Novel sulfamoylbenzoates as antifungal agents against Malassezia furfur

Article abstract of DOI:10.1016/j.mencom.2020.11.006

Novel polyfunctional arenesulfonamides as potential fungicides were prepared in eight steps from 3-amino-5-bromobenzoic acid. Among them, methyl 3-bromo-2-nitro-5-(N-phenylsulfamoyl)benzoate exhibiting significant cytotoxic activity against Malassezia fur

Full text of DOI:10.1016/j.mencom.2020.11.006

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 709–711
Novel sulfamoylbenzoates as antifungal agents against Malassezia furfur
Lena Trifonov,a Katerina Chumin,b Raanan Gvirtz,a,b Michal Afri,a
Edward E. Korshin,a Guy Cohen*b and Arie Gruzman*a
a Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 5290002 Ramat Gan, Israel.
E-mail: gruzmaa@biu.ac.il
b The Skin Research Institute, The Dead-Sea and Arava Science Center, 86910 Masada, Israel.
E-mail: guy@adssc.org
DOI: 10.1016/j.mencom.2020.11.006
Novel polyfunctional arenesulfonamides as potential
fungicides were prepared in eight steps from 3-amino-5-
bromobenzoic acid. Among them, methyl 3-bromo-2-nitro-5-
ꢀꢁꢂ reduction
of Malassezia
furfur
(N-phenylsulfamoyl)benzoate exhibiting significant cytotoxic
O
O
Br
CO2ꢀ
MeO2C
O2N
S
activity against Malassezia furfur is proposed as a lead for
the development of drug candidates against skin diseases
caused by the fungi, especially against seborrheic dermatitis.
ꢀ steps
Nꢀ
Nꢀ2
Br
Keywords: fungicides, medicinal chemistry, arenesulfonamides, Malassezia furfur, seborrheic dermatitis.
Among its many functions, the skin acts as a vital barrier against
pathogens.1–3 Residential microbiomes, including the lipophilic
species of Malassezia, are normally found on the skin surface.4,5
However, under certain conditions, such as immune deficiency,
diseases that hamper the skin barrier as well as wounds, these
species might be transformed to opportunistic pathogens that
might be involved in diverse dermatological disorders and even
systemic infections.6 The only cutaneous disease, Pityriasis
versicolor,ispurelycorrelatedwiththepresenceofMalassezia.7–9
In other dermatological disorders, the fungi play only secondary
but important roles either as an infectious agent or as a trigger.10
Malassezia fungi comprise a group of 14 species,11 while eight
members of this group with pathological potential, including
Malassezia furfur, have been isolated from human skin.5
Seborrheic dermatitis is the very common chronic
inflammatory skin disease whose pathophysiological aspects
are still poorly understood.12 Malassezia species, Malassezia
furfur in particular, has been associated with the progression
and the degree of severity of this disease.13 However, it was
postulated that certain immunological conditions lead to over-
colonisation of Malassezia furfur and that this induces an
abnormal host inflammatory response that correlates with non-
effective clearance of the skin microbes.10,14 These factors
accelerate epidermal or sebaceous abnormalities. Moreover,
not only skin diseases are attributed to Malassezia. The fungi
can cause systemic infections in severely immunocompromised
patients and in preterm infants admitted to intensive care
units.15,16
The most commonly used treatment against Malassezia-
related dermatological disorders is a combination of the topical
antifungal and anti-inflammatory drugs.12,17 Together with these
agents, additional therapeutic approaches are available for
physicians including lithium gluconate/succinate, coal tar,
salicylic acid, selenium sulfide, sodium sulfacetamide, glycerin,
benzoyl peroxide, aloe vera, mud treatment, phototherapy, and
phytotherapy.10,18,19 Sulfonamides represent an important class
of drugs.20–23 However, their antifungal activity against
Malassezia furfur has not yet been reported.
Here we report the synthesis and biological activity evaluation
of several novel sulfonamides 6a–d (Scheme 1) towards
NO2
NO2
Br
CO2H
Br
CO2Me
Br
CO2Me
i, ii, iii
iv, v
vi
NH2
NHAc
NH2
1
2
3
a R1 = Ph, R2 = H
b R1 = R2 = Et
NO2
NO2
NO2
Br
CO2Me
Br
CO2Me
Br
CO2Me
c NR1R2 =
vii
viii
N
N2+ Cl–
N
O
SO2NR1R2
6a–d
SO2Cl
d NR1R2 =
4
5
Scheme 1 Reagents and conditions: i, MeOH, SOCl2, 0 ® 25 °C, then reflux, 2 h; ii, Ac2O, Et3N, DMAP (cat.), THF, 25 °C, overnight; iii, HNO3, conc.
H2SO4, 0 ® 25 °C, then 25 °C, 30 min; iv, Ba(OH)2, MeOH–H2O, reflux, 18 h; v, MeOH, H2SO4 (cat.), 25 °C, sonication, 91 h; vi, NaNO2, conc. HCl/water,
0 °C, 15 min; vii, SO2, CuCl (cat.), HCl (aq.), –5 °C, then 0 °C, 75 min; viii, R1R2NH, CH2Cl2, 25 °C, overnight.
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2020, 30, 709–711
ꢂaꢄ
ꢂbꢄ
NO2
O
H
H
H
ꢅꢆ0
ꢅꢆ0
ꢅ2ꢆ
ꢅ00
ꢇꢆ
Br
H
O
H
ꢅ2ꢆ
ꢅ00
ꢇꢆ
N
H
ꢆ0
ꢆ0
ꢊ
O
H
ꢊ
2
ꢊ
ꢊ
2ꢆ
2ꢆ
0
H
N
O
H
H
O
H
H
0
0
ꢆ0
ꢀaꢈꢉM
ꢅ00
Br
H
Br
O2N
O
H
O
H
ꢀa
ꢀb
ꢀc
ꢀd
NO2
H
Figure 2 The impact of compounds on Malassezia furfur growth.
Malassezia furfur was treated with the indicated concentration of the
compounds or vehicle (DMSO). (a) Growth was determined fluorescently,
as described in the experimental section. (b) The dose-response (1–100 µm)
of compound 6a, n = 3, *p < 0.05.
N
H
H
O
O
2''
2'
Figure 1 Structure determination of the relevant experimental (for 2) and
theoretical (for 2' and 2'') HMQC (blue) and HMBC (red) 1H–13C
correlations in isomeric mono-nitro 5-acetamido-3-bromobenzoates.
was added to a cold concentrated aqueous solution of SO2 and
HCl35 in the presence of a cuprous chloride catalyst. This
afforded polyfunctionalized sulfonyl chloride 5 of ca. 70%
purity, which could be used crude. Its reactions with aniline,
diethylamine, piperidine and morpholine furnished the final
sulfonamides 6a–d, respectively.
The ability of these four compounds to inhibit the growth rate
of Malassezia furfur was tested in vitro. Compound 6a showed a
significant cytotoxic effect in the pharmacological concentration
for a topical application (50 µm) in which ~80% of the fungi
were killed [Figure 2(a),(b)]. All other compounds were not
active. Compound 6a is the only secondary sulfonamide among
all tested molecules, with its aniline moiety being the most
lipophilic compared to amine ones of compounds 6b–d. Thus,
we hypothesized that these two important issues, namely, the
presence of the less steric hindrances near the sulfonamide S–N
bond and the high lipophilicity of the aniline may be responsible
for the cytotoxic activity of compound 6a and the lack of activity
of other compounds.
In summary, several novel tetrasubstituted benzenesulfon-
amides 6a–d were synthesized. One of the congeners, namely,
methyl 3-bromo-2-nitro-5-(N-phenylsulfamoyl)benzoate 6a,
revealed an impressive antifungal cytotoxic activity (around
80% at 50 µm). This is the first report regarding a sulfonamide-
based compound that is active against Malassezia furfur. The
structural motif of 6a may be used as a lead for the development
of drug candidates against seborrheic dermatitis and probably
some other skin diseases caused by the fungi.
Malassezia furfur viability.Arenesulfonamides bearing in benzene
ring a combination of any type of carbonyl functionality, any
halogen substituent and nitro group have been scarcely explored
to date. To the best of our knowledge, only a few derivatives of
4-chloro (or -bromo)-2-nitro-5-sulfamoylbenzoic acid, described
as early as 1955,24 were later reported as advanced intermediates
in the syntheses of patented diuretics,25 anti-arrhythmics and Na-
channel blockers,26 as well as some specialty chemicals.27,28
In the synthesis of the novel 3-bromo-2-nitro-5-sulfamoyl-
benzoic acid derivatives 6a–d, commercially available
inexpensive 3-amino-5-bromobenzoic acid 1 was used as the
starting material (see Scheme 1). Its esterification29,30 and
N-acetylation29,31 was performed traditionally. Further nitration
can in principle afford a mixture of isomers 2, 2' and 2''
(Figure 1). According to the reported data,32,33 the use of conc.
HNO3 gave an equimolar 2/2' mixture while application of
conventional nitrating mixture (HNO3–H2SO4) cleanly produced
isomer 2. In our hands, such a processing yielded individual
mono-nitro derivative 2 in 70% yield. Its structure was
unambiguously confirmed by 1D (1H, 13C/DEPT) and 2D
(COSY, HMQC and HMBC) NMR experiments (see Figure 1)
as well as the negative mode HRMS. The HMBC spectrum (in
DMSO-d6) revealed intensive cross-peaks between a broadened
singlet of acetamide proton at 10.65 ppm with a signal of carbon
of N-acetyl fragment at 24.2 ppm and with two protonated three-
bond distanced aromatic carbon atoms C4H at 125.9 and C6H at
119.5 ppm. Additionally, in the HMBC spectrum, only the C6H
proton at 8.18 ppm and the methoxy-group protons at 3.87 ppm
exhibited an intensive three-bond correlation with the carbonyl
carbon of the methoxycarbonyl moiety at 162.3 ppm. As shown
in Figure 1, in the HMBC spectra of alternative mono-nitro
isomers 2' and 2'', just one three-bond correlation between the
acetamido-proton and the protonated aromatic carbons could be
theoretically observed.
This study was supported by a Bar-Ilan University new
faculty grant to AG. GC was partially supported by the Ministry
of Science and Technology (Israel). The Israel Ministry of
Immigration and Integration supported EEK through a Kamea
fellowship. The authors acknowledge Steve Manch for the
English editing of the manuscript.
In contrast to the reported selective deacetylation of the acetyl
amino-group in 2' without cleavage of the methyl ester
functionality,33 our attempts to similarly deprotect amino group
in compound 2 failed. Consequently, methyl 5-acetamido-3-
bromo-2-nitrobenzoate 2 was exhaustively hydrolysed to anilino
acid (86%) and, instead of the earlier reported O-methylation
with potentially explosive diazomethane,32 it was esterified with
methanol under acidic catalysis and sonication to afford anilino
ester 3 (62%).34 Without sonication the esterification proceeded
poorly (the yields were 10–20%). Further on, the anilino group
was replaced with a sulfonyl chloride moiety using a
modification35 of the conventional Meerwein method.36 For this
purpose, anilino ester 3 was converted to diazonium salt 4 which
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.11.006.
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