciprofloxacin con-
l
l
l
lower than ciprofloxacin against Enterococci and Staphylococci sp.
(entries 1–4, 6, 7, and 9). Also, this compound did not appear to
be affected by the drug resistance phenotype (vancomycin, meth-
icillin, or multidrug-resistant; entries 2–4 and 8). On the basis of
these encouraging results, it was decided to further evaluate the
activity of analogues of compound 7.
The general synthetic procedure for preparation of triazine
compounds10 1 and 2 is outlined in Scheme 1. It illustrates the
route employed for those derivatives where the key intermediate
is the dichlorotriazine 8. Nucleophilic displacement of chlorine
from cyanuric chloride with different aryl or aralkyl amines in
the presence of sodium bicarbonate gave dichlorotriazine 8 in high
Cl
N
Cl
HNR
a
b
N
N
N
N
N
N
R1N
H
Cl
Cl
RN
H
N
Cl
N
Cl
8
9
c
c
HNR
F
N
N
R1N
H
N
N
N
F
R1N
H
N
F
2
1
Scheme 1. Reagents and conditions: (a) aryl or aralkyl amine, THF/acetone/H2O, 5%
NaHCO3, 0 °C, 10 min; (b) aminoalkyl or aralkyl amine, 5% NaHCO3, THF/acetone/
H2O, 16 h overnight; (c) fluorophenylboronic acid, Pd(PPh3)4, 2 M aqueous Na2CO3,
DME, 90 °C, 16 h.

M. Saleh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 945–949
947
Table 2
In vitro antimicrobial activity of substituted triazines against selected organisms (MIC values are in lg/mL)
R
N
N
R1
N
H
N
R2
Compd
R
R1
R2
Antibacterial activity
Antifungal activity
C. albicans
A. nigera
E. faecium
S. epidermidis
B. cereus
5
-HN(CH2)5NH2
-HN(CH2)5NH2
-HN(CH2)5NH2
-HN(CH2)5NH2
128
64
8
16
>100
8
>100
8
-(CH2)2
OH
-HN
F
7
4
8
4
8
F
F
10
11
nt
16
nt
8
>100
>100
>100
>100
-(CH2)2
-(CH2)2
OH
OH
F
F
F
-(CH2)2
-(CH2)2
OH
OH
12
13
14
-N(CH2CH2NH2)2
-N(CH2CH2NH2)2
-HN(CH2)5NH2
8
4
8
2
8
>100
32
>100
>100
16
16
8
16
4
F
F
4
F
F
15
16
17
18
-HN(CH2)5NH2
-HN(CH2)5NH2
-HN(CH2)5NH2
-HN(CH2)5NH2
8
2
4
8
8
4
4
8
F
8
64
16
>100
F
F
4
16
16
4
F
CF3
N
N
16
>100
>100
>100
F
F
19
20
-HN(CH2)5NH2
-HN(CH2)5NH2
>100
32
16
32
>100
32
>100
>100
>100
>100
N
F
F
(continued on next page)

948
M. Saleh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 945–949
Table 2 (continued)
Compd
21
R
R1
R2
Antibacterial activity
Antifungal activity
C. albicans
A. nigera
E. faecium
S. epidermidis
B. cereus
-HN(CH2)6NH2
4
2
16
16
16
F
F
F
22
23
-HN(CH2)7NH2
-HN(CH2)5NH2
16
8
4
16
16
64
8
F
F
8
16
16
F
F
F
F
F
-HN
-HN
NH2
24
25
8
4
2
2
8
8
4
8
32
8
F
F
F
NH
NH
26
4
2
4
32
8
-HN
-HN
NH2
27
28
29
30
31
8
8
8
64
8
8
F
F
F
F
F
32
8
16
4
32
16
8
2
-HN
-HN
NH2
F
NH2
16
32
4
8
F
-HN(CH2)5NH2
8
8
>100
nd
OH
F
–(CH2)5NH2
8
2
nd
F
Streptomycin sulfate
>16
—
>16
—
8
—
—
Amphotericin B
—
1–413a
813b
a
Similar Results were obtained for compounds tested against A. niger using MICs in lg/mL or by disc-diffusion assay.
seen that a rigid amine at R is preferred at this position. Piperidine
(25) and tetramethylpiperidine (26) are the most effective substit-
uents among rigid amines evaluated against bacteria and A. niger.
It was next decided to synthesize analogues of triazine 7 in
which R1 = 3-fluorophenyl, R = amino n-pentylamine and R2 was
varied with substituted phenyl groups (Table 2). The 2-fluorophenyl
function (16) resulted in a loss of activity against both bacteria and
fungi while 4-fluorophenyl (15) displayed good in vitro activity
against the tested organisms compared to control. Substitution of
the phenyl ring (R2) with polar functions gave different activities.
For example, trifluoromethyl-phenyl (17) and 3,5-difluorophenyl
(23) retained activity against all selected organisms. Also, 3-

M. Saleh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 945–949
949
5. Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F.; Via, L. D. J. Med. Chem.
2004, 47, 4649.
6. Melato, S.; Prosperi, D.; Coghi, P.; Basilico, B.; Monti, D. ChemMedChem 2008, 3,
873. and references cited therein.
7. Xiong, Y.-Z.; Chen, F.-E.; Balzarini, J.; De Clercq, E.; Pannecouque, C. Eur. J. Med.
Chem. 2008, 43, 1230. and references cited therein.
8. (a) Zhou, C.; Min, J.; Liu, Z.; Young, Z.; Deshazer, H.; Gao, T.; Chang, Y.-T.;
Kallenbach, R. Bioorg. Med. Chem. Lett. 2008, 18, 1308; (b) Srinivas, K.; Srinivas,
U.; Bhanuprakash, K.; Harakishore, K.; Murthy, U. S. N.; Jayathirtha Rao, V. Eur.
J. Med. Chem. 2006, 41, 1240; (c) Poyser, J. P.; Telford, B.; Timms, D.; Block, M.
H.; Hales Neil, J. WO 1999/01442.
hydroxyphenyl (30) possessed comparable antibacterial but only
weak antifungal activities relative to 7. In contrast, the correspond-
ing analogue with R2 = 3-pyridine (18) or 5-fluoro-3-pyridine (20)
displayed a loss of activity against all strains. Interestingly, replace-
ment of 3-fluorophenyl (R1) of triazine 7 with 4-fluorophenyl (14)
resulted in an increase in antibacterial activity especially against
S. epidermidis and B. cereus, as well as reasonable activity against
C. albicans and A. niger. Also, an analogue of (14) was synthesized
in which R2 was the 3-pyridyl group (19). As in the case of com-
pounds 18 and 20, activity declined against the selected organisms
upon replacement of fluorophenyl with 3-pyridyl substituent. Di-
rect substitution of the triazine ring with 3-fluorophenyl at position
R and R2, maintaining pentylamine at R1 (31), resulted in an in-
crease in activity against S. epidermidis and C. albicans compared
to 7. An analogue of (14) was synthesized in which R1 is tyramine
(11) instead of 4-fluorophenyl. This compound possessed antibacte-
rial activity comparable with triazine 7 for S. epidermidis and B. cer-
eus. Similar antifungal results were obtained by replacement of the
R2 substituent of 11 (3-fluorophenyl) by 4-fluorophenyl (compound
10). The corresponding analogue with R2 4-fluoroaniline (5) yields
reduced activity. Interestingly, introduction of rigidity in R of tri-
azine 11 (compound 12) slightly improves the antibacterial and
the antifungal activities. However, replacement of R2 (3-fluoro-
phenyl) of 12 by 4-fluorophenyl 13 resulted in reduction of activity.
In summary, a number of low molecular weight synthetic mol-
ecules of structural type 2-(fluorophenyl)-4,6-disubstituted
[1,3,5]triazines (1) were prepared and evaluated for their antimi-
crobial activity against various gram-positive bacteria and fungi.
Three lead compounds 14, 15 and 25 displayed the best activity
against the five selected organisms. SAR studies demonstrate the
importance of the presence of at least one substituent such as a
3- or 4-fluorophenyl group attached directly to the triazine ring.
Also, it can be seen that a rigid diamine at one of the triazine sub-
stituents is preferred since activity is increased by introducing
rigidity at this position. This class of compounds is safe, nontoxic9
and displayed promising antimicrobial activity.
9. Unpublished results.
10. The purity and identity of all the products were monitored by LC/MS at 210 or
250 nm (Agilent 1100) using an analytical C18 column (75 Â 4.6 mm, 5
lm)
with a gradient of CH3CN–H2O (15–99%/10 min) containing 0.01% TFA as the
eluant. All compounds demonstrated >98% purity. 1H NMR and ESI-MS
characterization data were consistent with the expected structures. For
example, data for compound 7: 1H NMR (CD3OD, 400 MHz) d: 8.12 (d,
J = 7.8 Hz, 1H), 8.04 (d, JHF = 9.6 Hz, 1H), 7.72–7.79 (m, 1H), 7.67 (ddd, J = 8.0,
8.0, 5.7 Hz, 1H), 7.51 (ddd, J = 8.2, 8.2, 2.0 Hz, 1H), 7.38–7.45 (m, 2H), 6.96–7.01
(m, 1H), 3.61 (t, J = 7.0 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 1.83–1.95 (m, 2H), 1.73
(tt, J = 7.6, 7.6 Hz, 2H), 1.50–1.58 (m, 2H). 19F NMR (CD3OD, 377 MHz) d:
À113.45 to À113.35 (m, 1F), À113.99 (s, 1F). LRMS (ESI): m/z 385.2 (MH+).
HPLC: tR = 4.86 min; (254 nm) 100%.
Data for compound 14: 1H NMR (CD3OD, 400 MHz) d: 8.09 (d, J = 8.0 Hz, 1H),
8.02 (d, J = 8.6 Hz, 1H), 7.62–7.74 (m, 3H), 7.51 (dd, J = 8.6, 8.0 Hz, 1H), 7.19 (dd,
JHF = 8.7 Hz, JHH = 8.7 Hz, 2H), 3.56 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H),
1.66–1.79 (m, 4H), 1.33–1.54 (m, 2H). 19F NMR (CD3OD, 377 MHz) d: À113.47
(s, 1F), À118.70 (s, 1F). LRMS (ESI): m/z 385.2 (MH+). HPLC: tR = 4.65 min;
(254 nm) 95.0%.
Data for compound 15: 1H NMR (CD3OD, 400 MHz) d: 8.33 (dd, JHF = 5.3 Hz,
JHH = 8.6 Hz, 2H), 7.73–7.81 (m, 1H), 7.33–7.44 (m, 4H), 6.95–7.00 (m, 1H), 3.60
(t, J = 7.1 Hz, 2H) , 2.94 (t, J = 7.5 Hz, 2H), 1.69–1.83 (m, 4H), 1.50–1.57 (m, 2H).
19F NMR (CD3OD, 377 MHz) d: À106.08 (s, 1F), À114.09 (s, 1F). LRMS (ESI): m/z
385.2 (MH+). HPLC: tR = 4.73 min; (254 nm) 100%.
Data for compound 24: 1H NMR (CD3OD, 400 MHz) d: 8.17 (d, J = 7.8 Hz, 1H),
8.07 (d, JHF = 9.6 Hz, 1H), 7.59–7.70 (m, 2H), 7.33–7.52 (m, 3H), 6.96–7.02 (m,
1H), 3.53 (s, 2H), 2.91 (s, 2H), 1.14 (s, 6H). 19F NMR (CD3OD, 377 MHz) d:
À114.3 to À113.4 (m, 2F). LRMS (ESI): m/z 385.2 (MH+). HPLC: tR = 4.78 min;
(254 nm) 100%.
Data for compound 25: 1H NMR (CD3OD, 400 MHz) d: 8.13 (d, J = 8.0 Hz, 1H),
8.04 (d, J = 9.6 Hz, 1H), 7.74–7.84 (m, 1H), 8.04 (ddd, JHF = 5.5 Hz, JHH = 8.1,
8.1 Hz, 1H), 7.31–7.49 (m, 3H), 6.94–6.99 (m, 1H), 3.56–3.62 (m, 1H), 3.43–3.50
(m, 2H), 3.33–3.38 (m, 1H), 2.88–2.96 (m, 1H), 2.80 (t, J = 12.0 Hz, 1H), 2.24–
2.33 (m, 1H), 1.96–2.05 (m, 2H), 1.70–1.81 (m, 1H), 1.34–1.46 (m, 1H). 19F NMR
(CD3OD, 377 MHz) d: À113.90 (s, 1F), À114.26 (s, 1F). LRMS (ESI): m/z 397.2
(MH+). HPLC: tR = 4.84 min; (254 nm) 97.5%.
Data for compound 27: 1H NMR (CD3OD, 400 MHz) d: 8.11 (d, J = 7.8 Hz, 1H),
8.03 (d, JHF = 9.1 Hz, 1H), 7.76–7.83 (m, 1H), 7.67 (ddd, J = 8.0, 8.0, 5.7 Hz, 1H),
7.51 (ddd, J = 8.2, 8.2, 2.0 Hz, 1H), 7.37–7.45 (m, 2H), 6.95–7.00 (m, 1H), 3.45 (d,
J = 6.7 Hz, 2H), 2.79 (d, J = 7.0 Hz, 2H), 1.87–2.01 (m, 4H), 1.75–1.85 (m, 1H),
1.59–1.70 (m, 1H), 1.03–1.21 (m, 4H). 19F NMR (CD3OD, 377 MHz) d: À113.5 to
À113.4 (m, 1F), À114.08 (s, 1F). LRMS (ESI): m/z 425.2 (MH+). HPLC:
tR = 5.09 min; (254 nm) 100%.
Acknowledgment
We thank Lyne Marcil for the skillful preparation of this
manuscript.
Compound 31: 1H NMR (CDCl3, 400 MHz) d: 8.39 (br s, 3H), 8.26–8.71 (m, 2H),
8.11–8.16 (m, 2H), 7.67 (ddd, J = 7.8, 7.8, 5.7 Hz, 2H), 7.23–7.31 (m, 2H), 3.63–
3.69 (m, 2H), 2.98–3.06 (m, 2H), 1.81–1.86 (m, 2H), 1.70–1.77 (m, 2H), 1.58–
1.67 (m, 2H). 19F NMR (CDCl3, 377 MHz) d: À111.55 to À111.40 (m, 1F),
À112.60 to À112.55 (m, 1F). LRMS (ESI): m/z 370.2 (MH+). HPLC: tR = 5.19 min;
(254 nm) 100%.
References and notes
1. (a) Chu, D. T. W.; Plattner, J. J.; Katz, L. J. Med. Chem 1996, 39, 3853; (b) Beovic,
B. Int. J. Food Microbiol. 2006, 112, 280; (c) Finch, R.; Hunter, P. A. J. Antimicrob.
Chemother. 2006, 58, i3; (d) Suree, N.; Jung, M. E.; Clubb, R. T. Mini-Rev. Med.
Chem. 2007, 7, 991.
2. (a) Clark, A. M. Pharm. Res. 1996, 13, 1133; (b) Cowan, M. M. Clin. Microbiol. Rev.
1999, 12, 564; (c) Rex, J. H.; Walsh, T. J.; Sobel, J. D.; Filler, S. G.; Pappas, P. G.;
Dismukes, W. E.; Edwards, J. E. Clin. Infect. Dis. 2000, 30, 662; (d) Sanglard, D.;
Odds, F. C. Lancet Infect. Dis. 2002, 2, 73; (e) Buzzini, P.; Arapitsas, P.; Goretti,
M.; Branda, E.; Turchetti, B.; Pinelli, P.; Ieri, F.; Romani, A. Mini-Rev. Med. Chem.
2008, 8, 1179.
11. Bork, J. T.; Lee, J. W.; Chang, Y.-T. Tetrahedron Lett. 2003, 44, 6141.
12. Reich, M. F.; Fabio, P. F.; Lee, V. J.; Kuck, N. A.; Testa, R. T. J. Med. Chem. 1989, 32,
2474.
13. The activity of amphotericin B against C. albicans is not directly associated with
extracellular calcium concentration: (a) Rogers, P. D.; Kramer, R. E.; Crews, J. K.;
Lewis, R. E. J. Antimicrob. Chemother. 2003, 51, 305; In vitro activities of
amphotericin-B in combination with rifampin against Aspergillus species: (b)
Zarrin, M.; Najafi, M. R. Pak. J. Med. Sci. 2007, 23, 323.
3. Blotny, G. Tetrahedron 2006, 62, 9507. and references cited therein.
4. Baliani, A.; Bueno, G. J.; Stewart, M. L.; Yardlev, V.; Brun, R.; Barrett, M. P.;
Gilbert, I. H. J. Med. Chem. 2005, 48, 5570.