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.

Novelties in the Field of Anti‐infectives in 1997

“…In rat systemic infections due to Aspergillus, after an oral dose of 1.0 mg/kg b.i.d., it showed good activity (but less than that of amphoteri- cin B). It is more active than fluconazole in rabbit systemic candidosis [99].…”

Optimization of Fluconazol Synthesis: An Important Azole Antifungal Drug

“…A rota sintética proposta é composta por três etapas, onde a primeira consistiu na acilação de Friedel-Crafts no 1,3difluorobenzeno (3) com o uso de cloreto de α-cloroacetila com catálise por cloreto de alumínio (Esquema 5). 19…”

“…Os carbonos C-1, C-3, C-5 e C-6 apresentaram-se como duplos dupletos com diferentes constantes de acoplamentos. Já C-7 e C-9/9' puderam ser observados como dois dupletos com (J = 5 Hz) em 73,0 e 54,3 ppm, respectivamente.O espectro de RMN19 F mostrou os dois sinais referentes a F-2 e F-4, os quais geraram multipletos em -111,4 e -107,4 ppm devido ao acoplamento com os núcleos de hidrogênio presentes na molécula (Figura 8).…”

Treatment of murine cryptococcal meningitis with UR-9751 and UR-9746

“…UR-9746 at 10 mg kg ¼ 1 was superior to 1 mg kg ¼ 1 doses, uconazole and controls. were encouraging [6,7]. Both compounds were found to be active in ×itro and in ×i×o against Coccidiodes immitis [9,10], Candida sp.…”

“…Accordingly, there is a reason to search for new and potentially more effective alternatives to uconazole. Two such alternatives are the azoles UR-9751 and UR-9746 (from J. Uriach and Cia, S.A., Barcelona, Spain) [6]. Initial studies in mice suggested that these are ef cacious in murine cryptococcosis [7].…”