Toshiyuki Konosu

Synthesis and evaluation of N-substituted 1,4-oxazepanyl sordaricins as selective fungal EF-2 inhibitors

Sordaricin analogues possessing 6-methoxy-7-methyl-1,4-oxazepane moiety instead of the sugar part were synthesized and evaluated. It was found that N-substituents on the oxazepane ring had influence on biological activity. In particular, N-(2-methylpropenyl) derivative 12p exhibited potent in vitro antifungal activity. Furthermore, 12p maintained significant activity (MIC 0.25 microg/mL) against Candida albicans SANK51486 even in the presence of 20% horse serum.

Synthesis of Sordaricin Analogues as Potent Antifungal Agents against Candida albicans

Sordaricin derivatives possessing a cyclohexane ring appendage attached via an ether, thioether, amine, oxime, ester or amide linkage were synthesized and their antifungal activity was evaluated in vitro. Compounds containing a thioether bond or an oxime bond as a linkage exhibited potent MICs (< or = 0.125 microg/mL) against four Candida albicans strains including azole-low-susceptible strains. They were also active (MIC < or = 0.125 microg/mL) against Candida glabrata. Their in vivo efficacy was confirmed in a murine intravenous infection model with Candida albicans.

Concise synthesis of optically active oxirane precursors for the preparation of triazole antifungals using the Friedel-Crafts reaction of (S)-2-tosyloxypropionyl chloride

Optically active epoxide (2R,3S)-4, a key intermediate for the preparation of triazole antifungal agents (4R,5R)-1 and (2R,3R)-2 (X=2,4-F2), was synthesized. The Friedel-Crafts reaction between the (S)-lactic acid derivative (S)-10 and m-difluorobenzene gave the (R)-2-chloropropiophenone derivative (R)-11, which was converted into (2R,3R)-18 with sodium triazolide gave (2R,3S)-4. Similarly, the 4-chlorophenyl analog (2R,3S)-4′ was prepared.

Synthesis of bruceantin skeleton

Abstract A stereoselective synthesis of a compound (3), which satisfies all requirements for bruceantin skeleton and has preferable functional groups at suitable positions for the total synthesis of bruceantin, is described.

A novel approach to the stereoselective semi-synthesis of GM-237354 by employing a highly β-selective glycosylation

Synthesis of GM-237354 (1), a potent inhibitor of fungal elongation factor 2, was achieved starting from sordaricin using a highly stereoselective glycosylation reaction as a key step. Glycosylation utilizing 2-deoxy-2-iodo-glycopyranosyl acetate 6a gave glycoside 8 as a single product, and 8 was easily converted into 1.

Synthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agents

N-Benzyl pyrrolidinyl sordaricin derivatives have been synthesized from cis-4-hydroxy-D-proline in a stereocontrolled manner. These compounds maintained moderate antifungal activity against several pathogenic fungal strains. Their MIC values against Candida albicans were in the range of 0.25-2 microg/mL.