scholarly journals Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

1998 ◽  
Vol 42 (10) ◽  
pp. 2495-2502 ◽  
Author(s):  
Maurizio Del Poeta ◽  
Wiley A. Schell ◽  
Christine C. Dykstra ◽  
Susan Jones ◽  
Richard R. Tidwell ◽  
...  
Keyword(s):  
Fungicidal Activity ◽  
Antifungal Agents ◽  
In Vitro Activity ◽  
Primary Metabolites ◽  
Structure Activity ◽  
Fluconazole Resistant ◽  
Resistant Strains ◽  
Clinical Potential

ABSTRACT Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities againstCandida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active againstAspergillus fumigatus, Fusarium solani,Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential.

scholarly journals In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents.

1997 ◽  
Vol 41 (4) ◽  
pp. 763-766 ◽  
Author(s):  
M A Pfaller ◽  
S A Messer ◽  
S Coffman
Keyword(s):  
Amphotericin B ◽  
Fungicidal Activity ◽  
Antifungal Agents ◽  
Candida Parapsilosis ◽  
Clinical Laboratory ◽  
National Committee ◽  
In Vitro Activity ◽  
Medical Centers

LY303366 is a new semisynthetic echinocandin derivative with potent, broad-spectrum fungicidal activity. We investigated the in vitro activity of LY303366, amphotericin B, flucytosine (5FC), fluconazole, and itraconazole against 435 clinical yeast isolates (413 Candida and 22 Saccharomyces cerevisiae isolates) obtained from over 30 different medical centers. MICs for all five antifungal agents were determined by the National Committee for Clinical Laboratory Standards method with RPMI 1640 test medium. LY303366 was also tested in antibiotic medium 3 as specified by the manufacturer. Overall, LY303366 was quite active against all of the yeast isolates when tested in RPMI 1640 (MIC at which 90% of the isolates are inhibited [MIC90], 1.0 microg/ml) but appeared to be considerably more potent when tested in antibiotic medium 3 (MIC90, 0.03 microg/ml). When tested in antibiotic medium 3, LY303366 was 16- to >2,000-fold more active than itraconazole, fluconazole, amphotericin B, or 5FC against all species except Candida parapsilosis. When tested in RPMI 1640, LY303366 was comparable to amphotericin B and itraconazole and more active than fluconazole and 5FC. All of the isolates for which fluconazole and itraconazole had elevated MICs (> or = 128 and > or = 2.0 microg/ml, respectively) were inhibited by < or = 0.007 microg of LY303366/ml when tested in antibiotic medium 3 and < or = 0.5 microg/ml when tested in RPMI 1640. Based on these studies, LY303366 has promising antifungal activity and warrants further in vitro and in vivo investigation.

scholarly journals In Vitro Activities of Isavuconazole and Other Antifungal Agents against Candida Bloodstream Isolates

2007 ◽  
Vol 51 (5) ◽  
pp. 1818-1821 ◽  
Author(s):  
H. Seifert ◽  
U. Aurbach ◽  
D. Stefanik ◽  
O. Cornely
Keyword(s):  
Amphotericin B ◽  
Antifungal Agents ◽  
Tertiary Care ◽  
Common Species ◽  
University Hospital ◽  
Phase Iii ◽  
Highly Active ◽  
Fluconazole Resistant ◽  
Resistant Strains

ABSTRACT Isavuconazole is the active component of the new azole antifungal agent BAL8557, which is entering phase III clinical development. This study was conducted to compare the in vitro activities of isavuconazole and five other antifungal agents against 296 Candida isolates that were recovered consecutively from blood cultures between 1995 and 2004 at a tertiary care university hospital. Microdilution testing was done in accordance with CLSI (formerly NCCLS) guideline M27-A2 in RPMI-1640 MOPS (morpholinepropanesulfonic acid) broth. The antifungal agents tested were amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, and isavuconazole. C. albicans was the most common species, representing 57.1% of all isolates. There was no trend found in favor of non-Candida albicans species over time. In terms of MIC50s, isavuconazole was more active (0.004 mg/liter) than amphotericin B (0.5 mg/liter), itraconazole (0.008 mg/liter), voriconazole (0.03 mg/liter), flucytosine (0.125 mg/liter), and fluconazole (8 mg/liter). For isavuconazole, MIC50s/MIC90s ranged from 000.2/0.004 mg/liter for C. albicans to 0.25/0.5 mg/liter for C. glabrata. Two percent of isolates (C. glabrata and C. krusei) were resistant to fluconazole; C. albicans strains resistant to fluconazole were not detected. There were only two isolates with MICs for isavuconazole that were >0.5 mg/liter: both were C. glabrata isolates, and the MICs were 2 and 4 mg/liter, respectively. In conclusion, isavuconazole is highly active against Candida bloodstream isolates, including fluconazole-resistant strains. It was more active than itraconazole and voriconazole against C. albicans and C. glabrata and appears to be a promising agent against systemic Candida infections.

scholarly journals In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles

1998 ◽  
Vol 42 (10) ◽  
pp. 2503-2510 ◽  
Author(s):  
Maurizio Del Poeta ◽  
Wiley A. Schell ◽  
Christine C. Dykstra ◽  
Susan K. Jones ◽  
Richard R. Tidwell ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Candida Albicans ◽  
Fusarium Solani ◽  
Antifungal Agents ◽  
Antifungal Drugs ◽  
Inhibitory Compounds ◽  
Wide Range ◽  
Fluconazole Resistant ◽  
Resistant Strains

ABSTRACT Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities againstCandida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active againstAspergillus fumigatus, Fusarium solani,Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents.

scholarly journals Efficacy of BB-83698, a Novel Peptide Deformylase Inhibitor, in a Mouse Model of Pneumococcal Pneumonia

2004 ◽  
Vol 48 (1) ◽  
pp. 80-85 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. Mohler ◽  
J. P. Bédos
Keyword(s):  
Mouse Model ◽  
Lung Tissue ◽  
Resistant Strain ◽  
Peptide Deformylase ◽  
In Vitro Activity ◽  
Wild Type ◽  
Virulent Strains ◽  
Resistant Strains

ABSTRACT The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The Streptococcus pneumoniae isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 105 CFU (virulent strains) into immunocompetent mice or 107 CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 μg/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 μg/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 μg · h/ml for plasma and lung tissue, respectively. The emergence of S. pneumoniae isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against S. pneumoniae, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.

scholarly journals In Vitro Susceptibilities of Candida dubliniensisIsolates Tested against the New Triazole and Echinocandin Antifungal Agents

1999 ◽  
Vol 37 (3) ◽  
pp. 870-872 ◽  
Author(s):  
M. A. Pfaller ◽  
S. A. Messer ◽  
S. Gee ◽  
S. Joly ◽  
C. Pujol ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Agents ◽  
Clinical Laboratory ◽  
National Committee ◽  
Mucosal Disease ◽  
Fluconazole Resistant ◽  
Resistant Strains ◽  
Investigational Agents ◽  
Multidrug Resistance Transporters

Candida dubliniensis is a newly recognized fungal pathogen causing mucosal disease in AIDS patients. Although preliminary studies indicate that most strains of C. dubliniensis are susceptible to established antifungal agents, fluconazole-resistant strains have been detected. Furthermore, fluconazole-resistant strains are easily derived in vitro, and these strains exhibit increased expression of multidrug resistance transporters, especially MDR1. Because of the potential for the development of resistant strains of C. dubliniensis, it is prudent to explore the in vitro activities of several of the newer triazole and echinocandin antifungals against isolates of C. dubliniensis. In this study we tested 71 isolates of C. dubliniensis against the triazoles BMS-207147, Sch 56592, and voriconazole and a representative of the echinocandin class of antifungal agents, MK-0991. We compared the activities of these agents with those of the established antifungal agents fluconazole, itraconazole, amphotericin B, and 5-fluorocytosine (5FC) by using National Committee for Clinical Laboratory Standards microdilution reference methods. Our findings indicate that the vast majority of clinical isolates of C. dubliniensis are highly susceptible to both new and established antifungal agents. Strains with decreased susceptibilities to fluconazole remained susceptible to the investigational agents as well as to amphotericin B and 5FC. The increased potencies of the new triazole and echinocandin antifungal agents may provide effective therapeutic options for the treatment of infections due to C. dubliniensis.

scholarly journals Structure-activity relationship study for fungicidal activity of 1-(4-phenoxymethyl-2-phenyl-[1,3]dioxolan-2-ylmethyl)-1H-1,2,4-triazole derivatives against rice blast

2015 ◽  
Vol 55 (4) ◽  
pp. 383-388 ◽  
Author(s):  
Tomoki Hoshi ◽  
Kazuhiro Yamada ◽  
Yuko Yoshizawa ◽  
Keimei Oh
Keyword(s):  
Antifungal Activity ◽  
Rice Blast ◽  
Fungicidal Activity ◽  
Antifungal Agents ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Triazole Derivatives ◽  
Structure Activity ◽  
Ring Structures

Abstract To explore new antifungal agents for rice blast control, the antifungal activity of a series of novel 1,2,4-triazole derivatives against Magnaporthe oryzae has been evaluated. The antifungal activity was determined by using in vitro mycelial growth inhibition tests. Among the 19 test compounds, we found that the compound 1-(4-phenoxymethyl-2-phenyl-[1,3]dioxolan-2-ylmethyl)-1H-1,2,4- triazole (Gj) displayed potent antifungal activity against M. oryzae. The IC50 value was found approximately 3.8±0.5 μM and the IC50 value of propiconazole was found to be approximately 3.7±0.2 μM, respectively. Structure-activity relationship studies on aromatic ring structures provided insight and information about the structural requirements for antifungal activity of this synthetic series against M. oryzae.

scholarly journals Synthesis, Fungicidal Activity and SAR of 2-Thiazolamide/Pyrazolamide-Cyclohexylsulfonamides against Botrytis cinerea

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2607
Author(s):  
Zhang ◽  
Meng ◽  
Xie ◽  
Yang ◽  
Zhang ◽  
...  
Keyword(s):  
Fungicidal Activity ◽  
Condensation Reaction ◽  
Effective Concentration ◽  
Single Crystal Diffraction ◽  
X Ray ◽  
Structure Activity ◽  
Median Effective Concentration ◽  
Germination Experiment

In order to explore more efficient sulfonamides against Botrytis cinereal, 36 novel cyclohexylsulfonamides were synthesized by N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt) condensation reaction using chesulfamide as a lead compound, introducing thiazole and pyrazole active groups. Their structures were characterized by 1H-NMR, 13C-NMR, mass spectrum (MS), and elemental analysis. Compound III -31 was further confirmed by X-ray single crystal diffraction. The in vitro and in vivo fungicidal activities against B. cinerea were evaluated by three bioassay methods. The results of mycelial growth demonstrated that median effective concentration (EC50) values of nine compounds were close to boscalid (EC50 = 1.72 µg/mL) and procymidone (EC50 = 1.79 µg/mL) against B. cinerea (KZ-9). In the spore germination experiment, it was found that compounds III-19 and III-31 inhibited germination 93.89 and 98.00%, respectively; at 10 µg/mL, they approached boscalid (95.97%). In the tomato pot experiment, the control effects of two compounds (III-21 and III-27) were 89.80 and 87.90%, respectively, at 200 µg/mL which were significantly higher than boscalid (81.99%). The structure–activity relationship (SAR) was also discussed, which provided a valuable idea for developing new fungicides.

scholarly journals Efficacy of Cethromycin, a New Ketolide, against Streptococcus pneumoniae Susceptible or Resistant to Erythromycin in a Murine Pneumonia Model

2006 ◽  
Vol 50 (9) ◽  
pp. 3033-3038 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. Mohler ◽  
J. P. Bédos ◽  
C. Barau ◽  
B. Fantin
Keyword(s):  
Streptococcus Pneumoniae ◽  
Survival Rates ◽  
Administration Route ◽  
Serum Protein Binding ◽  
In Vitro Activity ◽  
Serotype 1 ◽  
Resistant Strains ◽  
Immunocompetent Mice

ABSTRACT Cethromycin is a ketolide with in vitro activity against macrolide-sensitive and -resistant strains of Streptococcus pneumoniae. We compared its in vivo efficacy to erythromycin in a mouse model of acute pneumonia induced by two virulent clinical strains: a serotype 3 susceptible strain (P-4241) (MICs: erythromycin, 0.03 μg/ml; cethromycin, 0.015 μg/ml) and a serotype 1 strain resistant to erythromycin (P-6254; phenotypically MLSB constitutive) (MICs: erythromycin, 1,024 μg/ml; cethromycin, 0.03 μg/ml). Immunocompetent mice were infected with 105 CFU of each strain. Six treatments given either subcutaneously (s.c.) or per os (p.o.) at 12-h intervals were initiated at 6 or 12 h after infection. Against P-4241, cethromycin given s.c. at 25 or 12.5 mg/kg protected 100% of the animals, with lungs and blood completely cleared of bacteria. Given p.o., cethromycin maintained its efficacy with 100 and 86% survival at 25 and 12.5 mg/kg, respectively. Erythromycin, given s.c. at 50 or 37.5 mg/kg, provided 50 and 38% survival rates, respectively. Against P-6254, cethromycin was effective at 25 mg/kg (100% survival) regardless of the administration route, whereas only 25 and 8% of animals survived after a 75-mg/kg erythromycin treatment given s.c. and p.o., respectively. The serum protein binding levels of cethromycin were 94.8 and 88.5% after doses of 12.5 and 25 mg/kg, respectively. The higher in vivo activity of cethromycin compared to erythromycin could be explained by favorable pharmacokinetic/pharmacodynamic indexes against P-6254 but not against P-4241.

scholarly journals In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum

2002 ◽  
Vol 46 (5) ◽  
pp. 1388-1393 ◽  
Author(s):  
Noboru Tsuchimori ◽  
Ryogo Hayashi ◽  
Naomi Kitamoto ◽  
Kentaro Asai ◽  
Tomoyuki Kitazaki ◽  
...  
Keyword(s):  
Clinical Isolates ◽  
Sterol Synthesis ◽  
In Vitro Activity ◽  
Promising Candidate ◽  
Once Daily ◽  
Fluconazole Resistant ◽  
Therapeutic Activities ◽  
In Vitro Antifungal Activity

ABSTRACT TAK-456 is a novel oral triazole compound with potent and broad-spectrum in vitro antifungal activity and strong in vivo efficacy against Candida albicans and Aspergillus fumigatus. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50% at 3 to 11 ng/ml. TAK-456 showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and Cryptococcus neoformans, except for Candida glabrata. The MICs at which 90% of the isolates tested were inhibited byTAK-456, fluconazole, itraconazole, voriconazole, and amphotericin B were 0.25, 4, 0.5, 0.13, and 0.5 μg/ml, respectively, for clinical isolates of C. albicans and 1, >64, 0.5, 0.5, and 0.5 μg/ml, respectively, for clinical isolates of A. fumigatus. Therapeutic activities of TAK-456 and reference triazoles against systemic lethal infections caused by C. albicans and A. fumigatus in mice were investigated by orally administering drugs once daily for 5 days, and efficacies of the compounds were evaluated by the prolongation of survival. In normal mice, TAK-456 and fluconazole were effective against infection caused by fluconazole-susceptible C. albicans at a dose of 1 mg/kg. In transiently neutropenic mice, therapeutic activity of TAK-456 at 1 mg/kg of body weight against infection with the same strain was stronger than those at 1 mg/kg of fluconazole. TAK-456 was effective against infections with two strains of fluconazole-resistant C. albicans at a dose of 10 mg/kg. TAK-456 also expressed activities similar to or higher than those of itraconazole against the infections caused by two strains of A. fumigatus in neutropenic mice at a dose of 10 mg/kg. These results suggest that TAK-456 is a promising candidate for development for the treatment of candidiasis and aspergillosis in humans.

Sign in / Sign up

Export Citation Format

Share Document