In vitro muscarinic activity of spiromuscarones and related analogs.

The cholinergic hypothesis of Alzheimer's disease suggests that cholinergic agonists may have therapeutic potential for treating the attendant memory deficits of the disease. As part of a program aimed at preparing metabolically stable, nonquaternary analogs of muscarone, 1-oxa-2,8-dimethyl-8-azaspiro[4.5]decan-3-one, 2a, and related analogs have been synthesized and their in vitro muscarinic activity evaluated. The synthetic strategy in the formation of the 1-spiro[4.5]decan-3-one ring system of 2a involved cyclization of the diol 4 in the presence of Nafion-Hg. The spiromuscarone 2a was found to displace [3H]Oxo-M binding with a Ki value of 7 nM. Affinities of the oxime and hydrazone analogs of 2a were lower than 2a. The compounds in these series were partial muscarinic agonists as demonstrated by stimulation of phosphatidyl inositol hydrolysis assay, with 2a showing the highest intrinsic intrinsic activity (60% as compared with carbachol). The results from this study indicate that an exo double bond at the C-3 position is essential for the receptor binding.

Perioperative creatine phosphokinase trends in elderly patients with hip fracture.

A prospective study of the serum levels of unfractionated creatine phosphokinase (CPK) in 69 consecutive elderly patients undergoing surgery for hip fracture is reported. Serum unfractionated CPK levels were measured on admission, on the evening following surgery and daily for the first five days post-operatively. All of the CPK levels measured on admission were within the normal range for this laboratory. A gradual rise in CPK levels followed surgery. On the evening following surgery 75% of values were greater than the upper limit of the normal reference range. The peak values were seen on day 1 post-operatively but 25% of values were still less than the reference maximum. A gradual decline was seen after this and at day 5 post operatively 50% of values were within the normal reference range. A single unfractionated CPK determination is not of diagnostic benefit in the post-operative period in elderly patients with hip fracture. However, patients with intracapsular and intertrochanteric fractures do not show elevation of unfractionated CPK levels prior to surgery.

Studies on antifungal agents. Novel cis-5-alkyl (or alkenyl)-3-phenyl-3-(1H-azol-1-ylmethyl)-2-methyl-isoxazolidine derivatives.

The preparation and in vitro antifungal activity of a novel series of cis-5-alkyl (or alkenyl)-3-phenyl-3-(1H-azol-1-ylmethyl)-2-methylisoxazol idines are described. The overall activity of the 3-(1H-imidazol-1-ylmethyl) analogues was higher than that of the corresponding 3-(1H-1,2,4-triazol-1-ylmethyl) derivatives. Compound 4b emerged as the most potent derivative. When compared to ketoconazole, several of the analogues tested demonstrated equipotent or superior activity against Trichophyton and Candida sp.

Studies on antifungal agents. In vitro activity of novel cis-5-alkoxy (or acyloxy)alkyl-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine derivatives.

The synthesis and in vitro antifungal activity of a novel series of cis-5-alkoxy(or acyloxy)alkyl-3-phenyl-3-(1H-imidazol-1-ylmethyl)- 2-methylisoxazolidine derivatives (6a-n) are described. The 5-[(4-chlorobenzyloxy)methyl] analogue 6h and the two 5-acyloxymethyl derivatives 6k,l demonstrated the best overall potency. Against Candida stellatoidea, the minimum inhibitory concentrations (MIC's) for 6h,k,l ranged between 0.7 and 2.0 micrograms/ml. The corresponding value for the standard drug ketoconazole was 7-20 micrograms/ml.

Novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-l-ylmethy)-2-methylisoxazolidine derivatives.

The synthesis and antifungal activity of a series of novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-1-ylmethyl)-2- methylisoxazolidine derivatives are described. When tested in vitro in solid agar assays, some of the compounds demonstrated moderate to potent activity against Trichophyton rubrum and Candida albicans.

Antifungal activity of novel 5-carbonyl derivatives of 3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines.

The synthesis and antifungal activity of a series of novel 5-carbonyl derivatives of 3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines (4) are discussed. The preparation of the title compounds involved a 1,3-dipolar cycloaddition reaction of alpha-substituted ketonitrones with either acrylic esters, acrylamide or methyl vinyl ketone to furnish cis/trans-diastereomeric mixtures of the desired 5-carbonyl isoxazolidines 4. The anifungal activity was evaluated in vitro in solid agar cultures. Some of the compounds tested exerted moderate to potent activity against a wide variety of dermatophytes and yeast and systemic fungi.

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. 20. Effect of the nitrogen substitution on the in vitro activity of novel 3,5-substituted isoxazolidines.

The effect of the nitrogen substitution on the in vitro antifungal activity of a series of novel cis-3,5-substituted isoxazolidine derivatives is investigated. The 2-(N-methyl) analogues 4-6 were found to be the most active compounds when tested in vitro against Trichophyton rubrum, Aspergillus fumigatus and Candida albicans, with MIC values ranging between 0.7 and 70 micrograms/ml.

Studies on antifungal agents. 19. Effect of the C-5-aromatic substitution on the in vitro activity of novel 3,5-substituted isoxazolidines.

The influence of the C-5-aromatic substitution on the in vitro antifungal activity of novel cis-3,5-substituted isoxazolidine derivatives was investigated. Compounds having a C-5-(substituted phenoxy)methyl group were found to be the most active against Trichophyton rubrum, Aspergillus fumigatus and Candida albicans with MIC values ranging from 0.7 to 70.0 micrograms/ml. Replacing the phenoxymethyl group with either naphthyl or 2-oxo-1,3-benzoxathiol-6-yl groups resulted in a diminished in vitro activity.

5-( [aryl or aryloxy (or thio)]methyl)-3-(1H-imidazol-1-ylmethyl)-3- (2-thienyl)-2-methylisoxazolidine derivatives as novel antifungal agents.

The in vitro antifungal activity of a novel series of cis- and trans-5-([aryl or aryloxy (or thio)]methyl)-3-(1H-imidazol-1-ylmethyl)-3- (2-thienyl)-2-methylisoxazolidines (13-24) was evaluated and compared with ketoconazole. The title series of compounds was prepared via a 1,3-dipolar cycloaddition reaction of 1-(2-thienyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxides with appropriate styrenes, allyl phenyl ethers, or allyl phenyl thioether precursors. The resulting products were mixtures of the corresponding cis- and trans-diastereomers which were readily separated by flash chromatography on neutral silica gel. The majority of compounds 13-24, when tested in solid agar cultures, exhibited moderate to potent activity against Trichophyton rubrum, Aspergillus fumigatus, and Candida albicans at concentrations ranging between less than or equal to 2.0 and 70.0 micrograms/mL.

Studies on antifungal agents. 23. Novel substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)- 2-alkylisoxazolidine derivatives.

The synthesis and antifungal activity of a novel series of substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-alkylisoxazolidine derivatives (15-30) are described. The synthesis of the title compounds was accomplished via a 1,3-dipolar cycloaddition reaction of alpha-substituted ketonitrones with appropriate styrene precursors. The compounds when tested in vitro in solid agar cultures exerted a very potent antifungal activity against a wide variety of yeast and systemic mycoses and dermatophytes, especially Trichophyton and Microsporum sp., Epidermophyton floccosum and Candida stellatoidea. The in vitro activity against Aspergillus fumigatus and Candida albicans was moderate to potent. Overall, the two bis(4-chlorophenyl) analogues 18 and 19 were the most potent in vitro compounds, showing MIC values ranging between 0.2 and 7.0 microgram/mL, as compared to 0.2-20.0 micrograms/mL for ketoconazole, which was used as the positive standard in all assays. When tested in vivo in the rat vaginal candidiasis model, derivative 18, although showing significant antifungal activity when compared to controls, was less effective than ketoconazole. The title 3,5-substituted isoxazolidine compounds represent a novel class of potent antifungal agents.

Studies on antifungal agents. 17. Effects of the C-5-substitution on the in vitro activity of novel 3,5-substituted isoxazolidines.

A number of novel 5-(substituted thiomethyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2- methylisoxazolidine derivatives were prepared and evaluated in vitro for antifungal activity in solid agar cultures against Trichophyton rubrum, Aspergillus fumigatus and Candida albicans. The effect of the 5-(substituted thiomethyl) group on the degree and scope of activity was studied and compared to that of the corresponding 5-phenoxymethyl and 5-[(substituted phenyl)thio(or amino)methyl] derivatives.