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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
20
|
| pubmed:dateCreated |
1995-11-8
|
| pubmed:abstractText |
A series of azole derivatives carrying an N-acylmorpholine ring are described. The compounds were chemically designed to simulate the lanosterol D ring, taking advantage of the conformational preferences of 2-alkyl-1-acylmorpholines. Three structural variables, the nature of the N-benzoyl group, the phenyl substituents, and the degree of oxidation at carbon 2 of the morpholine, were optimized for maximum activity. Only the (5R,6R) isomers showed antifungal activity. Cyclic hemiacetal (-)-39a (UR-9746) and cyclic ether (-)-41 (UR-9751) were selected for further development. In vitro, (-)-41 was clearly more active than (-)-39a and somewhat less active than the acyclic counterpart (-)-7. In vivo activity was assessed by a systemic (mouse) and a vaginal (rat) candidosis model. In the former, (-)-39a, (-)-41, and (-)-7 at 1 mg/kg given 1, 4, and 24 h postinfection displayed 90-100% protection from mortality on day 9. Compound (-)-39a was slightly more potent than (-)-41 and similar in potency to (-)-7. The three compounds were superior in potency to fluconazole and similar in potency in SCH-42427 in this test. In the vaginal model, (-)-39a and (-)-41 given daily during 3 days after infection at 0.5 mg/kg showed high levels of protection on days 10 and 15. At 0.25 mg/kg, (-)-39a was slightly more potent than SCH-42427 and (-)-7 and superior in potency to (-)-41 and fluconazole in this model. Preliminary 28-day toxicity tests at 100 mg/kg/day po in rats indicated no or very mild adverse effects for the two UR compounds.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Sep
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
29
|
| pubmed:volume |
38
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3918-32
|
| pubmed:dateRevised |
2003-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:7562925-Animals,
pubmed-meshheading:7562925-Antifungal Agents,
pubmed-meshheading:7562925-Azoles,
pubmed-meshheading:7562925-Candidiasis,
pubmed-meshheading:7562925-Female,
pubmed-meshheading:7562925-Male,
pubmed-meshheading:7562925-Mice,
pubmed-meshheading:7562925-Microbial Sensitivity Tests,
pubmed-meshheading:7562925-Rats,
pubmed-meshheading:7562925-Rats, Wistar,
pubmed-meshheading:7562925-Stereoisomerism,
pubmed-meshheading:7562925-Structure-Activity Relationship
|
| pubmed:year |
1995
|
| pubmed:articleTitle |
Synthesis and antifungal activity of new azole derivatives containing an N-acylmorpholine ring.
|
| pubmed:affiliation |
Research Center, J. Uriach & Cía. S.A., Barcelona, Spain.
|
| pubmed:publicationType |
Journal Article
|