Novel hybrids of fluconazole and furanones: Design, synthesis and antifungal activity

Article abstract of DOI:10.1016/j.bmcl.2011.06.022

During our efforts to develop new antifungal agents, a number of hybrid molecules containing furanones and fluconazole pharmacophores were designed and synthesized. The new chemical entities thus synthesized were tested for their potential as antifungal a

Full text of DOI:10.1016/j.bmcl.2011.06.022

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4873–4878
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel hybrids of fluconazole and furanones: Design, synthesis
and antifungal activity
Hanumant B. Borate a, , Sangmeshwer P. Sawargave a, Subhash P. Chavan a, Mohan A. Chandavarkar b,
⇑
Ramki Iyer b, Amit Tawte b, Deepali Rao b, Jaydeep V. Deore a, Ananada S. Kudale a, Pankaj S. Mahajan a,
Gopinath S. Kangire a
a Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b FDC Ltd, 142-148, S.V. Road, Jogeshwari (W), Mumbai 400 102, India
a r t i c l e i n f o
a b s t r a c t
Article history:
During our efforts to develop new antifungal agents, a number of hybrid molecules containing furanones
and fluconazole pharmacophores were designed and synthesized. The new chemical entities thus synthe-
sized were tested for their potential as antifungal agents against various fungal strains and it was
observed that the compounds with general structure 7 were potent inhibitors of Candida albicans ATCC
24433, Candida glabrata ATCC 90030, Candida tropicalis ATCC 750 and Candida neoformans ATCC 34664
while the fluconazole analogues 12 exhibited antifungal activity against Candida albicans ATCC 24433
and Candida glabrata ATCC 90030. The structure–activity relationship for these compounds is discussed.
The synthetic strategies used in the present work have potential to prepare a large number of compounds
for further refinement of structures to obtain molecules suitable for development as antifungal drugs.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 May 2011
Revised 3 June 2011
Accepted 8 June 2011
Available online 13 July 2011
Keywords:
Antifungal activity
Furanones
Fluconazole
In recent years there is an increase in the number of immuno-
compromised patients, such as those infected with HIV and under-
going organ transplantations or cancer chemotherapy and they
have to undergo long term antifungal therapy to fight against
opportunistic fungi. Though there are effective antifungal agents
available in the market, they have quite a few shortcomings such
as toxicity, limited range of activity for the fungal strains, high
price and limited penetration through central nervous system.
Also, the extensive use of antifungal agents like fluconazole (1)1,2
(Fig. 1) has increased the number of resistant fungi due to muta-
tions. This has made it necessary to design and synthesize new
drugs that can be used in place of current antifungal drugs like
amphotericin B or azole antifungals, for example, fluconazole (1),
against the mutated resistant fungal strains and as a result of
world-wide efforts, a number of fluconazole analogues have been
reported.3
As a part of our efforts3i,6a–f to develop new antifungal drugs, we
are in a process of exploring potential of various classes of com-
pounds. During the course of our work, we synthesized a number
of furanones 2b for structure–activity relationship study from
substituted phenylacetic acids via the intermediates 2c by a novel
synthetic strategy6a,f and observed that these compounds exhibited
good antifungal activity against Candida, Aspergillus or Fusarium
strains. It was also observed (Unpublished results) that some of
the compounds from this group exhibited antifungal activity against
various strains of dermatophytes like Microsporum, Trichophyton,
Epidermophyton etc. During the esterification of 2c, many times
we used to get the corresponding 5-methylene-3-aryl-2,5-dihydro-
furan-2-ones 3 in considerable amounts. The 5-methylene-furanon-
es 3 used to polymerize/decompose in a few days and hence were
not suitable for further development as antifungal drugs. Therefore,
we felt it necessary to modify these molecules in order to get stable
molecules and evaluate their potential as antifungal agents.
Also, it is known in literature that structural features of mole-
cules from two different classes having a particular biological activ-
ity can be combined to generate novel molecules with increase in
that particular biological activity in some cases.7 The research in
this direction in the area of antifungal activity has resulted in some
promising candidates suitable for further development for exam-
ple, Jiang and co-workers8 reported that ZJ-522 (5), a hybrid of
fluconazole (1) and butenafine (6), was about 50-fold more potent
than fluconazole against yeasts and 2- to 16-fold more potent than
fluconazole against filamentous fungi (Fig. 2).
Furanones are known to exhibit antifungal activity and there
are a number of papers describing synthesis, structure–activity
relationship study and modifications of various antifungal fura-
nones 2 and 3 based on structural features of incrustoporin (4).4
A recent publication by Pour and co-workers5 describing antifungal
activity
of
5-methylene-3-aryl-2,5-dihydrofuran-2-ones
3
prompted us to report our work in this field.
⇑
Corresponding author. Tel.: +91 20 25902546; fax: +91 20 25902629.
E-mail address: hb.borate@ncl.res.in (H.B. Borate).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.022

4874
H. B. Borate et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4873–4878
OH
O
Me
R
N
N
N
N
N
O
O
R
N
O
F
O
O
OR1
2a: R=Halo, dihalo, R1=COR2
Me
F
Fluconazole ( )
wherein R2=alkyl, aryl
3
4
Incrustoporin ( )
1
2b: R=Halo, methoxy-halo, dihalo,
R1=COR2 wherein R2=Allyl, (un)substituted
alkyl, (un)substituted aryl, pyrrolyl
2c: R=Halo, methoxy-halo, dihalo, R1=H
Figure 1. Structures of fluconazole, incrustoporin and incrustoporin analogues 2 and 3.
OH
F
N
N
F
N
The synthetic strategy employed for the preparation of the
fluconazole analogues 9a–c containing trisubstituted furanones is
shown in Scheme 3.
N
N
The reaction13 of aldehyde 12 with furanones 18a–c12 in meth-
anol in presence of piperidine afforded the desired fluconazole
analogues 9a–c respectively.
5: ZJ-522
6: Butenafine
Figure 2. Structures of ZJ-522 and butenafine.
It is known in literature10b that compounds having azlactone
moiety exhibit antifungal activity. The azlactones 13a–d were pre-
pared and screened for antifungal activity as analogues of hybrid
molecules 7, by synthetic sequence elucidated for 13a in Scheme 1,
by employing required substituted benzaldehyde that is, 4-
hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 3,5-
dimethoxy-4-hydroxybenzaldehyde and 3-hydroxy-4-methoxy-
benzaldehyde respectively (Fig. 4).
For further structure–activity relationship study, hybrid mole-
cules 19 containing 2-thioxothiazolidin-4-one moiety were pre-
pared14a as there are reports14b,c that the molecules containing
this structural feature exhibit antifungal activity. The reactions
used for preparation of these molecules, starting from the alde-
hydes 12 and rhodanine 20, are shown in Scheme 4.
New drug development is a lengthy process and a slight change
in structure of a particular molecule results in dramatic increase/
decrease in biological activity in many cases making it necessary
to screen various molecules with similar structural features and
study the structure–activity relationship. The hybrid molecules de-
scribed in the present work are novel compounds prepared in an
effort to come out with new antifungal drugs effective against var-
ious fungal strains. The concept involves the incorporation of var-
ious pharmacophores in a single molecule with the intention of
developing new compounds with dual drug action that is, single
drug capable of interacting simultaneously with multiple targets.
In order to study the antifungal activity of hybrid molecules
containing furanones and fluconazole pharmacophores, new mole-
cules with general structures 7, 8, and 9 (Fig. 3) were designed. It
was found that some of the synthesized molecules exhibited signif-
icant antifungal activity against various fungal strains and the re-
sults are presented herein.
The synthetic sequence used for preparation of hybrid mole-
cules 7 containing fluconazole pharmacophores and furanones is
shown in Scheme 1. Thus, the known epoxide 109 was reacted with
hydroxybenzaldehydes 11a–b to afford the fluconazole analogues
12a–b which upon reaction10a with hippuric acid in presence of
acetic anhydride and sodium acetate provided the azlactones
13a–b. The substituted phenylacetic acids 14a–b were obtained
by subjecting the azlactones 13a–b to heating with sodium
hydroxide followed by reaction with hydrogen peroxide in pres-
ence of sodium hydroxide at room temperature.10a The reaction11
of phenylacetic acids 14a–b with suitable chloroketones in pres-
ence of potassium carbonate afforded the desired hybrid molecules
7. The structures of these molecules were confirmed by spectral
methods.
The hybrid molecules synthesized were screened15 for anti-
fungal activity (Table 1) against Candida albicans ATCC 24433, Can-
dida glabrata ATCC 90030, Candida krusei ATCC 6258, Candida
tropicalis ATCC 750, Candida neoformans ATCC 34664, Aspergillus
fumigatus ATCC 46645, Aspergillus niger ATCC 16404 and Fusarium
proliferatum ATCC 10052. The compounds screened were racemic
and the chemical purity of the compounds prepared was checked
by HPLC and only the compounds with purity in the range of 95–
100% were screened for antifungal activity. It was found that the
compounds with general structure 7 exhibited very good anti-
fungal activity against C. albicans ATCC 24433 and C. glabrata ATCC
90030 and many compounds from this class had MIC50 values
comparable to fluconazole (Table 1, entries 3–12) indicating that
the replacement of one of the triazoles in fluconazole with the
groups present in the molecules 7 is tolerated. The compounds
from this class exhibited significant antifungal activity against C.
tropicalis ATCC 750 and C. neoformans ATCC 34664 also.
The fluconazole analogues with general structure 12a–d exhib-
ited antifungal activity against C. albicans ATCC 24433 and C. glab-
rata ATCC 90030 (Table 1, entries 13–16) while the corresponding
azlactones 13a–d showed no antifungal activity12 showing that
conversion of aldehyde moiety into the azlactone is not tolerated.
The fluconazole analogues 19a–b exhibited good antifungal activ-
ity against C. albicans ATCC 24433 (Table 1, entries 18 and 19)
while the compounds 19c–d did not show any antifungal activity12
against the fungal strains studied in the present work. The fura-
nones 16a and 17a exhibited good antifungal activity against C.
albicans ATCC 24433 and C. glabrata ATCC 90030 but they did not
exhibit any antifungal activity against rest of the fungal strains
studied in the present work.
The significant antifungal activity5 exhibited by compounds
with general structure 3 with exocyclic double bond prompted
us to synthesize the hybrid molecules 8 containing furanones with
exocyclic double bonds employing the synthetic strategy12 shown
in Scheme 2. The interesting observation was that this class of
compounds did not undergo elimination of tertiary hydroxyl group
present at the benzylic carbon.
The compound 8a decomposed in a few days at rt. The other
compounds from this class (8b and 8c) were also found to decom-
pose slowly at rt.

H. B. Borate et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4873–4878
4875
R4
O
R2
R3
R2
O
R1
D
R1
O
O
OH
C
OH
F
N
A
N
O
O
O
F
R1
N
OH
F
N
N
R2
O
F
N
N
O
F
N
N
B
F
7
8
9
Figure 3. Structures of fluconazole analogues 7, 8, and 9.
O
R1
O
O
F
N
H
R1
N
OH
H
N
+
N
K2CO3, TBAB,
EtOAc, 80 oC
N
F
O
F
Hippuric acid, Ac2O, NaOAc,
80 oC, 2 h
N
HO
11a: R1=H
10
12a: R1=H
11b: R1=OMe
12b: R1=OMe
F
R1
OH
O
OH
O
R1
a) Aq. NaOH, 85 oC
b) H2O2, aq. NaOH,
RT, 15 h
N
O
N
O
OH
N
N
N
N
O
F
F
N
1
13a: R1=H
14a
: R =H
F
1
1
14b
: R =OMe
13b
F
: R =OMe
R2
D
R1
O
R2COCH2Cl, K2CO3,
MeCN, reflux, 1-6 h
OH
C
N
O
N
A
O
F
N
7a: R1=H, R2=phenyl
7b: R1=H; R2=4-methoxyphenyl
B
F
1
2
7c
7d
: R =H; R =4-methylphenyl
1
2
: R =H; R =4-fluorophenyl
7e: R1=H; R2=2,4-difluorophenyl
7f: R1=H; R2=4-bromophenyl
7g: R1=OMe; R2=4-fluorophenyl
1
2
7h
: R =OMe; R =4-bromophenyl
1
2
7i
: R =OMe; R =2,4-difluorophenyl
7j: R1=H; R2=2-thienyl
Scheme 1. Synthesis of fluconazole analogues 7.
The above results indicated following points regarding the
structure–activity relationship of the compounds studied in the
present work.
pound nos 7a v/s 7d or 7e) while the 4-methoxy, 4-methyl or
4-bromo substituent reduced the antifungal activity slightly
(compound nos 7a v/s 7b, 7c or 7f).
4. The replacement of phenyl ring at 4-position of the furanone
ring D in 7 with a thiophene ring did not have any effect on anti-
fungal activity showing that the phenyl and thiophene moieties
are bioisosteric (compound no 7a v/s 7j).
5. The fluconazole analogues 12 exhibited antifungal activity of
varying degree. The compounds 12a–c containing phenyl ring
with aldehyde functionality at para position exhibited anti-
fungal activity against C. albicans ATCC 24433 and C. glabrata
ATCC 90030 while the analogue 12d with phenyl ring having
aldehyde functionality at meta position exhibited less anti-
fungal activity (Table 1, entries 13–16).
1. The hybrid molecules with general structure 7 exhibited very
good antifungal activity against C. albicans ATCC 24433 and C.
glabrata ATCC 90030 and significant antifungal activity against
C. tropicalis ATCC 750 and C. neoformans ATCC 34664.
2. The introduction of methoxy group on the aromatic ring C adja-
cent to fluconazole pharmacophores in the molecules with gen-
eral structure 7 decreased the antifungal activity (compound
nos 7d v/s 7g, 7e v/s 7i and 7f v/s 7h).
3. The substituents on the phenyl ring at 4-position of the fura-
none ring D in compounds 7 also affected the antifungal activity
to some extent. The 4-fluoro or 2,4-difluoro groups on this phe-
nyl ring were tolerated and the resultant compounds exhibited
antifungal activity similar to the parent compound 7a (com-
6. The antifungal activity of compounds 12a–d was lost com-
pletely when the aldehyde functionality was converted into
an azlactone moiety.12

4876
H. B. Borate et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4873–4878
R1
R2
OH
OH
F
N
O
O
N
O
F
O
N
OH
N
+
R1
O
K2CO3, MeCN,
80 oC, 6 h
N
O
F
Br
N
R2
1
2
14
15a
: R =R =F
16a: R1=R2=F
F
R1
R1
R2
OH
O
R2
PTSA, toluene,
110 oC, 5 h
DBU, MeCN,
air, RT
O
O
OH
F
OH
F
N
N
N
O
N
N
O
F
O
F
N
1
2
8a
: R =R =F
: R =Br, R =H
1
2
8b
1
2
8c: R1=Cl, R2=H
17a
: R =R =F
Scheme 2. Synthesis of fluconazole analogues 8.
R4
O
R3
R3
R4
O
O
O
H
Piperidine,
O
OH
F
methanol, RT, 15 h
N
R1
OH
N
N
N
N
R2
O
F
O
F
+
N
R1
R2
12
9a: R1=R2=F, R3=Cl, R4=H
9b: R1=R2=F, R3=R4=Cl
1
2
3
4
18a
: R =R =F, R =Cl, R =H
F
18b: R1=R2=F, R3=R4=Cl
1
4
2
3
9c
: R =R =H, R =Br, R =OMe
18c: R1=R4=H, R2=Br, R3=OMe
Scheme 3. Synthesis of fluconazole analogues 9.
O
OMe
R1
OH
N
N
O
O
F
OH
F
N
N
N
N
O
F
N
R2
N
O
F
1
2
13a
13b
: R =R =H
O
1
2
: R = OMe, R =H
13c: R1=R2=OMe
13d
Figure 4. Structures of fluconazole analogues 13a–d containing azlactone moiety.
7. The conversion of the aryl aldehyde functionality of compounds
12 into arylacetic acid 14 resulted into complete loss of
activity.12
8. The antifungal activity of compounds 12a–d was decreased or
lost completely when the aldehyde functionality was converted
into compounds 19 containing 2-thioxothiazolidin-4-one
moiety12 (compound nos 12a v/s 19a, 12b v/s 19b and 12c v/s
19c).
9. The fluconazole analogues with general structure 8 were not
enough stable to screen for antifungal activity while the com-
pounds 9 were stable but did not exhibit any antifungal
activity.12
In conclusion, we have synthesized a number of compounds
with different structural features and evaluated their antifungal
activity against various fungal strains using fluconazole and

H. B. Borate et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4873–4878
4877
O
R1
R1
R2
OH
F
N
OH
F
N
N
NH
S
O
AcOH, NaOAc
O
F
N
+
N
O
F
CHO
S
R2
N
NH
S
1
2
19a
19b
S
: R =R =H
20
1
2
12a: R1=R2=H
: R =H, R =OMe
19c: R1=R2=OMe
12b: R1=H, R2=OMe
12c: R1=R2=OMe
O
NH
CHO
O
S
S
OH
N
N
O
OH
F
N
NH
S
AcOH, NaOAc
N
N
+
F
O
MeO
S
N
F
MeO
19d
20
F
12d
Scheme 4. Synthesis of fluconazole analogues 19.
Table 1
Antifungal activity data
*
Sr. no.
Compd no.
MIC50
(
lg/ml)
Ca01
Cg01
Ck01
Ct01
Cn01
An01
0.25
NI 128
NI 4
NI 8
NI 4
NI 8
NI 8
NI 8
NI 8
Afm01
Fp01
1
2
3
AMB
FLU
7a
0.25
0.25
0.5
1
0.5
0.25
0.5
0.5
0.5
1
0.25
1
0.5
1
0.5
32
NI 4
NI 8
NI 4
8
0.5
1
2
4
2
1
2
4
2
4
NI 8
2
4
8
0.5
2
NI 4
2
2
1
2
1
2
8
NI 8
NI 8
2
16
8
0.5
NI 128
NI 4
NI 8
NI 4
NI 8
NI 8
NI 8
NI 8
2
NI 128
NI 4
NI 8
NI 4
NI 8
NI 8
NI 8
NI 8
NI 4
4
7b
5
7c
1
6
7d
0.5
0.5
2
0.5
2
7
7e
8
8
8
7f
9
7g
NI 16
NI 4
NI 8
NI 8
16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
7h
7i
7j
NI 4
NI 8
NI 8
NI 4
NI 8
NI 8
1
1
NI 8
NI 8
0.5
0.5
0.5
1
2
4
0.5
1
NI 16
8
NI 4
1
2
0.5
0.5
1
1
2
4
4
8
NI 16
8
NI 4
1
12a
12b
12c
12d
13a
19a
19b
19c
14a
9a
NI 128
NI 128
NI 128
NI 128
NI 4
NI 32
NI 16
NI 16
NI 128
NI 4
NI 128
NI 128
NI 128
NI 128
NI 4
NI 32
NI 16
NI 16
NI 128
NI 4
NI 128
NI 128
NI 128
NI 128
NI 4
NI 32
NI 16
NI 16
NI 128
NI 4
128
NI 128
NI 128
NI 4
NI 32
NI 16
NI 16
NI 128
NI 4
NI 8
NI 16
64
NI 128
NI 4
8
NI 16
NI 16
64
NI 4
8
8
16
NI 4
NI 32
NI 16
NI 16
64
NI 4
4
NI 16
16a
17a
NI 8
NI 16
NI 8
NI 16
NI 8
NI 16
2
Ca01: C. albicans ATCC 24433; Cg01: C. glabrata ATCC 90030; Ck01: C. krusei ATCC 6258; Ct01: C. tropicalis ATCC 750; Cn01: C. neoformans ATCC 34664; An01: A. niger ATCC
16404; Afm01: A. fumigatus ATCC 46645; Fp01: F. proliferatum ATCC 10052.
*
The highest concentration level tested was 128
lg/ml. Some of the compounds precipitated out above certain concentration. The values of concentration till which there
was no inhibition and/or above which there was partial/complete precipitation are indicated by ‘‘NI . . .’’ for example NI 16 means that there was no inhibition till 16
lg/ml
and/or compound started precipitating out at that concentration.The values for activity data for selected compounds are given here; the values for all the compounds
screened in the present work are given in the Supplementary data.
Acknowledgments
amphotericin B as standards. The hybrid molecules 7a–j exhibited
significant antifungal activity against C. albicans ATCC 24433, C.
glabrata ATCC 90030, C. tropicalis ATCC 750 and C. neoformans
ATCC 34664 with MIC50 values comparable to fluconazole. As the
SPS thanks UGC, New Delhi for the award of senior research
fellowship. Financial support from Department of Science and Tech-
nology, New Delhi and FDC Ltd, Mumbai is gratefully acknowledged.
present MIC50 values are for racemic compounds, there is a definite
possibility of having more active compounds after preparing the
Supplementary data
corresponding enantiomers of the active compounds. Thus the
Supplementary data (experimental procedures and spectral
present work would be very useful to get potential antifungal
data for all compounds prepared for antifungal activity testing)
agents.

4878
H. B. Borate et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4873–4878
Sawargave, S. P.; Maujan, S. R.; Chandavarkar, M. A; Vaiude, S. R.; Joshi, V. A.
Indian Patent Appl. No. 1595/MUM/2007.; (d) Borate, H. B.; Maujan, S. R.;
Sawargave, S. P.; Kelkar, R. G.; Wakharkar, R. D.; Chandavarkar, M. A; Vaiude, S.
R.; Joshi, V. A. Indian Patent Appl. No. 2306/MUM/2008.; (e) Chandavarkar, M.
A.; Kulkarni, V. M.; Shivkumar, P.; Shetty, R. S.; Bapat, U. R. WO 03/068142
(2003).; (f) Jadhav, V. H. Ph.D. thesis, Pune University 2007.
associated with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2011.06.022.
References and notes
7. Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem., Int. Ed. 2003, 42, 3996.
8. Gao, P.-H.; Cao, Y.-B.; Xu, Z.; Zhang, J.-D.; Zhang, W.-N.; Wang, Y.; Gu, J.; Cao, Y.-
Y.; Li, R.-Y.; Jia, X.-M.; Jiang, Y.-Y. Biol. Pharm. Bull. 2005, 28, 1414.
9. Upadhayaya, R. S.; Jain, S.; Sinha, N.; Kishore, N.; Chandra, R.; Arora, S. K. Eur. J.
Med. Chem. 2004, 39, 579.
10. (a) Mahajan, S. S.; Pikle, R. P. Indian J. Chem., Sect. B 2006, 45B, 1554; (b)
Sandhar, R. K.; Sharma, J. R.; Manrao, M. R. Indian J. Heterocycl. Chem. 2003, 13,
119.
11. (a) Black, W. C.; Brideau, C.; Chan, C.-C.; Charleson, S.; Cromlish, W.; Gordon, R.;
Grimm, E. L.; Hughes, G.; Leger, S.; Li, C.-S.; Riendeau, D.; Thérien, M.; Wang, Z.;
Xu, L.-J.; Prasit, P. Bioorg. Med. Chem. Lett. 2003, 13, 1195; (b) Wakharkar, R. D.;
Deshpande, V. H.; Landage, A. B.; Upadhyaya, B. K. Synth. Commun. 1987, 17,
1513; (c) Caturla, F.; Amat, M.; Reinoso, R. F.; Córdoba, M.; Warrellow, G.
Bioorg. Med. Chem. Lett. 2006, 16, 3209; (d) Chen, Q.-H.; Praveen Rao, P. N.;
Knaus, E. E. Bioorg. Med. Chem. 2006, 14, 7898; (e) Zargi, A.; Praveen Rao, P. N.;
Knaus, E. E. Bioorg. Med. Chem. 2007, 15, 1056.
12. The experimental procedures and spectral data for all compounds prepared
and the activity data for all the compounds screened for antifungal activity
testing in the present work are given as Supplementary data.
13. Chavan, S. P.; Pathak, A. B.; Pandey, A.; Kalkote, U. R. Synth. Commun. 2007, 37,
4253.
14. (a) Julian, P. L.; Sturg, B. M. J. Am. Chem. Soc. 1935, 57, 1126; (b) Brown, F. C.;
Bradsher, C. K.; Morgan, E. C.; Tetenbaum, M.; Wilder, P., Jr. J. Am. Chem. Soc.
1956, 78, 384; (c) Sortino, M.; Delgado, P.; Juárez, S.; Quiroga, J.; Abonía, R.;
Insuasty, B.; Nogueras, M.; Rodero, L.; Garibotto, F. M.; Enriz, R. D.; Zacchino, S.
A. Bioorg. Med. Chem. 2007, 15, 484.
15. (a) CLSI: Reference method for broth dilution antifungal susceptibility testing
of yeasts; Approved standard, second edition M27-A2, 2002. (b) CLSI:
Reference method for broth dilution antifungal susceptibility testing of
filamentous fungi; Approved standard M38-A, 2002.
1. Richardson, K.; Brammer, K. W.; Marriott, M. S.; Troke, P. F. Antimicrob. Agents
Chemother. 1985, 27, 32.
2. Kauffman, C. A.; Carver, P. L. Drugs 1997, 53, 539.
3. (a) Giraud, F.; Guillon, R.; Logé, C.; Pagniez, F.; Picot, C.; Le Borgne, M.; Le Pape,
P. Bioorg. Med. Chem. Lett. 2000, 10, 1893; (b) Lebouvier, N.; Pagniez, F.; Duflos,
M.; Pape, P. L.; Na, Y. M.; Baut, G. L.; Borgne, M. L. Bioorg. Med. Chem. Lett. 2007,
17, 3686; (c) Zhao, Q.-J.; Hu, H.-G.; Li, Y.-W.; Song, Y.; Cai, L.-Z.; Wu, Q.-Y.; Jiang,
Y.-Y. Chem. Biodiversity 2007, 4, 1472; (d) Lebouvier, N.; Pagniez, F.; Duflos, M.;
Pape, P. L.; Na, Y. M.; Bauta, G. L.; Borgne, M. L. Bioorg. Med. Chem. Lett. 2007, 17,
3686; (e) Katritzky, A. R.; Slavov, S. H.; Dobchev, D. A.; Karelson, M. Bioorg. Med.
Chem. 2008, 16, 7055; (f) Uchida, T.; Somada, A.; Kagoshima, Y.; Konosu, T.;
Oida, S. Bioorg. Med. Chem. Lett. 2008, 18, 6538; (g) Liu, P.; Zhu, S.; Li, P.; Xie, W.;
Jin, Y.; Sun, Q.; Wu, Q.; Sun, P.; Zhang, Y.; Yang, X.; Jiang, Y.; Zhang, D. Bioorg.
Med. Chem. Lett. 2008, 18, 3261; (h) Uchida, T.; Kagoshima, Y.; Konosu, T. Bioorg.
Med. Chem. Lett. 2009, 19, 2013; (i) Borate, H. B.; Maujan, S. R.; Sawargave, S. P.;
Chandavarkar, M. A.; Vaiude, S. R.; Joshi, V. A.; Wakharkar, R. D.; Iyer, R.; Kelkar,
R. G.; Chavan, S. P.; Kunte, S. S. Bioorg. Med.Chem. Lett. 2010, 20, 722; (j) Heeres,
J.; Meerpoel, L.; Lewi, P. Molecules 2010, 15, 4129.
4. (a) Pour, M.; Špulák, M.; Balšánek, V.; Kuneš, J.; Buchta, V.; Waisser, K. Bioorg.
Med. Chem. Lett. 2000, 10, 893; (b) Pour, M.; Špulák, M.; Buchta, V.; Kubanová,
P.; Vopršalová, M.; Wsól, V.; Fáková, H.; Koudelka, P.; Pourová, H.; Schiller, R. J.
Med. Chem. 2001, 44, 2701; (c) Vale-Silva, L. A.; Buchta, V.; Vokurková, D.; Pour,
M. Bioorg. Med. Chem. Lett. 2006, 16, 2492.
5. Šenel, P.; Tichotová, L.; Votruba, I.; Buchta, V.; Špulák, M.; Kuneš, J.; Nobilis, M.;
Krenk, O.; Pour, M. Bioorg. Med. Chem. 2010, 18, 1988.
6. (a) Gurjar, M. K.; Wakharkar, R. D.; Borate, H. B.; Kelkar, R. G.; Murugan, A.;
Chandavarkar, M. A.; Joshi, S. V.; Vaiude, S. R. US Patent US 2007/0259948 A-1;
Indian Patent no: 223238 (2008).; (b) Borate, H. B.; Maujan, S. R.; Sawargave, S.
P.; Chandavarkar, M. A.; Joshi, S. V.; Vaiude, S. R. Indian Patent Appl. No. 438/
MUM/2008; PCT International Appl. No. PCT/IN08/000571.; (c) Borate, H. B.;