scholarly journals Non-toxic Cobalt(III) Schiff Base Complexes with Broad Spectrum Antifungal Activity

2020 ◽  
Author(s):  
Angelo Frei ◽  
A. Paden King ◽  
Gabrielle J. Lowe ◽  
Amy K. Cain ◽  
Francesca L. Short ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antifungal Activity ◽  
Broad Spectrum ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Schiff Base Complexes ◽  
In Vivo Studies

Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it stands to reason to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad spectrum antifungal activity. Some of these complexes (1-3) show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg/kg are tolerated without adverse effects, paving the way for further in vivo studies of these complexes. <br>

scholarly journals Non-toxic Cobalt(III) Schiff Base Complexes with Broad Spectrum Antifungal Activity

2020 ◽  
Author(s):  
Angelo Frei ◽  
A. Paden King ◽  
Gabrielle J. Lowe ◽  
Amy K. Cain ◽  
Francesca L. Short ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antifungal Activity ◽  
Broad Spectrum ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Schiff Base Complexes ◽  
In Vivo Studies

Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it stands to reason to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad spectrum antifungal activity. Some of these complexes (1-3) show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg/kg are tolerated without adverse effects, paving the way for further in vivo studies of these complexes. <br>

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

scholarly journals EVALUATION OF ANTIFUNGAL AND ANTIBACTERIAL ACTIVITY OF SOME NEW BENZIMIDAZOLE DERIVATIVES

2018 ◽  
Vol 48 (2) ◽  
pp. 125-129
Author(s):  
K. ZOMORODIAN ◽  
S. KHABNADIDEH ◽  
L. ZAMANI ◽  
K. PAKSHIR ◽  
M. TAJADDOD
Keyword(s):  
Antifungal Activity ◽  
Fungal Infections ◽  
Antimicrobial Activities ◽  
Antifungal Drugs ◽  
In Vivo Studies ◽  
Benzimidazole Derivatives ◽  
Dilution Method ◽  
Gram Positive ◽  
Meta Position

The extensive use of antifungal drugs and their resistance against fungal infections have led to discover new antimicrobial compounds. We previously described synthesis of some new derivatives of 2-methylbenzimidazole (1a-5a) and 5,6dimethylbenzimidazol (1b-5b). Here we evaluated the antimicrobial activities of these compounds against different species of micro organisms including gram positive and gram negative bacteria as well as fungi. Broth micro-dilution method as recommended by clinical and laboratory standard institute (CLSI) was used for this purpose. The results show compounds 2-Methyl-1-(3-methylbenzyl)-1H-benzo [d]imidazole (5a) and 5,6-Dimethyl-1-(3-methyl benzyl)-1H-benzo[d]imidazole (5b) had the best antifungal activity against the examined fungi and gram positive bacteria. Moreover these two compounds inhibited the growth of azole resistant strains. By comparison the relationship between the structures and activities of the tested compounds revealed that the presence of methyl residue in meta position of benzyl group enhance the antifungal activity. Regarding a broad spectrum antifungal activities of some of the tested compounds, they might be a good candidate for further in vivo studies to evaluate their pharmacological activity and toxicity as a novel antifungal agents.

scholarly journals Nontoxic Cobalt(III) Schiff Base Complexes with Broad‐Spectrum Antifungal Activity

2020 ◽  
Author(s):  
Angelo Frei ◽  
A. Paden King ◽  
Gabrielle J. Lowe ◽  
Amy K. Cain ◽  
Francesca L. Short ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antifungal Activity ◽  
Broad Spectrum ◽  
Schiff Base Complexes

scholarly journals Antifungal In Vitro Activity of Pilosulin- and Ponericin-Like Peptides from the Giant Ant Dinoponera quadriceps and Synergistic Effects with Antimycotic Drugs

Antibiotics ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 354 ◽  
Author(s):  
Hilania Valéria Dodou Lima ◽  
Carolina Sidrim de Paula Cavalcante ◽  
Gandhi Rádis-Baptista
Keyword(s):  
Antifungal Activity ◽  
Antimicrobial Peptides ◽  
Broad Spectrum ◽  
Culture Medium ◽  
Fungal Infections ◽  
Synergistic Effects ◽  
Antifungal Drugs ◽  
Clinical Strain ◽  
Onset Of Action

Venoms from ants comprise a rich source of bioactive peptides, including antimicrobial peptides. From the proteome and peptidome of the giant ant Dinoponera quadriceps venom, members of five known classes of antimicrobial peptides were disclosed (e.g., dermaseptin-, defensin-, ICK-, pilosulin- and ponericin-like types). Based on comparative analysis, these family members have structural determinants that indicate they could display antimicrobial activities. In previous works, pilosulin- and ponericin-like peptides were demonstrated to be active against bacteria, fungi, and parasites. Herein, the antifungal activity of ponericin- and pilosulin-like peptides were assessed, aiming at the expansion of the knowledge about AMPs in predatory ants and the development of new microbicide strategies to deal with difficult-to-treat fungal infections. Synthetic pilosulin- (Dq-2562, Dq-1503, and Dq-1319) and ponericin-like (Dq-3162) peptides were evaluated for their fungicide and fungistatic activities against different species of Candida, including a drug-resistant clinical strain. The MICs and MLCs were determined for all peptides individually and in combination with general antifungal drugs by the microdilution method. The time-kill kinetic curves were set up by means of a luminescent reagent, of which the light signal is proportional to the number of viable cells. The candicidal synergism observed by the combination of subinhibitory concentrations of peptides and general antimycotic drugs were quantified by the checkerboard test and fluorescent dye permeation assay. The influence of ergosterol on the antifungal activity was verified by supplementation of culture medium. The pilosulin- (Dq-2562 and Dq-1503) and ponericin-like (Dq-3162) were the most active peptides, displaying a broad spectrum of antifungal activity in vitro, with MICs in the range of 0.625 to 10 µM. The combination of peptides and conventional antimycotic drugs displayed a synergistic reduction in the MIC values of individual peptides and drugs, while soluble ergosterol in the culture medium increased the MICs. The fungicide and fungistatic activity of the individual peptides and peptides in combination with antimycotics were time-dependent with a rapid onset of action and long-lasting effect, which involved membrane disruption as an underlying mechanism of their action. Altogether, pilosulin- and ponericin-like peptides from the giant ant D. quadriceps venom display a broad-spectrum of candicidal activity, what allows their inclusion in the row of the antifungal peptides and gives support for further studies on the development of strategies to fight candidiasis.

scholarly journals Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Tatiana Y. Hargrove ◽  
Edward P. Garvey ◽  
William J. Hoekstra ◽  
Christopher M. Yates ◽  
Zdzislaw Wawrzak ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Aspergillus Fumigatus ◽  
Broad Spectrum ◽  
Fungal Infections ◽  
Enzymatic Reaction ◽  
Heme Iron ◽  
Antifungal Drugs ◽  
Drug Candidate ◽  
Investigational Drug ◽  
Content Type

ABSTRACT Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungus Aspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatus CYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis of A. fumigatus CYP51/voriconazole and Candida albicans CYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two A. fumigatus strains (strains 32820 and 1022) displayed a direct correlation between the effects of the drugs on CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-A. fumigatus potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent.

scholarly journals The celecoxib derivative AR-12 has broad spectrum antifungal activity in vitro and improves the activity of fluconazole in a murine model of cryptococcosis

2016 ◽  
pp. AAC.01061-16 ◽  
Author(s):  
Kristy Koselny ◽  
Julianne Green ◽  
Louis DiDone ◽  
Justin P. Halterman ◽  
Annette W. Fothergill ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Murine Model ◽  
Antifungal Drugs ◽  
Dimorphic Fungi ◽  
New Class ◽  
Cancer Agent

Only one new class of antifungal drugs has been introduced into clinical practice in the last thirty years and, thus, the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib-derivative which has been tested in a Phase I clinical trial as an anti-cancer agent. AR-12 inhibits fungal acetyl CoA synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity including active against yeasts (e.g.,C. albicans, non-albicansCandidaspp.,C. neoformans); molds (e.g.,Fusarium,Mucor), and dimorphic fungi (Blastomyces,Histoplasma, andCoccidioides) with minimum inhibitory concentrations of 2-4 μg/mL. AR-12 is also active against azole- and echinocandin-resistantCandidaisolates and sub-inhibitory AR-12 concentrations increase susceptibility of fluconazole- and echinocandin-resistantCandidaisolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad spectrum antifungal activity.

Preparation, characterizations and evaluation of antifungal activity of eugenol-linalool emulgel against anthrophilic dermatophytic trichophyton rubrum

2021 ◽  
pp. 1-15
Author(s):  
Abdullah Akram ◽  
Muhammad Khalid Khan ◽  
Barkat Ali Khan
Keyword(s):  
Antifungal Activity ◽  
Skin Infection ◽  
Trichophyton Rubrum ◽  
Sem Analysis ◽  
Antifungal Drugs ◽  
In Vivo Studies ◽  
Stability Studies ◽  
Antifungal Activities

Trichophyton rubrum (T. Rubrum) is responsible for chronic cases of dermatophytosis which have high rates of resistance to antifungal drugs worldwide. The aim of this study was to formulate an emulgel of Eugenol-Linalool for the treatment of T. Rubrum infections. The emulgel was prepared by slow emulsification method and characterized for physical examination, pH analysis, swelling index, stability studies, spreading coefficient, SEM analysis, thermal analysis and PXRD studies. In-vitro antifungal activities were performed by growing T. rubrum on specialized media in petri dishes. In-vivo antifungal activity was performed in rabbits by inducing the skin infection by application of fungal strain. Results indicated that the emulgel formulation is highly stable and the physical properties of the emulgel remained quite feasible. No deterioration was observed in the formulation and the pH remained the same as the pH of skin. The viscosity and spreadability of the emulgel remained highly compatible. The results of in vitro and in vivo studies indicated that the Eugenol and Linalool both inhibited the growth of T. rubrum. Eugenol was more effective in inhibition of zone (38±0.01 mm) of T. rubrum as compared to Linalool (32.9±0.03 mm). Similarly it was observed that when the combination of both Linalool and Eugenol was used, the growth of T. rubrum (42±0.01 mm) was significantly (P <  0.05) inhibited. It is hence concluded that the emulgel containing Eugenol and Linalool possess strong in vitro and in vivo antifungal activities against the commercial strains of anthrophilic dermophytic T. Rubrum.

Carvacrol essential oil stimulates growth performance, immune response, and tolerance of Nile tilapia to Cryptococcus uniguttulatus infection

2020 ◽  
Vol 141 ◽  
pp. 1-14 ◽  
Author(s):  
HH Mahboub ◽  
YH Tartor
Keyword(s):  
Antifungal Activity ◽  
Growth Performance ◽  
Nile Tilapia ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fish Growth ◽  
Immunological Parameters ◽  
Species Production

This study investigated the antifungal activity of 5 essential oils (EOs) towards yeasts recovered from diseased fishes; and focused on the efficacy of one EO (carvacrol) on growth performance, non-specific immunity, and disease resistance of Nile tilapia Oreochromis niloticus against Cryptococcus uniguttulatus challenge. Thymoquinone, thymol, carvacrol, eugenol, and cinnamon were first tested in vitro against 20 clinical yeast strains in comparison with antifungal drugs (fluconazole, ketoconazole, itraconazole, amphotericin B, nystatin, and clotrimazole) using disc diffusion and broth microdilution methods. For the in vivo challenge, fish (n = 150) were divided into 5 groups (carvacrol prophylaxis, carvacrol treatment, itraconazole treatment, unchallenged control, and positive control; 30 fish group-1) with 3 replicates. Phagocytic activity, reactive oxygen species production, reactive nitrogen species production, myeloperoxidase, lysozyme activity, and total immunoglobulins were tested before and after challenge. Relative percent survival (RPS) and mortality percent were determined as indicators for functional immunity. EOs displayed divergent degrees of antifungal activity, and carvacrol was the most effective against the tested yeasts. The dietary additive of carvacrol significantly enhanced growth performance, all immunological parameters, and the RPS values (90%) compared to other treatments. This unique experimental model indicates that carvacrol seems promising not only for enhancing immunity and promoting fish growth, but also for controlling emerging fungal infections. Future studies should investigate different concentrations of carvacrol as well as its antifungal activity in different fish species.

scholarly journals Nontoxic Cobalt(III) Schiff Base Complexes with Broad‐Spectrum Antifungal Activity

2020 ◽  
Author(s):  
Angelo Frei ◽  
A. Paden King ◽  
Gabrielle J. Lowe ◽  
Amy K. Cain ◽  
Francesca L. Short ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antifungal Activity ◽  
Broad Spectrum ◽  
Schiff Base Complexes
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