ABSTRACT
Synthesis and in vitro antifungal activities of a novel triazole antifungal agent CS-758 (former name, R-120758) are described. The minimum inhibitory concentrations (MICs) of a series of dioxane-triazole compounds related to R-102557 were examined. Variation of the length of the chain between the dioxane ring and the phenyl ring revealed that the linkage with two double bonds is the most preferable. When a cyano group was introduced to the C4 position on the benzene ring, MICs improved further. A fluorine atom was introduced to obtain CS-758. The MICs of CS-758 surpassed those of fluconazole and itraconazole against Candida, Aspergillus and Cryptococcus species. The precursor (E,E)-aldehyde was synthesized stereoselectively from 3-fluoro-4-methylbenzonitrile using the Horner-Wadsworth-Emmons reaction.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungi/drug effects , Triazoles/chemical synthesis , Triazoles/pharmacology , Fluconazole/pharmacology , Indicators and Reagents , Itraconazole/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity TestsABSTRACT
Novel triazole compounds with a dioxane ring were synthesized. Condensation of the diol precursor 10 with various aromatic aldehydes 11-13 under acidic conditions afforded a series of dioxane-triazole compounds 14-16. The antifungal activities of the compounds 14-16 were evaluated in vivo in mice infection models against Candida and Aspergillus species. High activities were seen for the derivatives with one or two double bond(s) and an aromatic ring substituted with an electron-withdrawing group in the side chain. Among the derivatives, R-102557 (16R: Ar=4-(2,2,3,3-tetrafluoropropoxy)phenyl) showed excellent in vivo activities against Candida, Aspergillus and Cryptococcus species. It also showed high tolerance in a preliminary toxicity study in rats.
Subject(s)
Antifungal Agents/chemical synthesis , Dioxanes/chemical synthesis , Triazoles/chemical synthesis , Animals , Antifungal Agents/pharmacology , Antifungal Agents/toxicity , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillus flavus , Aspergillus fumigatus , Cryptococcosis/microbiology , Cryptococcus neoformans , Dioxanes/pharmacology , Dioxanes/toxicity , Mass Spectrometry , Mice , Microbial Sensitivity Tests , Rats , Rats, Inbred F344 , Spectrophotometry, Infrared , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/toxicityABSTRACT
Stereocontrolled synthesis of tricyclic carbapenem (5-azatrinem) derivatives 4, in which a piperidine ring is condensed to the carbapenem skeleton, was achieved. The pivotal tricyclic intermediate 2, allyl (8S,9R,10S)-5-(tert-butoxycarbonyl)-10-(R)-1-(tert-butyldimethylsilyl oxy)ethyl]-11-oxo-1,5-diazatricyclo[7.2.0.0(3,8)]undec-2- ene-2-carboxylate, was synthesized starting from an acetoxyazetidinone chiron 6 in a practical manner based on a C-C bond formation reaction between 6 and piperidinone-ester 5, palladium-catalyzed de(allyloxy)carbonylation of 7b and Wittig-type cyclization via an oxalimide 9. Selective deprotection of the N-Boc group of 2 was found to proceed smoothly by treatment with trimethylsilyl trifluoromethanesulfonate and 2,6-lutidine to give the amino compound 3, whose functionalization on the nitrogen atom to derivatives 10 followed by deprotection led to various 5-azatrinem acids 4. These compounds showed potent in vitro activities against gram-positive and gram-negative bacteria.
