Synthesis and antifungal activity of novel oxazolidin-2-one-linked 1,2,3-triazole derivatives

Article abstract of DOI:10.1039/c7md00442g

Novel oxazolidin-2-one-linked 1,2,3-triazole derivatives (4a-k) were synthesized by straightforward and versatile azide-enolate (3 + 2) cycloaddition. The series of compounds was screened for antifungal activity against four filamentous fungi as well as six yeast species of Candida spp. According to their efficiency and breadth of scope, they can be ordered as 4k > 4d > 4h > 4a, especially in relation to the activity displayed against Candida glabrata ATCC-34138, Trichosporon cutaneum ATCC-28592 and Mucor hiemalis ATCC-8690, i.e. compounds 4d, 4h and 4k showed excellent activity against C. glabrata (MIC 0.12, 0.25 and 0.12 μg mL^-1, respectively), better than that of itraconazole (MIC 1 μg ml^-1). The activity of compound 4d (MIC = 2 μg mL^-1) was higher than that observed for the standard antifungal drug (MIC = 8 μg mL^-1) against Trichosporon cutaneum, while compound 4k displayed an excellent antimycotic activity against Mucor hiemalis (MIC = 2 μg mL^-1vs. 4 μg mL^-1 for itraconazole). In addition, we describe herein a novel mild and eco-friendly synthetic protocol for obtaining β-ketosulfones (adducts to afford compounds 4a-k) from α-brominated carbonyls in an aqueous nanomicellar medium at room temperature.

Full text of DOI:10.1039/c7md00442g

View Article Online
View Journal
MedChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Ramírez-
Villalva, D. González-Calderón, R. Rojas-García, C. González-Romero, J. TAMARIZ, M. Morales-
Rodríguez , N. Zavala-Segovia and A. Fuentes-Benítes, Med. Chem. Commun., 2017, DOI:
10.1039/C7MD00442G.
This is an Accepted Manuscript, which has been through the
Volume 7 Number 1 January 2016 Pages 1–204
Royal Society of Chemistry peer review process and has been
accepted for publication.
MedChemComm
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Broadening the field of opportunity for medicinal chemists
www.rsc.org/medchemcomm
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
Themed issue: Antibiotic Resistance
ISSN 2040-2503
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
rsc.li/medchemcomm

Page 1 of 10
MedChemComm
View Article Online
DOI: 10.1039/C7MD00442G
Synthesis and antifungal activity of novel oxazolidinꢀ2ꢀone linkedꢀ
1,2,3ꢀtriazole derivatives
Alejandra RamírezꢀVillalva 1, Davir GonzálezꢀCalderón 1, Roxana I. RojasꢀGarcía 1, Carlos
GonzálezꢀRomero 1, Joaquín TamarízꢀMascarúa 3, Macario MoralesꢀRodríguez 2, Nieves
ZavalaꢀSegovia 4 and Aydeé FuentesꢀBenítes 1,*
1
Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo
Tollocan s/n, Toluca, Estado de México, 50120, Mexico.
2
Departamento de Microbiología, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo
Tollocan s/n, Toluca, Estado de México, 50120, Mexico.
3
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y
Plan de Ayala, Ciudad de México, 11340, México.
4
Centro Conjunto de Investigación en Química sustentable UAEM-UNAM. Carretera Toluca-Atlacomulco Km 14.5 Toluca, 52000,
México.
∗ Corresponding authors: Tel: +52 722 217 5109x113; Fax: +52 722 217 3890; Eꢀmail addresses: mpagfuentesb@uaemex.mx (A.
FuentesꢀBenítes).
[ABSTRACT] Novel oxazolidinꢀ2ꢀone linkedꢀ1,2,3ꢀtriazole derivatives (4a–k) were synthesized by
straightforward and versatile azideꢀenolate (3+2) cycloaddition. The series of compounds was screened for
antifungal activity against four filamentous fungi as well as six yeast species of Candida spp. According to
their efficiency and breadth of scope, they can be ordered as 4k>4d>4h>4a, especially in relation to the activity
displayed against Candida glabrata ATCCꢀ34138, Trichosporon cutaneum ATCCꢀ28592 and Mucor hiemalis
ATCCꢀ8690, i.e. compounds 4d, 4h and 4k showed excellent activity against C. glabrata (MIC 0.12, 0.25 and
0.12 ꢁg/mL, respectively), better than that of itraconazole (MIC 1 ꢁg/ml). The activity of compound 4d (MIC =
2 ꢁg/mL) was higher than that observed for the standard antifungal drug (MIC = 8 ꢁg/mL) against
Trichosporon cutaneum, while compound 4k displayed an excellent antimycotic activity in Mucor hiemalis
(MIC = 2 ꢁg/mL vs 4 ꢁg/mL for itraconazole). In addition, we describe herein a novel mild and ecoꢀfriendly
synthetic protocol for the obtaining of βꢀketosulfones (adducts to afford compounds 4a–k) from αꢀbrominated
carbonyls in aqueous nanomicellar medium at room temperature.
[Keywords] oxazolidinꢀ2ꢀone derivatives; 1,2,3ꢀTriazole derivatives; Antifungal activity; Azideꢀenolate
cycloaddition
1. Introduction
Both oxazolidinꢀ2ꢀone [1] and 1,2,3ꢀtriazole [2] cores are very wellꢀrecognized pharmacophores in
literature. They have become extremely versatile in medicinal chemistry, featuring a number of clinically used

MedChemComm
Page 2 of 10
View Article Online
DOI: 10.1039/C7MD00442G
drugs (e.g. Linezolid 1 or Tazobactam 2, Figure 1). Consequently, several antimicrobials based on one or the
other scaffold, have been reported in literature [3]. On the other hand, the study of both cores in the same
molecule (3) as an antibacterial has been reported [4] and patented (e.g. 3a [5] and 3b [6]). In this year ꢀ2017ꢀ
Melinta Therapeutics Inc. announces FDA acceptance of Investigational New Drug (IND) application for
topical Radezolid 3c, a secondꢀgeneration oxazolidinone/triazole discovered by Melinta scientists as novel
antibiotics to treat serious bacterial infections [7]. Curiously, antifungal activity has not been demonstrated for
these kinds of compounds, to the best of our knowledge.
Despite the mechanism of action of oxazolidinones [8] and triazole [9] cores has been described, the inhibition
of monoamine oxidase A (MAOꢀA) [4a] as well as the RNAꢀbinding process [4g] have been proposed as mode
of action for oxazolidinꢀ2ꢀone linkedꢀ1,2,3ꢀtriazole.
Due to the strong resistance of fungi to current drugs, there is a continuous search for antifungal agents. As
part of our ongoing research, we herein describe the synthesis and biological evaluation of novel oxazolidinꢀ2ꢀ
one linkedꢀ1,2,3ꢀtriazole 4 derivatives.
2. Chemistry
Our initial study began by obtaining starting materials, azide/oxazolidinꢀ2ꢀone 8 and ketones 11 (Scheme
1). Firstly, chlorine derivative 7 was synthesized (61%) by the coupling between 2ꢀchloroethyl isocyanate 6
and benzoin 5 [10]. Subsequently, the nucleophilic substitution of 7 by the azide ion furnished compound 8
(58%).

Page 3 of 10
MedChemComm
View Article Online
DOI: 10.1039/C7MD00442G
Figure 1. The novel series of compounds 4 involves the extremely important oxazolidinꢀ2ꢀone and 1,2,3ꢀtriazole pharmacophoric
cores. A similar feature is found in antimicrobial oxazolidinꢀ2ꢀone linkedꢀ1,2,3ꢀtriazole 3, including lead compounds 1 and 2.
Ketones 11a–11g were synthesized since, unlike 11i–11j, they are not commercially available (ketone 11h
was kindly donated by SyntexꢀLa Roche). For these purposes, we have developed a novel organic solventꢀfree
synthesis of βꢀketosulfones in aqueous nanomicellar medium by the concomitant use of the surfactant reagent
SPGSꢀ550ꢀM or ‘Nok’ (now available from SigmaꢀAldrich [11]) and sodium pꢀtoluenesulfinate from αꢀ
bromoketones. The surfactant nature of NOK (a third generation surfactant) allows it to act as an efficient
nanoreactor in catalytic amounts. The study and scope of this novel methodology is described in the electronic
supplementary information (ESI) in greater detail. Therefore, we decided to apply such methodology in the
synthesis of compound 11 from 10, which in turn was accomplished by the reported protocols [12] with Nꢀ
bromosuccinimide (NBS) as the bromine source.

MedChemComm
Page 4 of 10
View Article Online
DOI: 10.1039/C7MD00442G
OH
Ph
Cl
O
O
Ph
(i)
(ii)
O
5
N3
O
N
Cl
O
N
+
Ph
Ph
Ph
Ph
NCO
7 (61%)
8 (58%)
6
O
O
O
O
O
(iv)
(iii)
S
Br
R2
R2
R2
11a (91%)
10a (82%)
9a: R2= Ph
11b
11c
(87%)
(84%)
10b
10c
(80%)
(84%)
2
9b
: R = -CH Ph
p
3
2
9c
: R = -NO Ph
9d: R2= -NO Ph
p
11d (81%)
10d (81%)
10e
2
11e
(79%)
11f (92%)
11g
(80%)
10f (77%)
10g
m
p
2
2
9e
: R = -Cl-Ph
(90%)
(80%)
9f: R2= thiophen-2-yl
2
9g
: R = 5-chlorothiophen-2-yl
Scheme 1. Reagents and conditions: (i) N2, 180 ºC, 24 h. (ii) NaN3 (1.1 eq), DMF anh., 60 ºC, 12 h, N2. (iii) NBS (1.1 eq),
TsOH•H2O (1.0 eq), MeCN, 60 ºC, 4 h. (iv) SPGSꢀ550ꢀM aq. (2% w/w), pꢀTolꢀSO2Na (1.5 eq), r.t., 12 h.
Table 1
Synthesis of oxazolidinꢀ2ꢀone linkedꢀ1,2,3ꢀtriazoles 4a–k from azide 8 by the
coupling with active ketones 11.
O
N
N
O
DBU
R1
O
N
N
8
R1
+
R2
DMF anh.
50-60 ºC
12 h
11
R2
Ph
Ph
4
Triazoleb
Entrya
Ketone
11a: R2= Ph, R1= SO2ꢀpꢀTol
11b: R2= p-CH3Ph, R1= SO2ꢀpꢀTol
11c: R2= pꢀNO2ꢀPh, R1= SO2ꢀpꢀTol
11d: R2= mꢀNO2Ph, R1= SO2ꢀpꢀTol
11e: R2= pꢀClꢀPh, R1= SO2ꢀpꢀTol
(Yield%)c
4a (68)
4b (61)
4c (74)
4d (70)
4e (72)
4f (68)
1
2
3
4
5
6
11f: R2= thiophenꢀ2ꢀyl, R1= SO2ꢀpꢀTol
4g (64)
4h (71)
4i (73)
4j (71)
4k (67)
7
11g: R2= 5ꢀchlorothiophenꢀ2ꢀyl, R1= SO2ꢀpꢀTol
11h: R2= Pentyl, R1= SO2Ph
11i: R2= CH3, R1= COCH3
11j: R2= Ph, R1= COPh
11k: R2= Ph, R1= CN
8
9
10
11
a Reaction conditions: To a solution of compound 8 (1.0 eq) and 11 (1.0 eq) in DMF anh. was
added (2.0 eq) to DBU. The reaction mixture was stirred at 50ꢀ60 ºC for 12–24 h.
b Confirmed by 1HꢀNMR, 13CꢀNMR and MS.
c Yields refer to chromatographically pure isolated compounds.
Although Cuꢀcatalyzed azideꢀalkyne cycloaddition (CuAAC) is the conventional method for obtaining
1,2,3ꢀtriazole moieties [13], other strategies have emerged as alternatives for such a purpose. We previously

Page 5 of 10
MedChemComm
View Article Online
DOI: 10.1039/C7MD00442G
reported [14] a novel synthetic protocol to achieve the efficient assembly of 1,4,5ꢀtrisubstituted 1,2,3ꢀtriazole
cores through an azide–enolate cycloaddition. In consequence, oxazolidinꢀ2ꢀone linkedꢀ1,2,3ꢀtriazole 4
derivatives were synthesized by the efficient 1,3ꢀdipolar cycloaddition of azide/oxazolidinꢀ2ꢀone in the
presence of enolates prepared in situ from ketones 11 activated by DBU as base. Table 1 summarizes these
outcomes.
3. Microbiology
Compounds 4a-k were tested for their in vitro activity against four filamentous fungi: Aspergillus
fumigatus ATCCꢀ16907, Trichosporon cutaneum ATCCꢀ28592, Rhizopus oryzae ATCCꢀ10329 and Mucor
hiemalis ATCCꢀ8690. These compounds were also evaluated, employing standardized microbiological
methods developed by the CLSI, against six yeast specimens: Candida albicans ATCCꢀ10231, Candida utilis
ATCCꢀ9226, Candida tropicalis ATCCꢀ13803, Candida parapsilopsis ATCCꢀ22019, Candida glabrata
ATCCꢀ34138, and Candida krusei ATCCꢀ14243. Then, the sensitivity of the filamentous microorganisms was
determined by the microdilution M38ꢀA method [15], and that of the yeast fungi with the M27ꢀA3 method
[16].
Such antifungal activity was compared to that of itraconazole as the standard antifungal drug. The
minimum inhibitory concentration (MIC) values of the standard and compounds 4a-k, expressed in
micrograms per milliliter, were determined in 96ꢀwell plates using MOPS (3ꢀ [Nꢀmorpholino] propanesulfonic
acid buffered RPMIꢀ1640 medium, Sigmaꢀ Aldrich).
4. Results and discussion
The antifungal activity of the test compounds is summarized in Table 2. Compounds 4d, 4h and 4k showed
excellent activity against C. glabrata (MIC 0.12, 0.25 and 0.12 ꢁg/mL, respectively), better than that of
itraconazole (MIC 1 ꢁg/ml). The activity of compound 4d (MIC = 2 ꢁg/mL) was higher than that observed for
the standard antifungal drug (MIC = 8 ꢁg/mL) against Trichosporon cutaneum, while compound 4k displayed
an excellent antimycotic activity in Mucor hiemalis (MIC = 2 ꢁg/mL vs 4 ꢁg/mL for itraconazole). Compounds
4a, 4c and 4e proved to be moderate antifungal agents against Aspergillus fumigatus strains. The current results
suggest that the presence of either a ꢀCN or pꢀNO2Ph group at position 5 of the triazole cores increases the
biological activity of these compounds in both yeast and filamentous fungi.
These outcomes can also be described by ‘sensitivity’ parameters of yeasts, according to the breakpoints
described in the M27ꢀA3 document (Table 3). In general, C. glabrata, C. krusei and C. parapsilosis showed

MedChemComm
Page 6 of 10
View Article Online
DOI: 10.1039/C7MD00442G
some susceptibility to the test compounds, whereas C. albicans, C. tropicalis and C. utilis were resistant to all
of them.
5. Conclusion
In summary, eleven oxazolidinꢀ2ꢀone linkedꢀ1,2,3ꢀtriazole 4a–k derivatives were synthesized in good yields
based on the azideꢀenolate 1,3ꢀdipolar cycloaddition. In vitro assays demonstrated that compound 4k is the
most efficient antimicrobial agent, since it was either better than or comparable to itraconazole against three
species (C. glabrata, M. hiemalis and T. cutaneum). The second best antimicrobial activity was evidenced by
compound 4d, which was much better against two species (C. glabrata and T. cutaneum) than the reference
drug. In consequence, these ones can be considered as drug candidates for future complementary biological
studies. In addition, we have developed a novel organic solventꢀfree synthesis of βꢀketosulfones with aqueous
nanomicellar medium. The surfactant nature of SPGSꢀ550ꢀM or ‘NOK’ (a third generation surfactant) allows it
to act as an efficient nanoreactor in catalytic amounts. The notable advantages of this methodology over those
previously reported include its simplicity of handling, mild conditions, high yields, cheap reagents and great
tolerance of functional groups.
TABLE 2.
In vitro antifungal activities of synthetized compounds (MIC, µg/mL)
Compound
C. alb
C. trop
C. uti
C. kru
C. gla
C. par
M. hie
4
A. fum T. cut
R. ory
16
16
16
16
16
16
16
16
8
4a
8
1
8
8
8
4
0.5
8
1
2
8
0.25
8
2
8
8
8
8
2
8
8
8
8
8
8
8
8
4b
16
16
16
16
16
16
16
16
16
2
4c
4
8
4
0.25
8
4
2
4d
8
8
8
0.12
4
0.5
8
16
4
4e
8
8
8
8
4f
8
8
8
8
1
8
8
4g
8
8
8
2
2
4
16
16
16
16
16
1
4h
8
8
8
8
0.25
2
8
4i
4j
8
8
8
8
4
8
8
8
8
2
8
16
16
1
4k
8
8
8
0.5
0.25
0.12
1
8
Standarda
0.03
0.06
0.25
0.06
4
Abbreviations: C. alb., Candida albicans; C. trop., Candida tropicalis; C. uti., Candida utilis; C. kru., Candida krusei; C.gla., Candida glabrata, C.
par., Candida parapsilosis; M. hie., Mucor hiemalis; A. fum., Aspergillus fumigatus; T. cut., Trichosporon cutaneum; R. ory., Rhizopus oryzae.
a Itraconazole.
Table 3
Determination of the sensitivity of yeast (according to document M27ꢀA3): Susceptible (S), doseꢀdependent
sensitive (SDD) and resistant (R).
Compound
C. alb
C. trop
C. uti
C. kru
C. gla
C. par
R
R
R
R
R
R
R
R
R
R
R
R
SDD
R
SDD
R
R
R
R
S
R
SDD
R
SDD
4a
4b
4c
4d

Page 7 of 10
MedChemComm
View Article Online
DOI: 10.1039/C7MD00442G
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
SDD
R
R
R
R
R
R
4e
4f
4g
4h
4i
R
R
S
R
R
S
R
R
SDD
R
SDD
SDD
R
S
R
R
R
S
4j
4k
Standarda
Abbreviations: C. alb., Candida albicans; C. trop., Candida tropicalis; C. uti., Candida utilis; C. kru., Candida krusei;
C.gla., Candida glabrata, C. par., Candida parapsilosis.
a Itraconazole. Interpretive criteria: Breakpoints (MIC, µg/mL) = 0.12 [S], 0.25–0.5 [SDD], 1[R].
Acknowledgments
We gratefully acknowledge financial support from the Secretaría de Investigación
y Estudios
Avanzados/UAEMéx (project No. 3804/2014/CID) and CONACYTꢀMexico (postgraduate scholarship No.
227581 and No. 273644). The authors would also like to thank the referees for their valuable comments and
suggestions, Signa S.A. de C.V. for kindly donating some solvents and reagents, and L. TrianaꢀCruz (CCIQS
UAEMex‒UNAM) for technical support.
Supplementary Material
Supplementary data (experimental procedures, characterization data of all compounds and copies of 13C,
1H, spectra, as well as the study on the synthesis of βꢀketosulfones,) associated with this article can be found in
the online version
Conflict of Interest
The authors declare no competing interest.
References
(1) (a) N. Pandit, R. K. Singla, B. Shrivastava, Int. J. Med. Chem. 2012 (2012), 24 pages. (b) K. J. Shaw,
M. R. Barbachyn, Ann. N.Y. Acad. Sci. 2011, 1241, 48–70.
(2) (a) A. Massarotti, S. Aprile, V. Mercalli, E. Del Grosso, G. Grosa, G. Sorba, G. C. Tron,
ChemMedChem 2014, 9, 2497–2508. (b) S.G. Agalave, S.R. Maujan, V.S. Pore, Chem. Asian J.
2011, 6, 2696–2718. (c) R. Kharb, P. C. Sharma, M. S. Yar, J. Enzyme Inhib. Med. Chem. 2011, 26,
1ꢀ21.

MedChemComm
Page 8 of 10
View Article Online
DOI: 10.1039/C7MD00442G
(3) Oxazolidinone scaffolds: (a) O. A. Phillips, L. H. Sharaf, Expert Opinion On Therapeutic Patents,
2016, 26, 591–605. (b) K. Michalska, I. Karpiuk, M. Król, S. Tyski, Bioorg. Med. Chem. 2013, 21,
577–591. (c) K. Michalska, I. Karpiuk, M. Król, S. Tyski, Bioorg. Med. Chem. 2013, 21, 577–591.
1,2,3ꢀTriazole scaffolds: (d) F. de Carvalho da Silva, M.F. do Carmo Cardoso, P. GarciaꢀFerreira,
V.F. Ferreira, Biological properties of 1Hꢀ1,2,3ꢀ and 2H ꢀ1,2,3ꢀtriazoles, in: W. Dehaen, V.A.
Bakulev (Eds.), Chemistry of 1,2,3ꢀtriazoles, Springer International Publishing, Switzerland, 2015,
pp. 117–165, DOI: 10.1007/7081_2014_124
(4) (a) M. V. Nora de Souza, Expert Opin. Ther. Patents 2008, 18, 1101–1105. (b) F. Reck, F. Zhou, M.
Girardot, G. Kern, C. J. Eyermann, N. J. Hales, R. R. Ramsay, M. B. Gravestock, J. Med. Chem.
2005, 48, 499–506. (c) J. A. Demaray, J. E. Thuener, M. N. Dawson, S. J. Sucheck, Bioorg. Med.
Chem. Lett. 2008, 18, 4868–4871. (d) O. A. Phillips, E. E. Udo, S. M. Samuel, Eur. J. Med. Chem.
2008, 43, 1095–1104. (e) O. A. Phillips, E. E. Udo, M. E. AbdelꢀHamid, R. Varghese, Eur. J. Med.
Chem. 2009, 44, 3217–3227. (f) H. Fan, Y. Chen, Z. Jiang, S. Zhang, D. Zhong, R. Ji, Y. Yang, Eur.
J. Med. Chem. 2008, 43, 1706–1714. (g) G. AcquaahꢀHarrison, S. Zhou, J. V. Hines, S. C. Bergmeier,
J. Comb. Chem. 2010, 12, 491ꢀ496.
(5) M. B. Gravestock, M. J. Betts, D. A. Griffin, I. R. Matthews, Oxazolidinone derivatives with
antibacterial activity. PCT Int. Appl. WO 0181350, 2001 (Astrazeneca U.K. Limited, Astrazeneca
AB, Sweden).
(6) A. L. Choy, V. P. V. N. Josyula, Benzisoxazole oxazolidinones as antibacterial agents. PCT Int. Appl.
WO 2007088438 A2, 2007, Pfizer Products Inc., US).
(7) http://melinta.com/
(8) (a) B. Bozdogan, P. C. Appelbaum, Int. J. Antimicrob. Agent 2004, 23, 113–119. (b) A. Chan, J.
Cross, Y. He, B. Lippa, D. Ryan, Antibacterial Drugs (Chapter 10). In: J. J. Li, E. J. Corey (Ed), Drug
Discovery: Practices, Processes, and Perspectives. John Wiley & Sons, Inc. Hoboken, New Jersey,
2013. pp. 412ꢀ413. DOI: 10.1002/9781118354483.ch10
(9) (a) F. Schiaffella, A. Macchiarulo, L. Milanese, A. Vecchiarelli, G Costantino, D. Pietrella, J. Med.
Chem. 2005, 48, 7658–66. (b) J. Y. Choi, L. M. Podust, W. R. Roush, Chem. Rev. 2014, 114,
11242–11271.
(10) B. M. Santoyo, C. GonzálezꢀRomero, O. Merino, R. MartínezꢀPalou, A. FuentesꢀBenites, H. A.
JiménezꢀVázquez, F. Delgado, J. Tamariz, Eur. J. Org. Chem. 2009, 2009, 2505–2518.
(11) SigmaꢀAldrich catalog number: 776033
(12) J. C. Lee, Y. H. Bae, S. K. Chang, Bull. Korean Chem. Soc. 2003, 24, 407–408.

Page 9 of 10
MedChemComm
View Article Online
DOI: 10.1039/C7MD00442G
(13) (a) N. Jung, S. Bräse, Click Reactions: AzideꢀAlkyne Cycloaddition. KirkꢀOthmer Encyclopedia of
Chemical Technology. 2013, 1–43. DOI: 10.1002/0471238961.clicjung.a01 (b) S. Chandrasekaran
(ed), Click Reactions in Organic Synthesis, WileyꢀVCH, Weinheim, Germany, 2016. DOI:
10.1002/9783527694174
(14) D. GonzálezꢀCalderón, I. SantillánꢀIniesta, C. A. GonzálezꢀGonzález, A. FuentesꢀBenítes, C.
GonzálezꢀRomero. Tetrahedron Lett. 2015, 56, 514–516.
(15) (a) National Committee for Clinical Laboratory Standards Institute (CLSI), Document M38ꢀA2:
Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi,
Approved Standard, Second Edition, Clinical and Laboratory Standards Institute, Wayne, PA, 2002;
(b) A.L. Barry, An overview of the Clinical and Laboratory Standards Institute (CLSI) and its impact
on antimicrobial susceptibility tests, in: R. Schwalbe, L. SteeleꢀMoore, A.C. Goodwin (Eds.),
Antimicrobial Susceptibility Testing Protocols, CRC Press Taylor & Francis Group, Florida, 2007,
pp. 1ꢀ6. ISBN: 9780824741006; (c) A. EspinelꢀIngroff, E. Canton, Antifungal susceptibility testing of
filamentous fungi, in: R. Schwalbe, L. SteeleꢀMoore, A.C. Goodwin (Eds.), Antimicrobial
Susceptibility Testing Protocols, CRC Press Taylor & Francis Group, Florida, 2007, pp. 209ꢀ241.
ISBN: 9780824741006.
(16) (a) National Committee for Clinical and Laboratory Standards Institute (CLSI), M27ꢀA3: Reference
Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Approved Standard, Third
Edition, Clinical and Laboratory Standards Institute, Wayne, PA, 2008. ISBN: 1ꢀ56238ꢀ666ꢀ2; (b) A.
EspinelꢀIngroff, E. Cantón, Antifungal susceptibility testing of yeasts, in: R. Schwalbe, L. Steeleꢀ
Moore, A.C. Goodwin (Eds.), Antimicrobial Susceptibility Testing Protocols, CRC Press Taylor &
Francis Group, Florida, 2007, pp. 173ꢀ208. ISBN: 9780824741006; (c) A.W. Fothergill, Antifungal
Susceptibility Testing: Clinical Laboratory and Standards Institute (CLSI) methods, in: G.S. Hall
(Ed.), Interactions of Yeasts, Moulds, and Antifungal Agents. How to Detect Resistance, Springer
ScienceꢀBusiness Media, 2012, pp. 65ꢀ74, DOI: 10.1007/978ꢀ1ꢀ59745ꢀ134ꢀ5_2 (d) M. A. Pfaller, D.
J. Diekema. J. Clinical Microbiol. 2012, 50, 2846–2856. (e) M. C. Arendrup, G. GarciaꢀEffron, C.
LassꢀFlörl, A. G. López, J. L. RodriguezꢀTudela, M. CuencaꢀEstrella, D. S. Perlin, Antimicrob.
Agents Chemother. 2010, 54, 426ꢀ439.

MedChemComm
Page 10 of 10
View Article Online
DOI: 10.1039/C7MD00442G
Graphical Abstract
O
Ph
O
O
N3
O
N
N
Ph
azide-enolate
cycloaddition
Antifungal
studies
Good activity against:
Candida glabrata
Ph
Ph
N
Trichosporon cutaneum
Mucor hiemalis
N
O
filamentous and
yeast fungi
N