M. Arai et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2733–2736
2735
Table 1. In vitro antifungal activity of pyrrolidinyl sordaricins
MIC (mg/mL)
Organism
FCZa
1
3
4a
4b
4c
21
Candida albicans ATCC24433
Candida albicans SANK51486
Candida albicans TIMM3164b
Candida albicans ATCC64550b
Candida parapsilosis ATCC90018
Candida glabrata ATCC90030
Candida tropicalis ATCC750
0.5
0.25
>4
>4
0.5
>4
2
0.5
0.25
0.5
0.5
>4
>4
0.5
0.25
>4
0.03
0.02
0.03
0.03
1
0.5
2
0.5
0.25
0.5
0.5
0.25
0.13
0.5
0.5
0.25
1
2
0.5
1
>16
0.25
0.13
0.25
>16
>16
>16
8
>16
>16
>16
16
4
>16
>16
>16
>16
4
>16
>16
>16
>16
4
>16
>16
Cryptococcus neoformans TIMM1855
Aspergillus fumigatus ATCC26430
>4
>4
Candida albicans ATCC24433c
Candida albicans SANK51486c
NTd
NTd
4
NTd
0.5
0.25
4
1
1
0.5
1
0.5
8
4
aFluconazole.
bLow susceptibility to fluconazole (MIC >4).
cIn the presence of horse serum (20%).
dNot tested.
using thioacetic acid, and was transformed to thioacetate
17. Treatment of 17 with sodium methoxide generated
sodium thiolate in situ. Sequential treatment of the triflate
9 constructed the thioether linkage in 18. Removal of the
Boc groupin 18 proceeded smoothly, to give pyrrolidine
19. Benzylation of the secondary amine 19 gave rise to
tertiary amine 20. Finally, the carboxyl groupof 20 was
deprotected to afford the desired thioether analogue 21.
In conclusion, we synthesized a novel series of sordar-
icin derivatives possessing a pyrrolidine ring instead of
the sugar. These compounds exhibited good antifungal
activity. Introduction of the pyrrolidine moiety proved
to be an efficient strategy to reduce the influence of
serum. In particular, the N-piperonyl pyrrolidine deri-
vative 4c can be considered as a promising lead com-
pound. These findings encourage us to continue
studying further sordaricin analogues.
Antifungal activity
Acknowledgements
With compounds 4a–c and 21 in hand, in vitro anti-
fungal activity was examined.15 The results are sum-
marized in Table 1.
The authors thank Dr. T. Uchida of Sankyo Co., Ltd.
for helpful discussion.
These synthesized compounds exhibited good activity
(MICs: 0.13–2 mg/mL) against Candida albicans includ-
ing strains with decreased susceptibility to fluconazole.
However, they did not have as much activity as the
oxazepane derivative 3. Against Candida tropicalis, they
showed only moderate activity (MICs: 4–8 mg/mL).
Against Candida palapsilosis, Candida glabrata, Crypto-
coccus neoformans and Aspergillus fumigatus, they
showed almost no activity.
References and Notes
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Among this series, 4c was the most effective compound,
and exhibited MICs of 0.13–0.5 mg/mL against C. albi-
cans. Moreover, it maintained certain activity even in
the medium supplemented with 20% horse serum; the
MICs determined in the presence of serum were four-
fold higher than the corresponding MICs under serum-
free conditions.
In comparison with 4c, thioether 21 exhibited slightly
less antifungal activity. However, the MICs determined
in the presence of serum were 16-fold higher than the
corresponding MICs under serum-free conditions. The
finding suggests that the hydrophobicity of the thioether
linkage in 21 may be concerned with the influence of
serum on antifungal activity.
10. Herreros, E.; Almela, M. J.; Lozano, S.; Heras, F. G.;
Gargallo-Viola, D. Antimicrob. Agents Chemother. 2001, 45,
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