In vitro and in vivo activities of SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida.

SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from 64 microg/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus and Aspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD(50)s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD(50)s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD(50)s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistant Candida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD(50)s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD(50)s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against serious Aspergillus or Candida infections.

Sch 39304, a new antifungal agent: oral and topical treatment of vaginal and superficial infections.

Sch 39304 is a new broad spectrum triazole antifungal agent that is active, orally and topically, against superficial Trichophyton mentagrophytes and vaginal Candida albicans infections. Sch 39304 was compared to fluconazole (FLZ) in a T. mentagrophytes infection model in guinea pigs. Following topical administration, Sch 39304 (0.125%, twice daily, 10 days), was 5-8-fold more effective than FLZ, based on culture and lesion score results. Following oral administration, Sch 39304 (2.5 mg kg-1, once daily, 10 days) produced a dramatic reduction in lesion scores and was 20-fold more active than FLZ; however, due to the length of time it takes for the drugs to reach the infected area of the skin and eradicate the infections, most animals remained culture positive with both drugs. Sch 39304 was also compared with FLZ in a vaginal C. albicans infection in hamsters. Following oral administration (4 days), Sch 39304 (1.6 mg kg-1), cured all hamsters and was 4-fold more active than FLZ. In addition, Sch 39304 as a single oral dose (10 mg kg-1) also cured all hamsters. When treatment was intravaginal (8 days), Sch 39304 was again more active than FLZ (2-fold), and also micronazole (8-fold), with 100% of the hamsters cured at concentrations as low at 0.025%.

Relationship among physicochemical properties, skin permeability, and topical activity of the racemic compound and pure enantiomers of a new antifungal.

The topical antifungal Sch-39304 is a racemic compound comprised of two enantiomers, Sch-42427 and Sch-42426, only one of which (Sch-42427) is pharmacologically active. The pure enantiomers have a lower melting point and, therefore, a higher solubility than the racemic compound. Because of these differences in physicochemical properties, the concentration of the pure enantiomers in vehicles and in the skin was predicted to be an order of magnitude higher than the racemic compound. It was hoped that the pharmacological activity would also be higher. By measuring the flux of the chiral forms through human cadaver skin, the expected differences in skin solubility were confirmed. However, only a minimal difference between racemate and active enantiomer was observed in the lesion scores using a guinea pig dermatophyte model. By fitting the data to the Emax pharmacodynamic model, it is demonstrated that the maximum effect occurs at a concentration lower than the saturated concentration of the less soluble racemic compound. The data illustrate that the efficacy of topically active compounds may not be linearly related to drug concentration in either the vehicle or the skin.

Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.

In vitro and in vivo activities of SCH 42427, the active enantiomer of the antifungal agent SCH 39304.

SCH 39304, a new triazole antifungal agent, is a 50:50 racemic mixture of two enantiomers, SCH 42427 and SCH 42426. The activities of these three compounds were compared in a series of in vitro and in vivo experiments. SCH 42427 was twofold more active in vitro against a variety of yeasts and dermatophytes than SCH 39304, while SCH 42426 was inactive (MICs greater than 64 micrograms/ml). In a systemic Candida albicans infection in mice, SCH 42427 administered orally (p.o.) (50% protective dose [PD50], 0.17 mg/kg of body weight; 50% effective dose, [ED50], 0.47 mg/kg) had greater efficacy than SCH 39304 (PD50, 0.21 mg/kg; ED50, 0.62 mg/kg) and SCH 42426 (greater than 100 mg/kg for PD50 and ED50). In a pulmonary Aspergillus flavus infection in mice, SCH 42427 p.o. (PD50, 13 mg/kg) was also more effective than SCH 39304 (18 mg/kg) and SCH 42426 (greater than 250 mg/kg). In a C. albicans vaginal infection in hamsters, SCH 42427 p.o. (ED50, 3.5 mg/kg) was more active than SCH 39304 (8.5 mg/kg) and SCH 42426 (320 mg/kg). Following topical administration, against a Trichophyton mentagrophytes infection in guinea pigs, SCH 42427 was about 2-fold more active than SCH 39304 and about 100-fold more active than SCH 42426. These and other results indicated that SCH 42427 is the active enantiomer, responsible for all the antifungal activity observed with SCH 39304.

Comparison of SCH 39304, fluconazole, and ketoconazole for treatment of systemic infections in mice.

SCH 39304 was compared with fluconazole and ketoconazole in a systemic Candida albicans infection in mice (10(6) CFU per mouse). Results were based on survival rates and CFU in kidneys following once-daily oral treatment of 2, 5, or 10 days duration. In normal mice, SCH 39304 (dose to reduce kidney counts by 4 log units, 0.5 mg/kg of body weight) was 3 and 200 times more active than fluconazole and ketoconazole, respectively. In immunocompromised mice (gamma irradiation, 600 rads), SCH 39304 (dose to reduce kidney counts by 4 log units, 1.3 mg/kg) was 35 and greater than 100 times more active than fluconazole and ketoconazole, respectively. In normal mice, when the infecting inoculum varied from 10(5) to 10(7) CFU, only a fivefold increase in the dose to reduce kidney counts by 4 log units was observed with SCH 39304. Excellent protection was also seen when mice were treated with a single oral dose of SCH 39304 up to 24 h prior to infection with C. albicans. Studies in a systemic C. albicans infection model indicated that SCH 39304 is equally efficacious following either oral or intravenous administration. In a systemic Aspergillus flavus infection, mice treated with SCH 39304 (5 mg/kg) survived twice as long (16 days) as those treated with fluconazole (50 mg/kg) or controls did.

Comparative in vitro and in vivo evaluation of N-D-ornithyl amphotericin B methyl ester, amphotericin B methyl ester, and amphotericin B.

N-D-Ornithyl amphotericin B methyl ester (O-AME), a semisynthetic derivative of amphotericin B methyl ester (AME), was compared with amphotericin B (AMB) and AME. In vitro, O-AME was more active than the other two against Candida spp. and other fungi and was only slightly affected by inoculum size, addition of serum, or changes in pH. In vivo, the dose of O-AME required to produce a 10,000-fold reduction of Candida albicans in a mouse kidney infection was similar to that of AMB and 1/10 that of AME. After intravenous treatment of infected mice and rats and subcutaneous treatment of mice, average 50% protective doses for O-AME and AMB were similar. Acute intravenous 50% lethal doses in mice indicated that O-AME was one-ninth as toxic as AMB but twice as toxic as AME. Acute renal function tests in rats indicated that Sch 28191 was less than 1/10 as toxic as AMB and slightly more toxic than AME. On this basis, the calculated advantage relative to AMB (with AMB equal to 1) was 8 for O-AME and 1.5 for AME.

Amino acid analogs. III: New syntheses of monomethyl- and monophenylglutamic acids.

Glutamic acid analogs containing 3- and 4-methyl and 2-, 3-, and 4-phenyl substituents were prepared. The 3- and 4-methyl- and 3- and 4-phenylglutamic acids did not inhibit Plasmodium berghei and were nontoxic to the host (mice) at 640 mg/kg. The five analogs in addition to 2-methlglutamic acid were inactive against Lactobacillus casei at 1000 mug/ml in a defined medium: against Escherichia coli, only 2-methylglutamic acid caused 27% inhibition at 10,000 mug/ml. All six analogs failed to inhibit Aspergillus niger, Aspergillus oryzae, Trichoderma viride, and Myrothecium verrucaria in a defined medium below 10,000 mug/ml.

Reversal of fungitoxicity of 8-quinolinols and their copper (II) bischelates. I. Amino acids and related compounds.

The effect of amino acids and related compounds on the toxicity of 8-quinolinols and their copper (II) bischelates to Aspergillus oryzae (ATCC 1011) Was studied. None of the compounds tested except the thiol-containing compounds, cysteine, cysteamine, glutathione, and N-acetylcysteine reversed the inhibitory action of 8-quinolinol but not that of 5-iodo-8-quinolinol or bis (8-quinolinolato) copper (II). It appears that the mechanism(s) of fungitoxicity of 8-quinolinol is different from that of 5-iodo-8-quinolinol or bis(8-quinolinolato) copper (II.).

Antifungal properties of 2-alkenoic acids and 2-bromo alkanoic acids.

The antifungal activity of homologous series of 2-alkenoic and 2-bromo alkanoic acids was determined against Aspergillus niger, Trichoderma viride, Myrothecium verrucaria, and Trichophyton mentagrophytes and compared with data on analogous alkanoic and 2-fluoro alkanoic acids. The fungitoxicity of all of the series of compounds was determined by chain length, pH of the medium, and presence or absence of adsorbents such as serum albumin. The order of toxicity on a molecular basis, by using a scale where the most active series is 1.0, is 2-bromo alkanoic acids (1.0) > 2-fluoro alkanoic acids (1.2) > alkanoic acids (1.4) > 2-alkenoic acids (2.5).

Antifungal activity of 5-, 7-, and 5,7-substituted 2-methyl-8-quinolinols.

2-Methyl-8-quinolinol and sixteen 5-, 7-, and 5,7-substituted derivatives with fluoro, chloro, bromo, iodo, nitro, and amino substituents were tested for in vitro antifungal activity against five fungi, Aspergillus niger, A. oryzae, Trichoderma viride, Myrothecium verrucaria, and Trichophyton mentagrophytes. The 5,7-dichloro and 5,7-dibromo derivatives were the most fungitoxic of the compounds tested. With the exception of these two compounds and 5-iodo-2-methyl-8-quinolinol, the 2-methyl analogues were less active than the corresponding 8-quinolinols.

Antifungal activity of substituted nitrobenzenes and anilines.

Series of 1,3-dihalogeno-5-nitrobenzenes, 3- and 3,5-halogenoanilines, and 2,6-dihalogeno-4-nitroanilines were tested for fungitoxicity against Aspergillus niger, A. oryzae, Trichoderma viride, Myrothecium verrucaria, and Trichophyton mentagrophytes in shaken culture by using Sabouraud dextrose broth enriched with yeast extract as the test medium. 1,3-Dichloro-5-nitrobenzene, 1,3-dibromo-5-nitrobenzene, 3-iodoaniline, 3,5-dichloroaniline, and 3,5-dibromoaniline were found to possess sufficient activity, compared with 8-quinolinol, to warrant further study.