Synthesis and oral antifungal activity of novel azolylpropanolones and related compounds.

To find orally active antifungal agents, novel imidazolyl- and 1,2,4-triazolylpropanolones I and related compounds II-IV were synthesized. Compounds I were derived from ketones V (method A), alpha-diketone IX (method B), alpha-hydroxy ketones X (method C), alpha-chloro ketone XII (method D), and enones VI (method E). Diols II, synthesized from I with NaBH4, were cyclized to five-membered cyclic compounds III by using N,N'-carbonyldiimidazole, thionyl chloride, N,N'-(thiocarbonyl)diimidazole, bromochloromethane, 2,2-dimethoxypropane, and cyclohexanone dimethyl ketal. Diols IV were synthesized from I by Grignard reaction (method F), hydroxymethylation of X (method G), and reaction of ketones XXI with 1-[(trimethylsily)methyl]-1,2,4-triazole (method H). Compounds I-IV were examined for their antifungal activities in vitro by evaluation of broth dilution MIC values against three species of fungi and the inhibitory effect on pseudomycelium of Candida albicans, and they were examined for oral efficacy in vivo against subacute systemic candidiasis in mice and superficial dermatophytosis in guinea pigs. Compounds 2, 12, 38, 39, and 92 exhibited strong oral antifungal activity. An asymmetric synthesis and the structure-activity relationships of the compounds examined are discussed.

Postoperative bronchopleural fistula: clinical and experimental study.

It is a well-known fact that in pulmonary tuberculosis patients treated by resection, the quality of the suture material used for closing the bronchial stump plays an important role in the pathogenesis of postoperative bronchopleural fistula. Of 426 cases treated surgically and in whom silk suture thread was used, 23 developed bronchopleural fistula, whereas none of the 220 cases sutured with nylon monofilament developed abnormality. Statistical analysis of 100 surgical cases with silk thread suture and of 100 cases with nylon monofilament suture showed that the two groups had no marked differences as to background factors. Howevers, as compared with the silk-thread suture group, the nylon-monofilament suture group revealed more consistently favorable postoperative bronchoscopic findings. Experimental studies with dogs showed a similar lack of complications when the monofilament suture material was used, as contrasted were conducted in hospital by the same surgical personnel using the same procedures, it can be said that, to insure prevention of complications, the suture material for bronchial stump closure should be of non-irritating nature and preferably of monofilament strength and quality, such as nylon monofilament.

Reaction of 3-acetonyl-5-cyano-1,2,4-thiadiazole with phenylhydrazine hydrochlorides: indolization and phenylpyrazolation.

Treatment of 3-acetonyl-5-cyano-1,2,4-thiadiazole (1) with 4-methyl or 4-methoxyphenylhydrazine hydrochloride provided 5-cyano-3-(2,5-dimethylindol-3-yl)-1,2,4-thiadiazole (2) or 5-cyano-3-(5-methoxy-2-methylindol-3-yl)-1,2,4-thiadiazole (3) as the sole product, respectively. In contrast, treatment of 1 with phenylhydrazine hydrochloride resulted in the formation of 5-cyano-3-(2-methylindol-3-yl)-1,2,4-thiadiazole (4) and the unexpected 5-cyano-3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-1,2,4-thiadiazole (5). In a similar manner, when 1 was treated with 4-chlorophenylhydrazine hydrochloride, indolization was suppressed by phenylpyrazolation giving rise to 5-cyano-3-(5-chloro-2-methylindol-3-yl)-1,2,4-thiadiazole (6) and 5-cyano-3-[1-(4-chlorophenyl)-3,5-dimethylpyrazol-4-yl]-1,2,4-thia diazole (7). The reaction mechanism is discussed. Compounds 4, 5 and 6 exhibited weak antimicrobial activity against Helicobacter pylori.