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amphotericin B, which remains the “gold standard” in mycol-
ogy because of its wide spectrum of activity, all the other
compounds can be considered as inactive.
However, we must note that the screening of antifungal
activity only on the basis of in vitro techniques can be uncer-
tain, as demonstrated these last years during the development
of the new class of echinocandins. Indeed, the fungal cell is
particularly complex, and according to the target of antifun-
gal classes and their site of activity, MIC results can show
wide variations between strains and species.
10 ml of dioxane was slowly added. The solution was warmed
at 80 °C for 30 min. and the succinamic acid 1 crystallize by
cooling. The white crystals were filtered off, dried and recrys-
tallized from dioxane.
1a: m.p. 144 °C (85%). IR (KBr): m CO 1691; 1642.
1b: m.p. 171 °C (90%). IR (KBr): m CO 1697; 1642.
1C: m.p. 108 °C (90%). IR (KBr): m CO 1731; 1641.
1d: m.p. 101 °C (85%). IR (KBr): m CO 1414; 1642.
1e: m.p. 96 °C (85%). IR (KBr): m CO 1695; 1650.
5.2. General procedure for the preparation
of compounds 2
4. Conclusions
One gram of the succinamic acid was dissolved into 10 ml
of ether and 13 ml of thionyl chloride was slowly added. The
solution was allowed to r.t. for 6 h and the diisoimide was
filtered off, washed with 2 × 5 ml of ether and recrystallized.
2a: Rose crystals, m.p.: 210 °C. IR: 1791, 1696 cm−1. 1H
NMR (CDCl3): 4.78 (s, 4H, CH2); 7.31–7.38 (m, 10H, Ar).
2b: Rose crystals, m.p.: 228 °C. IR: 1789, 1774, 1701 cm−1.
1H NMR (CDCl3): 1.23–2.13 (m, 20H, CH2); 3.75–3.82 (m,
2H, CH).
The reaction of thionyl chloride with succinamic acids
appeared to be a useful method for the synthesis of
S-containing heterocyclic compounds such as 1,4-dithiins,
which were usually obtained with yields close to 50%. In the
high majority of examples, the products crystallized sponta-
neously and the products did not require further purification.
Some dithiin diimides (compounds 3a, 3c, 3d and 3e) have
a moderate antibacterial activity against Gram-positive organ-
isms (S. aureus and E. faecalis), but E. coli and P. aerugi-
nosa were resistant.
The antifungal activity of the new dithiins compounds 3c,
3d and 3e against some yeasts and moulds of medical inter-
est could open a new way of investigation for future. To con-
firm the potential value of these new compounds, a large num-
ber of strains should be tested for the species which appear
sensitive to the products, especially C. albicans, C. krusei
and A. fumigatus. Indeed there is a need for research of new
antifungals to address infections due to an expanding num-
ber of opportunistic fungi.
5.3. General procedure for the preparation
of compounds 3
By the same method used for the preparation of the com-
pounds 2, using dioxane as solvent.
3a: Green needles, m.p.: 224 °C. IR: 1712, 1697 cm−1. 1H
NMR (CDCl3): 4.64 (s, 4H, CH2); 7.31–7.35 (m, 10H, Ar).
3c: Green needles, m.p.: 220 °C. IR: 1713, 1696 cm−1. 1H
NMR (DMSO d6): 1.35 (d, 12H, CH3, J = 6.9 Hz); 4.23–4.30
(m, 2H, CH).
3d: Green needles, m.p.: 211 °C. IR: 1714, 1693 cm−1. 1H
NMR (DMSO d6): 0.88 (t, 6H, CH3, J = 7.38 Hz); 1.48–1.61
(m, 4H, CH2); 3.45 (t, 4H, CH2, J = 7.09 Hz).
3e: Green needles, m.p.: 214 °C. IR: 1713, 1693 cm−1. 1H
NMR (DMSO d6): 0.91 (t, 6H, CH3, J = 7.35 Hz); 1.26–1.35
(m, 4H, CH2); 1.51–1.58 (m, 4H, CH2);.3.49 (t, 4H, CH2,
J = 7.05 Hz).
Conversely, dithin diisoimides (compounds 2a and 2b) are
totally inactive despites of their close structure similarities
with the dithin diimides. The present study adds new data in
the relationships of imides and their antimicrobial activities
5. Experimental part
6. Bacteriological assays
Melting points were taken on a Leitz 350 heated stage
microscope and are not corrected. H NMR spectra were
1
In vitro antimicrobial activities of the compounds were
determined by the twofold broth dilution method in Mueller
Hinton nutrient broth. The concentration of mother solutions
was 1024 µg ml–1 (50/50 water–methyl sulfoxide). Minimal
Inhibitory Concentration (MIC), was defined as the lowest
drug concentration resulting in complete inhibition of growth
after 18 h of incubation at 37 °C. Methyl sulfoxide has no
antibacterial activity at a concentration up to 20% in water.
The tested organisms were Staphylococcus aureus ATCC
25923, Enterococcus faecalis ATCC 29212, Escherichia coli
ATCC 25922 and Pseudomonas aeruginosa ATCC 27853.
recorded on a BrukerAvance DPX 400 and a WP80 DS instru-
ments and were reported in ppm downfield from internal tet-
ramethylsilane. Chemical shifts were reported in ppm (d) rela-
tive to TMS. IR spectra were run on a Bruker IF
55 spectrometer. Elemental analyses were within 0.35 of
the theoretical values. Analytical thin layer chromatography
was performed on a plastic sheet (0.2 mm, silica gel 60 F254
,
Merck). Silica gel 60 (70–230 mesh, Merck) was used for
column chromatography.
5.1. General procedure for the preparation
of compounds 1
7. Antifungal assays
Fifteen millimols of succinic anhydride were dissolved into
10 ml of dioxane and 15 mmol of the correspondent amine in
Antifungal susceptibility testing was determined by the ref-
erence methods of the Clinical and Laboratory Standards Insti-