Synthesis and Antifungal Activities of R-102557 and Related Dioxane-Triazole Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 48; no. 5; pp. 694 - 707
• Main Authors: OIDA, Sadao, TAJIMA, Yawara, KONOSU, Toshiyuki, NAKAMURA, Yoshie, SOMADA, Atsushi, TANAKA, Teruo, HABUKI, Shinobu, HARASAKI, Tamako, KAMAI, Yasuki, FUKUOKA, Takashi, OHYA, Satoshi, YASUDA, Hiroshi
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.05.2000; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; antifungal; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Aspergillosis - drug therapy; Aspergillosis - microbiology; Aspergillus flavus; Aspergillus fumigatus; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cryptococcosis - microbiology; Cryptococcus neoformans; Dioxanes - chemical synthesis; Dioxanes - pharmacology; Dioxanes - toxicity; lanosterol 14-demethylase; Life Sciences & Biomedicine; Mass Spectrometry; Medical sciences; Mice; Microbial Sensitivity Tests; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; R-102557; Rats; Rats, Inbred F344; Science & Technology; Spectrophotometry, Infrared; Stereoisomerism; Structure-Activity Relationship; synthesis; triazole; Triazoles - chemical synthesis; Triazoles - pharmacology; Triazoles - toxicity; synthesis; AZOLES; ROUTE; ORAL TRIAZOLE; STEREOISOMERS; PRECURSOR; ER-30346; R-102557; triazole; AGENT; antifungal; LANOSTEROL; structure-activity relationship; lanosterol 14-demethylase; Candida albicans; Candidiasis; Five membered ring; Intraperitoneal administration; Mycosis; Cryptococcus neoformans; Nitrogen heterocycle; Oxygen heterocycle; Fungi; Stereoselectivity; Aspergillus; Antifungal agent; Structure activity relation; Tertiary alcohol; Six membered ring; Fungi Imperfecti; Chemical synthesis; Thallophyta; Organic hydroxysulfide; Dioxane derivatives; Rodentia; Benzene derivatives; Cryptococcosis; Oral administration; In vitro; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Aspergillosis; Triazole derivatives; Fluorine Organic compounds
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.48.694

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 th side chain. Among the derivatives, R-102557 (16R : Ar=4-(2, 2, 3, 3)-tetrafluoropropoxy)phenyl)showed excellent in vivo activities against Candida, As-pergillus and Cryptococcus species. It also showed high tolerance in a preliminary toxicity study in rats.