Synthesis, characterization and in-vitro antifungal evaluation of some dithiocarbamic acid derivatives

Article abstract of DOI:10.1211/146080899128734901

Some new N, N-disubstituted dithiocarbamates derived from α-acetonaphthone and their precursors, potassium salts of dithiocarbamic acid, were prepared and evaluated for antifungal activity. Synthesis involved the reaction of α-chloro-2-acetonaphthone or α-chloro-4-methoxy-1-acetonaphthone with the potassium salts of N, N-disubstituted dithiocarbamic acid (5a-g). Compounds 5a-g were readily produced by reaction of equivalent amounts of the appropriate secondary amine, potassium hydroxide and carbon disulphide. The purity of the final derivatives, N, N-disubstituted dithiocarbamates 6a-g and 7a-g, was determined elemental analyses and TLC, and assignment of structures was confirmed by IR, ¹H NMR, ¹³C NMR and MS. Preliminary evaluation of the antifungal activity of derivatives 5a-g, 6a-g and 7a-g was determined in-vitro at a 2.5 or 5.0% concentration against different fungal species using tolnaftate as a reference drug. The potassium salts 5a-g were the most potent derivatives of the tested series. Compounds 5a-g showed significant broad spectrum antifungal activity. Combination of the dithiocarbamate with acetonaphthonyl moiety, represented by the 6a-g and 7a-g series, resulted in a decrease in or complete loss of antifungal activity in certain derivatives. Compounds derived from 4-methoxy-1-acetonaphthone (7a-g) were generally superior to their 4-nonsubstituted congeners (6a-g). The morpholino dithiocarbamate derivative 7e was equipotent or superior to the reference drug against the tested dermatophytes species and Rhodotorula rubra at a 5% concentration. In addition, 7e exhibited inhibitory activity against Chrysosporium tropicum, Emericella nidulans, Penicillium aurantiogriseum and Aspergillus sydowii. Some derivatives of both series showed selective activity against certain fungi, (e.g. 6f against Phoma glomerata and Scopulariopsis acremonium; 6g against Emericella nidulans and Phoma glomerata; 7c against Geotrichum candidum and Mucor circinelloides; 7d against Geotrichum candidum, Penicillium aurantiogriseum and Rodotorula rubra and 7f against Mucor circinelloides).

Full text of DOI:10.1211/146080899128734901

Pharm. Pharmacol. Commun. 1999, 5: 315±322
Received January 29, 1999
Accepted February 11, 1999
# 1999 Pharm. Pharmacol. Commun.
Synthesis, Characterization and In-vitro Antifungal Evaluation of
Some Dithiocarbamic Acid Derivatives
NADIA M. MAHFOUZ AND AHMAD M. MOHARRAM*
Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, and *Department of Botany,
Faculty of Science, Assiut University, Assiut 71526, Egypt
Abstract
Some new N, N-disubstituted dithiocarbamates derived from a-acetonaphthone and their
precursors, potassium salts of dithiocarbamic acid, were prepared and evaluated for
antifungal activity.
Synthesis involved the reaction of a-chloro-2-acetonaphthone or a-chloro-4-methoxy-1-
acetonaphthone with the potassium salts of N, N-disubstituted dithiocarbamic acid (5a±g).
Compounds 5a±g were readily produced by reaction of equivalent amounts of the
appropriate secondary amine, potassium hydroxide and carbon disulphide. The purity of
the ®nal derivatives, N, N-disubstituted dithiocarbamates 6a±g and 7a±g, was determined
by elemental analyses and TLC, and assignment of structures was con®rmed by IR,
1H NMR,13C NMR and MS.
Preliminary evaluation of the antifungal activity of derivatives 5a±g, 6a±g and 7a±g
was determined in-vitro at a 2Á5 or 5Á0% concentration against different fungal species
using tolnaftate as a reference drug. The potassium salts 5a±g were the most potent
derivatives of the tested series. Compounds 5a±e showed signi®cant broad spectrum
antifungal activity. Combination of the dithiocarbamate with acetonaphthonyl moiety,
represented by the 6a±g and 7a±g series, resulted in a decrease in or complete loss of
antifungal activity in certain derivatives. Compounds derived from 4-methoxy-1-aceto-
naphthone (7a±g) were generally superior to their 4-nonsubstituted congeners (6a±g). The
morpholino dithiocarbamate derivative 7e was equipotent or superior to the reference drug
against the tested dermatophytes species and Rhodotorula rubra at a 5% concentration. In
addition, 7e exhibited inhibitory activity against Chrysosporium tropicum, Emericella
nidulans, Penicillium aurantiogriseum and Aspergillus sydowii. Some derivatives of both
series showed selective activity against certain fungi, (e.g. 6f against Phoma glomerata and
Scopulariopsis acremonium; 6g against Emericella nidulans and Phoma glomerata; 7c
against Geotrichum candidum and Mucor circinelloides; 7d against Geotrichum candidum,
Penicillium aurantiogriseum and Rodotorula rubra and 7f against Mucor circinelloides).
Antifungal activity is related to a substructural
fragment of the molecule, the pharmacophore. Such
moieties include divalent sulphur attached to an
electron-de®cient carbon atom (Caujolle et al 1995;
stantinou-Garoufalia et al 1992; Foroumadi et al
1998). Of these derivatives the potassium salts of
N, N-disubstituted carbamodithioic acid (Shah et al
1997) and their esters (Ates et al 1995; GuÈrsoy et al
1996; Noguer & Marty 1997) showed potent anti-
fungal activity.
Several naphthaline-containing compounds also
have antifungal activity and some are well known
antimycotic agents (Artico et al 1992; Nussbaumer
et al 1993; Auzzas et al 1998). Tolnaftate (Figure 1)
is a topical antifungal agent that incorporates both
a naphthaline nucleus and an N, N-disubstituted
Â
Klimesova et al 1996). This was the basis for the
synthesis of numerous sulphur-containing com-
pounds with antifungal activity against various
fungal species (Al-Nakib et al 1992; Papakon-
Correspondence: N. M. Mahfouz, Department of Pharma-
ceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut
University, Assiut 71526, Egypt.

316
NADIA M. MAHFOUZ AND AHMAD M. MOHARRAM
of anhydrous aluminum chloride (2Á4 g, 0Á018 mol)
in dried methylene chloride (50 mL) was added
chloroacetylchloride (2Á03 g, 0Á018 mol). The
resulting mixture was slowly added at room tem-
perature to naphthaline (1) or 1-methoxynaphtha-
line (2; 0Á015 mol) dissolved in dried methylene
chloride (25 mL). The reaction mixture was stirred
overnight at ambient temperature, poured gradually
onto ice and acidi®ed with concentrated HCl with
vigorous stirring. The aqueous layer was further
extracted with methylene chloride (2 6 50 mL) and
the combined organic extracts were washed with
water (100 mL), dried over anhydrous Na2SO4,
®ltered and evaporated under reduced pressure. The
oily residue obtained was crystallized from ether±
petroleum ether to give a pale-yellow crystalline
product. Compound 3: mp 64±66ꢀC, reported mp
65±66ꢀC (Synch 1956) and compound 4: mp 68±
69ꢀC, reported mp 70Á5±71ꢀC (Jacobs et al 1946).
Figure 1. Structure of tolnaftate.
thiocarbamate moiety (Weinberg 1996). It is
assumed that the dithiocarbamate moiety could be
considered an isosteric group for the thiocarbamate
function. Some potassium salts of N, N-disubsti-tuted
dithiocarbamic acid (5a±g) and their combination
with acetonaphthones (6a±g and 7a±g) were there-
fore synthesized as potential antifungal agents.
In the ®rst group, 6a±g, the variable dithio-
carbamate moiety was linked at C-2 of the naph-
thaline nucleus through an acetyl spacer, while in
the second series, 7a±g, the dithiocarbamate resi-
due attached to the a-carbon of 4-methoxy-1-aceto-
naphthone. The interdependence of the antifungal
activity on these structural variations is discussed.
Potassium dithiocarbamates 5a±g. Potassium
hydroxide (0Á03 mol) was dissolved in ethanol
(250 mL) with constant stirring and the appropriate
secondary amine (0Á03 mol) was added. The reac-
tion mixture was cooled in an ice bath and CS2
(0Á03 mol) was added dropwise and the stirring was
continued for 1 h at ambient temperature. Ethanol
was distilled off under reduced pressure and the
residue was triturated with anhydrous diethylether
until precipitation of the products was complete
and then ®ltered to give quantitative yields of the
potassium dithiocarbamate derivatives 5a±g.
Materials and Methods
Chemistry
Tolnaftate was obtained from Cairo Co. for Drugs
and Chemical Industries, Cairo, Egypt. All reagents
and chemicals were of reagent grade. Melting
points were determined in open-glass capillaries on
an electrothermal melting-point apparatus (Fa.
Sturat Scienti®c, UK) and are uncorrected. Pre-
coated silica gel 60 F-254 plates (Merck) were used
for thin-layer chromatography (TLC) and spots
were detected by UV. Elemental analysis (C, H and
N) was performed at the Department of Chemistry,
Assiut University, Assiut, Egypt. IR spectra (KBr
discs) were recorded on a Schimadzu-408 Spectro-
a-Acetonaphthonyl N,N- disubstituted dithiocarba-
mate derivatives 6a±g and 7a±g. Equimolar
amounts of a-chloro-2-acetonaphthone (3) or a-
chloro-4-methoxy-1-acetonaphthone (4) and the
corresponding potassium dithiocarbamate deriva-
tives (5a±g) were re¯uxed in ethanol (5b±f) or
acetonitrile (5a) for 1 h. After cooling, the reaction
mixture was evaporated under reduced pressure and
the products were washed well with water, and
crystallized from the appropriate solvent. Tables 1
and 2 summarize the physicochemical properties
of the synthesized compounds.
Reaction of 5a and 3 in ethanol gave compound
10: yield 65%; mp 91±93ꢀC (methanol) which was
identi®ed as O-ethyl a-2-acetonaphthonylcarbono-
dithioic acid ester.1 HNMR (CDCl3, d ppm): 1Á5 (t,
3H, J ˆ 7 Hz, CH2CH3); 4Á6 (q, 2H J ˆ 7 Hz,
CH2CH3); 4Á8 (s, 2H, COCH2 ); 7Á5±8Á1 (m, 6H,
naph-H3-8) and 8Á5 (s, 1H, naph-H1). 13CNMR (d6-
DMSO, d ppm): 13Á4 (CH3); 42Á6 (COCH2S); 70Á3
(OCH2); 123Á3 (naph-C-3); 126Á7 (naph-C-7); 127Á4
(naph-C-5); 128Á1 (naph-C-4); 128Á5 (naph-C-6);
129Á3 (naph-C-8); 130Á1 (naph-C-1); 131Á8 (naph-
1
photometer. HNMR spectra were determined on a
Varian EM-60 Spectrometer in d6-DMSO or CDCl3
using tetramethylsilane (TMS) as internal standard
and chemical shifts are in d ppm.13CNMR spectra
were recorded on a Varian Gemini-300 spectro-
meter at the Research Institute for Wakan-Yaku,
Toyama, Japan. d6-DMSO was used as a solvent
and chemical shifts are in d ppm relative to TMS.
MS were obtained using a Shimadzu GC=MS
Spectrometer QP-5000 (Shimadzu Co. Kyoto,
Japan) at the Institute of Pharmaceutical Chemistry,
Vienna University, Vienna, Austria.
a-Chloro-2-acetonaphthone (3) and a-chloro-4-
methoxy-1-acetonaphthone (4). To a suspension

DITHIOCARBAMIC ACID DERIVATIVES
Table 1. Physicochemical data of compounds 6a±g.
317
Compound
NR1R2
Yield (%)
Mp (ꢀC)
Formula (MW)
Elemental analysis (%)
H
C
N
6a
62
167±169a
C20H17NOS2
(351Á48)
67Á98
4Á70
4Á40
(68Á35)
(4Á88)
(3Á99)
6b
6c
6d
6e
6f
78
92
95
93
91
94
82±84b, c
140±141b
114±116a, c
134±136b, c
162±165a
182±184b
c
C17H19NOS2
(317Á09)
C17H17NOS2
(315Á45)
C18H19NOS2
(329Á09)
C17H17NO2S2
(331Á45)
C18H20N2OS2
64Á69
5Á97
3Á88
(64Á32)
(6Á03)
(4Á41)
64Á25
5Á08
4Á45
(64Á75)
(5Á44)
(4Á44)
65Á31
6Á00
3Á87
(65Á75)
(5Á82)
(4Á24)
61Á33
5Á40
3Á83
(61Á62)
(5Á18)
(4Á23)
62Á46
5Á42
8Á60
(344Á49)
C23H22N2OS2
(406Á56)
(62Á76)
(5Á85)
(8Á13)
6g
68Á18
5Á50
6Á54
(67Á95)
(5Á45)
(6Á89)
a
b
Recrystallization solvent: methanol-acetone, ethanol. Reported melting points of compounds: 6b 74ꢀC; 6d, 105±106ꢀC; 6e,
d
130±131ꢀC (Erdogan et al 1988). Calculated values are in parentheses.
C-9); 132Á7 (naph-C-2); 134Á8 (naph-C-10); 191Á7
(C ˆ O); 212Á7 (C ˆ S). Elemental analysis: found:
C, 60Á00; H, 4Á84; calculated for C15H14O2S2,
(290Á394); C, 59Á98; H, 4Á40.
diam.) containing spores and hyphae were trans-
ferred aseptically to screw-topped vials containing
20 mL sterile distilled water. After thorough shak-
ing, 1-mL samples of the spore suspension were
pipetted into sterile Petri dishes, followed by the
addition of 15 mL liqui®ed SDA medium which
was then left to solidify.
The tested compounds and tolnaftate were dis-
solved in dimethylsulphoxide to give 2Á5 or 5Á0%
concentrations. Antifungal activity was determined
according to the method reported by Bauer et al
(1966) using 3-mm diameter ®lter-paper discs
(Watmann No. 3) loaded with 10 mL of the solution
under investigation (250 or 500 mg=disc, 2Á5% or
5% concn, respectively). The discs were placed on
the surface of the fungal cultures which were then
incubated at 30ꢀC. The diameter of the inhibition
zone around each disc was measured.
Reaction of 5a with 4 gave the corresponding
analogue 11: yield 63%; mp 74±77ꢀC (methanol)
which was identi®ed as O-ethyl a-[1-(4-meth-
oxy)-acetonaphthonyl]carbonodithioic acid ester.
1HNMR (CDCl3, d ppm): 1Á3 (t, 3H, J ˆ 7 Hz,
CH2CH3); 4Á0 (s, 3H, OCH3); 4Á6 (q overlapped with
s, 4H COCH2 and OCH2CH3); 6Á8 (d, 1H, J ˆ 9 Hz,
naph-H3); 7Á5±7Á9 (m, 2H, naph-H6, H7); 8Á2 (d, 1H,
J ˆ 8 Hz, naph-H2); 8Á4 (dd, 1H, J ˆ 8, 3 Hz, naph-
H5) and 9Á0 (dd, 1H, J ˆ 8, 4 Hz, naph-H8). Ele-
mental analysis: found: C, 61Á57; H, 5Á16; calculated
for C16H16O3S2; (320Á419); C, 62Á04; H, 4Á86.
Evaluation of in-vitro antifungal activity
The fungal species were previously isolated from
cases of human dermatophytosis (Moubasher et al
1992). The fungi were grown in sterilized 9-cm
Petri dishes containing Sabouraud's Dextrose Agar
(SDA) supplemented with 0Á05% chloramphenicol
to suppress bacterial contamination (Al-Doory
1980). From these cultures, agar discs (10 mm
Results and Discussion
Synthesis and characterization
The synthetic pathway for synthesis of the title
compounds 5a±g, 6a±g and 7a±g is illustrated in

318
NADIA M. MAHFOUZ AND AHMAD M. MOHARRAM
Table 2. Physicochemical data of compounds 7a±g.
Compound
NR1R2
Yield (%)
Mp (ꢀC)
Formula (MW)
Elemental analysis (%)
H
C
N
7a
7b
7c
7d
7e
7f
57
72
89
93
94
92
96
175±176a
127±129b
145±147c
169±171c
138±140c
141±143c
163±165c
c
C21H19NO2S2
(381Á09)
C18H21NO2S2
(347Á10)
C18H19NO2S2
(345Á50)
C19H21NO2S2
(359Á50)
C18H19NO3S2
(345Á50)
C19H22N2O2S2
(374Á11)
C24H24N2O2S2
66Á61
5Á14
3Á00
(66Á13)
(5Á02)
(3Á67)
62Á35
6Á00
3Á35
(62Á22)
(6Á09)
(4Á03)
63Á12
5Á40
4Á14
(62Á59)
(5Á55)
(4Á06)
63Á50
6Á30
3Á56
(63Á49)
(5Á89)
(3Á09)
59Á50
5Á13
4Á11
(59Á81)
(5Á30)
(3Á87)
61Á31
5Á90
7Á23
(60Á93)
(5Á92)
(7Á48)
7g
65Á60
5Á36
6Á50
(436Á13)
(66Á04)
(5Á55)
(6Á42)
a
b
d
Recrystallization solvent: methanol-ethylacetate, ethanol, ethanol-dioxan. Calculated values are in parentheses.
Figure 2. The precursors a-chloro-2-aceto-
naphthone (3) and a-chloro-4-methoxy-1-aceto-
naphthone (4) were obtained by Friedel-Craft's
acylation of the corresponding naphthaline (1) or its
1-methoxy derivative (2), respectively. To obtain
the ®nal compounds 6a±g and 7a±g, it was
necessary to prepare the potassium salts of N, N-
disubstituted dithiocarbamic acid 5a±g by the
reaction of the appropriate amines with CS2 and
KOH at room temperature. The potassium salts
were re¯uxed with 3 or 4 to afford the ®nal com-
pounds 6a±g and 7a±g, respectively. Physical data
are given in Tables 1 and 2 .
Reaction of potassium N-methyl-N-phenyl-
dithiocarbamate (5a) with 3 or 4 in ethanol resulted
in the formation of the corresponding O-ethyl
carbonodithioic acid ester 10 or 11 instead of the
expected a-acetonaphthonyl-N-methyl-N-phenyldi-
thiocarbamate derivative 6a or 7a (Figure 3). The
reaction proceeds through a second-order mechan-
ism as reported for carbonyl and the corresponding
nitrogen and sulphur analogues (March 1984). The
delocalization of the lone pair of electrons on the
Figure 2. Synthetic pathway for the synthesis of compounds
5a±g, 6a±g and 7a±g.
aryl nitrogen of compounds 6a and 7a renders the

DITHIOCARBAMIC ACID DERIVATIVES
319
addition to the other signals of the acetonaphthone
moiety. The spectra of compound 11 also revealed
a singlet at d ꢁ 4 ppm, due to methoxy protons.
13CNMR of compound 10 showed CH3 at
d ꢁ 13Á4 ppm and two signals at d ꢁ 42Á5 and
70Á3 ppm assigned to the methylene C-atoms, CH2S
and OCH2, respectively. The spectra also revealed
®ve quaternary C-atoms, three of which are char-
acteristic for naphthaline C-atoms (C-9, C-2 and C-
10 at d ꢁ 131Á8, 132Á7 and 134Á8 ppm, respec-
tively). The down®eld shifted signals at d ꢁ 191Á7
and 212Á7 ppm are characteristic for C ˆ O and
C ˆ S, respectively. Chemical shifts of the
remaining C-atoms of the naphthaline ring
appeared as expected.
Compounds 6b, 6d and 6e, which were pre-
viously synthesized, showed higher melting points
than the reported values (Erdogan et al 1988). The
purity of these compounds was assessed by TLC
and elemental analyses (Table 1), and their struc-
1
tures were con®rmed by IR, H NMR, 13C NMR
and MS.
The IR spectra of compounds 6a±g and 7a±g
showed the characteristic stretching vibrations at
1
1
1650±1683 cm
(C ˆ O) and 1222±1276 cm
(C ˆ S), in addition to out-of-plane bending vibra-
tion of the naphthaline ring. In 1HNMR spectra, the
signals of the respective H-atoms were assigned on
the basis of chemical shifts, multiplicities and
coupling constants. The spectra showed up®eld
shifted signals at d ꢁ 1Á2±4Á3 ppm due to amine
protons, and a singlet signal at d ꢁ 5 ppm assigned
to the CH2S group. The spectra of compounds 7a±
g revealed an additional signal due to OCH3 which
appeared as a separate singlet at d ꢁ 4 ppm (7a, 7c
and 7g) or overlapped with the amine moiety in
other derivatives (7b and 7d±f). The signals of the
naphthaline nucleus in the two series, 6a±g and
7a±g, appeared as expected at different d values
due to variation in the substitution pattern in both
series. The chemical shifts in the same series were
almost identical whatever the type of substitution
of the amine moiety.
Figure 3. Suggested mechanism for formation of compounds
10 and 11.
positive charge at the C atom of the thiocarbonyl
group of 6a or 7a more pronounced, facilitating the
nucleophilic attack of ethanol to give the inter-
mediate 8 or 9, respectively. Cleavage of the C N
bond of the latter compounds leads to the formation
of compounds 10 and 11. When acetonitrile was
used instead of ethanol, the desired products a-
acetonaphthonyl-N-methyl-N-phenyl dithiocarba-
mate derivatives 6a and 7a were obtained in rea-
sonable yields. In the case of the aliphatic and
alicyclic amines, localization of the lone pair of
electrons on the amine nitrogen increased the C N
bond character and ensured the formation of the
desired compounds 6b±g and 7b±g regardless of
the solvent used.
For 13CNMR data, the signals in the proton
decoupled spectra were assigned to their speci®c
carbon atoms by comparison of their chemical
shifts with similar compounds and application of
some additivity rules (Kalinowski et al 1984; Sil-
verstein & Webster 1998). The carbonyl and thio-
carbonyl C atoms were easily identi®ed by their
low intensity and characteristic down®eld-shifted
signal at d ꢁ 192±197 ppm. The acetyl carbonyl C
atom appeared up®eld relative to its isoster, thio-
carbonyl C atom. The chemical shifts of the latter
in the different compounds varied according to the
type of the adjacent amine moiety. The C atoms of
The structures of O-ethyl carbonodithioic acid
esters 10 and 11 were con®rmed by elemental
analyses and spectral data. 1HNMR spectra showed
the signals characteristic for CH2CH3 group, in

320
NADIA M. MAHFOUZ AND AHMAD M. MOHARRAM
the naphthaline nucleus resonate in the aromatic
region at different d-values. However, it is easy to
recognize the quaternary C atoms by their low
intensity. The spectra also revealed signals in the
up®eld region at d ꢁ 65±11 ppm assigned to
methoxy (7b and 7f) and amine C atoms. The C
atoms of the N, N-diethylamino group of compound
7b were nonequivalent and appeared at different
chemical shifts. This may be attributed to the slow
rate of rotation around the hindered C ˆ N bond as
has been observed for similar compounds (Kali-
nowski et al 1984). In all compounds, the signal of
the a-C atom of the spacer overlapped with the
peaks of the solvent (d6-DMSO), except for com-
pound 7b where it was down®eld shifted to
d ꢁ 45 ppm due to the hindered rotation around
C ˆ N bond.
compound 6c under electron impact is depicted in
Figure 4 as a representative example.
Antifungal screening
The ®lter-paper disc method (Bauer et al 1966) was
used for evaluation of the in-vitro antifungal
activity of compounds 5a±g, 6a±g and 7a±g
against various fungal species using SDA. The
results are summarized in Tables 3 and 4 . The
screening of the potassium salts 5a±g for potential
antifungal activity was based on the previously
reported antimycotic activity of some sodium salts
of dithiocarbamic acid against different Candida
species (Shah et al 1997). In this series, compounds
5a±e displayed broad spectrum antifungal activity
at both concentrations (2Á5 and 5Á0%) against all the
tested fungi (Table 3). Potassium salts derived from
N-methylaniline (5a) and morpholine (5c) had
greater antifungal activity than the reference drug,
tolnaftate.
The mass spectra of compounds 6c, 6e, 6f and
7d±g showed molecular ion peaks which con-
®rmed their molecular weights and generated ionic
fragments that veri®ed their structures. The major
fragmentation pathway involved cleavage of the
C S bond of the dithiocarbamate moiety which
was in accordance with the literature (Capan et al
1993). The proposed fragmentation pattern of
Combination of the potassium salts 5a±g with a
naphthaline nucleus through an acetyl spacer
resulted in the derivatives 6a±g and 7a±g. These
modi®cations led to a drastic decrease in, or
Figure 4. Mass fragmentation of compound 6c.

DITHIOCARBAMIC ACID DERIVATIVES
321
Table 3. Antifungal activity of some potassium salts of N, N-disubstituted dithiocarbamic acid derivatives and tolnaftate.
Fungal species
Inhibition zone (mm)
5d 5e
5a
5b
5c
5fb
5g
Tolnaftate
2Á5% 5% 2Á5% 5% 2Á5% 5% 2Á5% 5% 2Á5% 5% 2Á5% 2Á5% 5% 2Á5% 5%
Aspergillus alutaceus
Aspergillus fumigatus
Aspergillus niger
Aspergillus sydowii
Aspergillus terreus
22
20
18
10
20
25
18
20
20
18
17
20
25
15
10
12
20
40
30
30
35
30
40
30
45
40
30
30
35
40
20
30
30
50
40
30
50
8
10
5
10
8
35
15
10
20
12
40
8
40
20
30
20
25
35
20
20
20
30
40
15
32
20
12
15
10
15
20
15
12
15
15
12
20
25
10
10
18
15
20
10
10
40
35
40
40
35
60
35
50
45
40
40
50
60
40
40
45
50
60
40
50
10
10
10
15
12
12
8
15
15
18
25
20
20
15
15
30
20
30
30
30
10
10
25
30
30
15
15
±
8
10
7
8
15
12
10
10
35
14
12
28
15
30
40
30
10
12
32
30
45
14
25
±
10
±
±
10
±
±
±
±
±
±
±
±
±
10
±
±
±
±
±
±
±
±
±
±
±
12
±
±
12
±
±
12
10
20
±
15
10
15
10
10
±
18
±
18
±
10
10
±
10
15
±
16
25
12
±
±
±
20
±
23
±
15
30
±
12
20
±
18
30
15
10
±
6
Botryotrichum piluliferum
Candida albicans
25
6
10
10
10
20
12
10
25
15
±
18
±
Chrysosporium tropicum
Emericella nidulans
Fusarium oxysporum
Geotrichum candidum
Microsporum canis
Microsporum gypseum
Nectrio haematococca
Penicillium funiculosum
Stachybotrys chartarum
Trichophyton gourvilli
20
18
12
10
20
15
8
10
10
20
25
10
15
8
18
10
15
10
12
±
12
10
10
20
±
±
±
15
7
20
±
±
±
15
15
18
10
10
12
20
20
10
10
±
15
10
12
10
35
23
7
40
26
10
±
Trichophyton mentagrophytes 20
Trichophyton rubrum 16
Trichothecium roseum 20
20
±
bNot determined at 5%; ±, inactive.
Table 4. Antifungal activity of N, N-disubstituted dithiocarbamate derivatives and tolnaftate.
Fungal species
Inhibition zone (mm)
Compounds
Tolnaftate
2Á5%
5%
2Á5%
5%
Aspergillus alutaceus
Aspergillus sydowii
Chrysosporium tropicum
Emericella nidulans
7e
7e
7e
6g
7e
7c
7d
7e
7e
7c
7f
7d
7e
6f
6g
7d
7e
6f
±
10
12
ND
16
ND
ND
10
12
15
15
11
20
8
18
±
10
12
20
±
12
15
Geotrichum candidum
±
±
8
Microsporum canis
Microsporum gypseum
Mucor circinelloides
35
30
6
10
11
25
8
13
10
32
8
40
30
25
12
ND
30
15
10
10
ND
ND
ND
ND
ND
ND
ND
ND
ND
10
Penicillium aurantiogriseum
Phoma glomerata
±
±
±
30
18
Rhodotorula rubra
ND
Scopulariopsis acremonium
Trichophyton gourvilli
Trichophyton mentagrophytes
±
35
23
±
40
26
7e
7e
10
ND, not determined; ±, inactive.
and Phoma glomerata (Table 4). Introduction of a
methoxy group at C-4 and shifting the dithio-
carbamate moiety to C-1 of the naphthaline
nucleus, resulting in 7a±g, led to partial restora-
tion of activity (Table 4). The morpholino deri-
complete loss of antifungal activity in certain
derivatives. In the series 6a±g, 6f exhibited weak
and selective activity against Phoma glomerata
and Scopulariopsis acremonium, whereas 6g
showed weak activity against Emericella nidulans

322
NADIA M. MAHFOUZ AND AHMAD M. MOHARRAM
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vative 7e showed equipotent or superior activity
against the tested dermatophytic species Asper-
gillus alutaceus and Rhodotorula rubra compared
with tolnaftate. Compound 7e also revealed inhi-
bitory activity against Pencillium aurantiogriseum
and Aspergillus sydowii; tolnaftate showed no
activity against either of these fungi. Compound
7c exhibited weak and selective activity against
Geotrichum candidum and Mucor circinelloides.
Some ef®cacy of compound 7d was found against
R. rubra, P. aurantiogriseum and G. candidum.
The latter two fungi were not sensitive to tolnaf-
tate. Compound 7f was equipotent with the
reference drug against Mucor circinelloides. The
derivatives 6a±e, 7a, 7b and 7g were completely
inactive against all the tested fungal isolates listed
in Tables 3 and 4 .
In conclusion, potassium salts of N, N-disub-
stituted dithiocarbamic acid displayed higher and
broad spectrum activity against true dermatophytes,
as well as opportunistic nondermatophyte fungal
species among all the tested compounds. Combi-
nation of these derivatives with a naphthaline
nucleus through an acetyl spacer resulted in a
drastic decrease or complete loss of antifungal
activity of some derivatives in comparison with
tolnaftate. Derivatives 6a±g were much less active
than their congeners 7a±g, which may be attributed
to the presence of the methoxy group in 7a±g. The
morpholino analogue 7e was the most active
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We thank Dr Ernst Urban, Institut fuÈr Pharmazeu-
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help in carrying out the MS measurements.
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