G. B. Mullen

Selection of orally active antifungal agents from 3,5-substituted isoxazolidine derivatives based on acute efficacy-safety profiles.

Routine in vitro screening of a new synthetic series of 3,5-substituted 2-methylisoxazolidines revealed that three imidazole analogs (PR 967-248, PR 967-234, and PR 969-566) and, to a lesser extent, a triazole analog (PR 988-399) exerted rather potent antifungal activity against three systemic and four dermatophytic classes of fungi. When tested in vivo for ability to eradicate Candida vaginitis in the rat, the triazole derivative, PR 988-399, was effective after oral administration. In this in vivo test for efficacy, PR 967-234 and PR 969-566 reduced but did not eradicate the infection, while PR 967-248 was inactive. PR 988-399 was, moreover, 4- to 13-fold less potent than the three imidazoles in inhibiting testosterone synthesis in isolated rat Leydig cells. After oral or intravenous administration, PR 988-399 and PR 969-566 elicited the fewest cardiovascular and behavioural side effects in conscious dogs. The rat safety study consisted of oral dosing followed by evaluation of the exploratory motor activity of the naive animals in a novel environment. Motor activity was suppressed least by PR 988-399 and most by PR 969-566. In a battery of mouse behavioural-neuromuscular-drug interaction tests, PR 988-399 and PR 969-566 produced the fewest central-behavioural-neuromuscular signs. These efficacy-safety evaluations were performed with ketoconazole as a positive reference standard. The sequence of drug testing with respect to efficacy-safety considerations appears to be a suitable approach for early detection of orally active antifungal agents such as PR 988-399 for more advanced development.

Studies on antifungal agents. 27. Novel 5-{[(substituted phenyl)thio]-methyl}isoxazolidines

Abstract The synthesis and antifungal activity of a series of novel 5-(substituted phenyl)thio]methylisoxazolidine derivatives are discussed. The title compounds were prepared by 1,3-dipolar cycloaddition reaction of α-substituted ketonitrones with allyl phenyl sulfides to provide diastereometric mixtures of the corresponding cis/trans -analogues. When tested in solid agar cultures, the title derivatives exerted moderate to potent in vitro antifungal activity against a number of dermatophytes and fungi causing systemic infections. The minimum inhibitory concentration (MIC) values ranged between

Adamantylmethyl analogues of chloramphenicol

Abstract The synthesis and biological activity of novel adamantylmethyl analogues of chloramphenicol are described. Substituting the polar para -nitro group on the phenyl ring with a non-polar lipophilic adamantylmethyl moiety resulted in a diminished antimicrobial activity. At a daily dose of 3 mg/kg the threo -4-[2′-tricyclo[3.3.1.1 3,7 ]decylidene)-methyl-1-[1″, 3″-dihydroxy-2″-(α,α-dichloroacetamido)propyl]benzene caused a significant loss of humoral immuno-competence in the T-dependent Kennedy plaque assay in mice.