Design Of Novel Antifungal Agents Research Articles

Carbon Dots as Bioactive Antifungal Nanomaterials.

Nowadays, the widespread diffusion of infections caused by opportunistic fungi represents a demanding threat for global health security. This phenomenon has also worsened by the emergence of contagious events in hospitalisation environments and by the fact that many fungi have developed harsh and serious resistance mechanisms to the traditional antimycotic drugs. Hence, the design of novel antifungal agents is a key factor to counteract mycotic infections and resistance. Within this context, nanomaterials are gaining increasing attention thanks to their biocidal character. Among these, carbon dots (CDs) represent a class of zero-dimensional, photoluminescent and quasi-spherical nanoparticles which, for their great and tuneable features, have found applications in catalysis, sensing and biomedicine. Nevertheless, only a few works define and recapitulate their antifungal properties. Therefore, we aim to give an overview about the recent advances in the synthesis of CDs active against infective fungi. We described the general features of CDs and fungal cells, by highlighting some of the most common antimycotic mechanisms. Then, we evaluated the effects of CDs, antimicrobial drugs-loaded CDs and CDs-incorporated packaging systems on different fungi and analysed the use of CDs as fluorescent nano-trackers for bioimaging, showing, to all effects, their promising application as antifungal agents.

Preparation of terpene-derived fungicidal candidates with a 1,3,4-thiadiazole moiety for natural product-inspired agrochemical discovery

For the purpose of sufficient potential fungicidal candidate development from natural plant secondary metabolites, a series of terpene-derived compounds containing a 1,3,4-thiadiazole moiety were designed and prepared. The antifungal activity of the target compounds was evaluated by mycelial growth rate inhibition. A systematic and comprehensive evaluation of antifungal activity against Valsa mali indicated that the target compounds exerted relatively satisfactory inhibitory effect, and some compounds showed superior activity to the commercial pesticide boscalid. The notable compound, 3-fluoro- N -(5-(4-isopropylcyclohexa-1,3-dien-1-yl)− 1,3,4-thiadiazol-2-yl) benzenesulfonamide ( 4a27 ) showed a satisfactory EC 50 value of 3.785 μ g/mL. The conspicuous effect caused by compound 4a27 on the composition and function of the cell membrane and cell wall was confirmed in subsequent studies on the biochemistry and physiology responses of V. mali . In addition, the mycelial morphology, organelles, ergosterol content, and pectinase activity were affected by the test compound. The structure-activity relationship (SAR) studies revealed that the 1,3,4-thiadiazole and sulfoxide scaffold introduction were crucial for activity improvement. Moreover, a satisfactory quantitative structure-activity relationship (QSAR) model with four descriptors ( R 2 = 0.9035, F = 53.86, s 2 = 0.0158) was obtained through linear regression analysis. This systematic study provides inspiration for the rational design of novel antifungal agents with high efficacies. • 28 novel thiadiazole amide derivatives were prepared from natural turpentine. • Antifungal activity, preliminary mode of action and QSAR was carried out. • Compound 4a27 is a novel potent and bio-based fungicidal candidate.

Prioritization of Drugs for Fungal Keratitis Eye Infections: An In-Silico Analysis

The fungal keratitis (FK) infections that cause cornea inflammations are more virulent than other bacterial keratitis infections and remain one of the most ethereal and challenging infections for ophthalmologists to diagnose and treat. Thus, the urgency in understanding the current perspectives of antifungal agents and their interactions with novel therapeutic targets and the identification of novel anti-fungal agents are at the frontline of studies in the pharmaceutical industry. In this study, DNA dependent RNA polymerase was modelled and virtually screened against eight antifungal agents, and it was found that Itraconazole (−22.0427 kJ/mol), Ketoconazole (−20.2194 kJ/mol), and Voriconazole (−12.6388 kJ/mol) exhibited better binding interactions. further, the structural and electronic properties of Itraconazole calculated through density functional theory studies revealed the sites of chemical reactivity that are vital in the compounds for possible interactions with RNA polymerase (RNAP). Hence, this study explores the binding efficacies of various anti-fungal agents through docking studies and their chemical entities, which might pave a significant path for the design of novel anti-fungal agents against hyalohyphomycetes causing keratitis.

Characterization and Antifungal Mechanism of Green Nanoparticles Derived from Chitin Induced Exometabolites of <i>Trichoderma</i> Interfusant

Background: Nanoparticles have great potential in management of different diseases as they have better antimicrobial properties and are stable under harsh process conditions. The use of nanoparticles as antifungal agents, have been considered as alternate, cost-effective and eco friendly management strategy for the control of phytopathogens. Green silver nanoparticles are stable and regarded safe to human beings. Silver in the green-nano form constituted an important class of materials that are involved in electrochemistry, magnetism, biology, environmental science. Methods: The potent Trichoderma interfusant (Fu21) derived by protoplast fusion of mycoparasitic T. virens NBAII Tvs12 and multistress (fungicides and abiotic stress) tolerant T. koningii MTCC796. The chitin-induced exometabolites harvested by culturing the diverse and stress tolerant Trichoderma fusant (Fu21) and utilized for synthesis of green silver nanoparticles (Ag-NPs). Green Ag-NPs characterized for size (PSA), shape (SEM), stability (ZETA) and purity (EDAX). Findings: A Fourier transform infrared spectroscopy results indicated the involvement of different functional groups of exometabolites in the synthesis of green Ag-NPs, which gave the specific signature spectra in electromagnetic spectrum. We investigated novel route and mechanism of mycelial degradation at minimum inhibitory concentration (MIC) of green nanoformulation (20 µg Ag.ml-1) to restrain phytopathogen Sclerotium rolfsii. The antifungal action of green Ag-NPs on MIC at 3 DAI elevated the mycelial cell membrane leakages (sugars and proteins), lipid peroxidation, depressed the activity of respiratory chain dehydrogenases and destroyed the structure of S. rolfsii mycelia (SEM morphology) which cause phytopathogen to die eventually. Interpretation: The study developed green nano-product as a potential template for the design of novel antifungal agents to overcome the issue of infection in plant fungal diseases and broken up the food chain for fungicides toxicity to human beings. Overall, study achieved to (1) eliminate the use of human hazardious fungicides, (2) provide a sustainable use of nano-product, and (3) present a new business model fitting into the criteria of green and sustainable chemistry for better human health. Funding Statement: The authors state: This research did not receive any specific funding. Declaration of Interests: Authors declare that there are no conflicts of interest. Ethics Approval Statement: The authors declare: Not applicable.

Pharmacophore modeling and 3D QSAR studies of aryl amine derivatives as potential lumazine synthase inhibitors

Design and discovery of novel antifungal compounds is the need of time, more than ever before due to the unavailability of effective antifungal therapy to treat resistant fungal infections. Due to morphological and functional similarities of fungi both with plant cell and human cell, the search for effective targets leading to specificity of antifungal drug action becomes all that more difficult. For the design of novel antifungal agents, it is necessary to comprehend the life cycle, morphology, metabolic pathways, etc. of fungi scientifically and systematically to identify critical targets for antifungal drug design. Fungi specific riboflavin metabolism involves lumazine synthase catalyzed synthesis of 6,7-dimethyl-8-D-ribityl lumazine which is converted to riboflavin by a riboflavin synthase. Therefore lumazine synthase has been targeted for the design of newer antifungal agents. The pharmacophore modeling and 3D QSAR studies were carried out on 32 N-substituted aryl amine derivatives as fungal lumazine synthase inhibitors. The selected model of 3D QSAR showed positive correlation of electronic descriptors with antifungal activity while steric and hydrophobic descriptors showed negative correlation with antifungal activity. The resulting model exhibited good q2 and r2 values up to 0.9109 and 0.845 respectively.

Design, synthesis and antifungal activity of isosteric analogues of benzoheterocyclic N-myristoyltransferase inhibitors

N-myristoyltransferase (NMT) has been a promising new target for the design of novel antifungal agents with new mode of action. A series of benzoxazole and indole derivatives were designed and synthesized as isosteric analogues of benzoheterocyclic NMT Inhibitors. In vitro antifungal assay indicated that the benzoxazole derivatives were far more potent than the indoles. Molecular docking studies revealed that the hydrogen bonding interaction between the benzoheterocyclic core and NMT might be essential in the orientation of the inhibitor to a proper position. The antifungal activity of benzoxazole derivative 8f was comparable or superior to that of fluconazole, which can serve as a good starting point for further studies of structural diversity of the benzoheterocyclic NMT inhibitors.

Evolutionary trace analysis of CYP51 family: implication for site-directed mutagenesis and novel antifungal drug design

Lanosterol 14alpha-demethylase (CYP51) is an essential enzyme in the fungal life cycle and also an important target for the antifungal drug development. Based on the multiple sequence alignments of CYP51 family, an evolutionary tree of the CYP51 family was constructed by the evolutionary trace (ET) method. The identified trace residues could provide a reliable and rational guide to the design of CYP51 mutations and give more information about the detailed mechanism of substrate (drug) recognition and binding. The reliability of ET analysis to identify residues of functional importance was validated by the reported site-directed mutagenesis studies of CYP51s. Several residues in the active site were also validated by our mutagenesis studies. Mapping the identified trace residues onto the active site of the modeled structure of Candida albicans CYP51 (CACYP51) may provide useful information for the design of novel antifungal agents.

Carbohydrate Chain Terminators: Rational Design of Novel Carbohydrate‐Based Antifungal Agents

Carbohydrate Chain Terminators: Rational Design of Novel Carbohydrate‐Based Antifungal Agents

3D-QSAR and molecular docking studies on benzothiazole derivatives as Candida albicans N-myristoyltransferase inhibitors

N-Myristoyltransferase has been a promising new target for the design of novel antifungal agents with new mode of action. Molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) methods, CoMFA and CoMSIA, were applied to a set of novel benzothiazole Candida albicans N-myristoyltransferase (CaNmt) inhibitors. The binding mode of the compounds at the active site of CaNmt was explored using flexible docking method and various hydrophobic and hydrogen-bonding interactions were observed between the benzothiazole inhibitors and the target enzyme. The best CoMFA and CoMSIA models had a cross-validated coefficient q 2 of 0.733 and 0.738, respectively, which showed high correlative and predictive abilities on both the test set and training set. The 3D contour maps of CoMFA and CoMSIA provided smooth and interpretable explanation of the structure–activity relationship for the compounds. The analysis of the 3D contour plots permitted interesting conclusions about the effects of different substituent groups at different position of the benzothiazole ring, which will guide the design of novel CaNmt inhibitors with higher activity.

Membrane transporters and antifungal drug resistance.

Over the last 30 years or so, the incidence of invasive fungal infections in man has risen dramatically. Patients that become severely immunocompromised because of underlying diseases such as leukemia or recently, acquired immunodeficiency syndrome or patients who undergo cancer chemotherapy or organ transplantation, are particularly susceptible to opportunistic fungal infections. Although Candida species continue to be the major pathogenic fungi in these patients, cryptococcosis, aspergillosis, and coccidioidomycosis, among others, have become increasingly important mycoses. Antifungal drugs currently being used in clinic include polyene antibiotics, azole derivatives and 5-fluorocytosine. With the exception of the latter, all other drugs possess mechanisms of action aimed at disrupting the integrity of the fungal cell membrane by either interfering with the biosynthesis of membrane sterols or by inhibiting sterol functions. However, one significant obstacle preventing successful antifungal therapy is the dramatic increase in drug resistance, especially against azole antimycotics. Among the major mechanisms by which fungi invoke drug resistance is the overexpession of extrusion pumps able to facilitate the efflux of cytotoxic drugs from the cell thus leading to decreased drug accumulation and diminished concentrations. Since the initial observations that azole resistance by fungi may be caused by overexpression of multidrug efflux transporter genes, significant advances have been achieved primarily with Saccharomyces cerevisiae and Candida albicans. The purpose of this review is to discuss various aspects of multidrug resistance in fungi such as antifungal drug mechanisms of action and fungal molecular genetics in the context of targeted drug discovery. The role that membrane transporter proteins play in drug resistance in various species of Candida, Aspergillus and Cryptococcus will be address in more detail, as will be their importance as selective drug targets in the design of novel antifungal agents.

Crystallographic studies of homoserine dehydrogenase for the design of novel antifungal agents

Crystallographic studies of homoserine dehydrogenase for the design of novel antifungal agents