title: Synthesis and antifungal activity of new azole derivatives containing an N-acylmorpholine ring.
abstract: 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.
authors.affiliation: Research Center, J. Uriach & Cía. S.A., Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Bartroli
authors.forename: E
authors.initials: E
authors.lastname: Turmo
authors.forename: M
authors.initials: M
authors.lastname: Algueró
authors.forename: E
authors.initials: E
authors.lastname: Boncompte
authors.forename: M L
authors.initials: ML
authors.lastname: Vericat
authors.forename: J
authors.initials: J
authors.lastname: García-Rafanell
authors.forename: J
authors.initials: J
authors.lastname: Forn
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001393:Azoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002177:Candidiasis / Q000188:drug therapy; D005260:Female; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D001393:Azoles