Promising Antifungal Activity Research Articles

Unlocking olive rhizobacteria: harnessing biocontrol power to combat olive root rot and promote plant growth.

Olive trees are susceptible to various diseases, notably root rot caused by Pythium spp., which presents significant challenges to cultivation. Conventional chemical control methods have limitations, necessitating exploration of eco-friendly alternatives like biological control strategies. This study aims to evaluate the potential of rhizobacteria in managing Pythium schmitthenneri-induced root rot in olive trees. We screened 140 bacteria isolated from olive tree rhizospheres for antifungal activity against the pathogen in vitro. Twelve isolates exhibited promising antifungal activity, identified through 16S rDNA gene sequencing as primarily Bacillus, Pseudomonas, Stenotrophomonas, and Alcaligenes species. Particularly, Pseudomonas koreensis (A28 and A29), Pseudomonas reinekei (A16), and Bacillus halotolerans (A10) were the highest effective strains. Mechanistic investigations revealed positive protease production in all twelve isolates, with eight producing amylase and cellulase. Chitinase activity was absent, while five solubilized tricalcium phosphate. Furthermore, eight secreted hydrocyanic acid (HCN), ten synthesized indole-3-acetic acid (IAA), and nine produced siderophores. Variability existed in antimicrobial substance production, including bacillomycin (seven isolates), iturin (eleven isolates), fengycin (two isolates), and surfactin (three isolates). Plant growth-promoting rhizobacteria (PGPR) capabilities were assessed using canola (Brassica napus) seedlings, showing enhanced growth in treated seedlings compared to controls. Greenhouse experiments confirmed the biocontrol efficacy of P. koreensis A28 and Bacillus subtilis C6 against root rot disease. These findings suggest these strains could serve as promising tools for managing olive tree root rot, offering a sustainable alternative to hazardous agrochemicals.

Microwave-Assisted Synthesis of Bis-1,2,3-Triazole Based Benzophenones, In Vitro Antimicrobial Activity and Molecular Docking Studies.

In this work, we have adopted an easy route to synthesizing bis-1,2,3-triazole-based benzophenone compounds via a 1,3-dipolar cycloaddition reaction (Click Chemistry). All the target compounds achieved better yields though the microwave-assisted method than the conventional method. Target compounds structure were confirmed based on the IR, 1H NMR, 13C NMR and HR Mass analysis. Additionally, we have carried out in vitro antibacterial and antifungal activities with Ciprofloxacin and Fluconazole standard drugs, respectively. The compounds 5b, 5f, 5i, 5k and 5n antibacterial, 5a, 5e, 5g, 5i, and 5k showed promising antifungal activity with respect to standard drugs. Further, molecular docking study performed against DNA gyrase and Lanosterol 14-alpha demethylase envisioned promising binding interactions with a good docking score.

Unlocking Chiral Sulfinimidoyl Electrophiles: Asymmetric Synthesis of Sulfinamides Catalyzed by Anionic Stereogenic-at-Cobalt(III) Complexes.

Asymmetric catalysis involving a sulfoxide electrophile intermediate presents an efficient methodology for accessing stereogenic-at-sulfur compounds, such as sulfinate esters, sulfinamides, etc., which have garnered increasing attention in modern pharmaceutical sciences. However, as the aza-analog of sulfoxide electrophiles, the asymmetric issues about electrophilic sulfinimidoyl species remain largely unexplored and represent a significant challenge in sulfur stereochemistry. Herein, we exhibit an anionic stereogenic-at-cobalt(III) complex-catalyzed asymmetric synthesis of chiral sulfinamides via chiral sulfinimidoyl iodide intermediates. Mechanistic investigations reveal that the catalytic cycle is initiated by asymmetric oxidative iodination, generating sulfinimidoyl iodides. These active intermediates subsequently undergo an enantiospecific nucleophilic substitution with water, affording a diverse array of enantioenriched sulfinamides. Notably, these sulfinamides exhibit promising antifungal activities against Sclerotinia sclerotiorum and serve as ideal platform molecules facilitating the stereospecific transformation into various stereogenic aza-sulfur compounds.

Synthesis, Spectroscopic Characterization, Docking and Biological Screening of Novel Chalcones and Their Pyrazoline Derivatives

The novel chalcones and their pyrazoline derivatives were synthesized by the Claisen–Schmidt condensation method. The aim of the synthesis was their broad spectrum of pharmacological activities. These compounds were characterized by FTIR technique and NMR (1H, 13C). The synthesized moieties were screened for their in vitro biological activities, including antibacterial, antifungal, antioxidant, and cytotoxic activities. Among the synthesized compounds, 3b showed more promising antifungal activity, better than the standard fluconazole and cytotoxicity with LD50 (92.5 µg/mL). The second important compound was 5b with higher antioxidant potential with IC50 (90 µg/mL) and at the same time better antibacterial activity with MIC 20 μg. Molecular docking studies was performed to elucidate the molecular basis of the experimental inhibitory activities of new synthetic compounds. The calculated final docking energies for 3b, 4b and 5b against DNA gyrase were -7.6, -8.4 and -9.8 Kcal/mol, while against cytochrome P450 they were -10.3, -10.5 and -12.6 - respectively. The docking results showed that the ligand molecules can be a substrate binding region for the active site.

Chemical profile, antioxidant, antifungal, and cytotoxic activities of propolis from the stingless bee Tetragona clavipes.

Propolis is derived from plant resin and bees' salivary secretions, are commonly used in folk medicine. Studies on propolis from stingless bees have increased in recent years, highlighting their relevance due to the variety of species and the bioactive components. However, scientific records confirming these activities in species occurring in Brazil are still scarce. In that context, this study aims to determine the chemical profile and the antioxidant, antifungal, and cytotoxic activities of the stingless bees Tetragona clavipes propolis. The hydroalcoholic extract was prepared, and its chemical profile was determined by Fourier transform ion cyclotron resonance mass spectrometry combined with a direct infusion electrospray ionization. Total polyphenols and flavonoid content were determined by colorimetric methods. We determined the antioxidant activity by the ability to scavenge the free radicals 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid). The antifungal activity was evaluated by determining the minimum inhibitory concentration and minimum fungicidal concentration against Aspergillus fumigatus, Trichophyton rubrum, Candida albicans, and Candida parapisilosis. The results revealed high contents of total phenolics and promising antioxidant and antifungal activities. T. clavipes propolis from the rainy season showed better antioxidant and antifungal activities and higher content of flavonoids, with less variability of chemical species. The extracts exhibited fungistatic activity for C. albicans, C. parapisilosis, and A. fumigatus and fungicide for T. rubrum. Additionally, a sample collected during the rainy season demonstrated synergism with fluconazole and amphotericin B for T. rubrum and additivity for C. albicans and C. parapisilosis. In summary, the results of T. clavipes propolis revealed elevated levels of total phenolics, indicating its potential as a rich source of bioactive compounds, significant antioxidant activity, and promising antifungal activity against common pathogenic fungi. These findings contribute to our understanding of the therapeutic potential of T. clavipes propolis and provide a basis for further research and development of natural products for various applications in medicine and healthcare.

Biological effectiveness of Agave striata and Fouquieria splendens extracts against Pythium aphanidermatum and Rhizoctonia solani in vitro

Background/Objective. Pythium aphanidermatum and Rhizoctonia solani are pathogens that affect agricultural crops. The objective of this study was to evaluate some Agave striata and Fouquieria splendens methanolic extracts, from the Chihuahuan Desert, against those fungi, in search for biological control alternatives. Materials and Methods. Pathogens from chili plants were isolated and identified using morphological and molecular methods. Methanolic extracts from both plants were prepared, and the antioxidant capacity (AC), the total polyphenol content (TPC), and the antifungal compounds via HPLC-MS were assessed. The antifungal effectiveness was tested at concentrations of 3.9-2000 mg L-1 using a poisoned medium assay, where fungi structural damage was observed. Results. The F. splendens and A. striata extracts exhibited 55% and 68% AC, as well as 61 mg/g and 112 mg/g TPC, respectively. Both extracts contained caffeic acid and quercetin, while F. splendens also exhibited eriodyctiol, kaempferol, and luteolin; A. striata contained pinocembrin and theaflavin B. F. splendens attained 100% inhibition of P. aphanidermatum at 250 mg L-1, and of R. solani at 500 mg L-1, whereas A. striata achieved 100% inhibition at 1000 mg L-1 in both cases. The extracts produced lysis in P. aphanidermatum oogonia and mycelial fragmentation in R. solani. Conclusion. The F. splendens and A. striata methanolic extracts demonstrate promising antifungal activity against P. aphanidermatum and R. solani, suggesting that these natural compounds might be useful as a biological alternative for pathogen control in agricultural crops.

Pyrazole Amides Towards Trailblazing Antimicrobial Research: Bridging in Vivo Insights and Molecular Docking Studies

Antimicrobial resistance presents a significant threat to contemporary healthcare systems, making it increasingly difficult to treat infections that were once easily managed. This study aims to assess the efficacy of pyrazole benzamide derivatives (M5a–M5o), which were synthesized for their antimicrobial and antifungal activities. These compounds were tested against methicillin resistant staphylococcus aureus (MRSA), vancomycin resistant staphylococcus aureus (VRSA), mycobacterium tuberculosis H37Rv and other resistant species. The minimum inhibitory concentrations (MIC) were determined using standardized protocols to evaluate their potency and effectiveness. Molecular docking studies were also conducted to explore potential interactions and binding affinities at the molecular level, providing further insights into their antimicrobial and anti-tubercular mechanisms. Compounds M5i, M5k, and M5b emerged as the most potent, displaying MIC value of 3.12 μg/ml. These compounds show great potential as new agents in addressing the growing problem of antimicrobial resistance. Molecular docking studies against Enoyl-[acyl-carrier-protein] reductase (4DRE), revealed key interactions, with compound M5n showing a docking energy of -9.8 kcal/mol and compound M5g at -9.6 kcal/mol. These compounds formed important hydrogen bonds and π-interactions with residues like Lys165, Gly14, Ser94, and Ile21. Overall, the findings indicate that specific pyrazole-benzamide derivatives exhibit promising antimicrobial and antifungal activities, underscoring their potential as therapeutic agents. Additionally, the integration of molecular docking studies proves valuable in guiding the development and optimization of these compounds for future therapeutic applications.

Advancements in Combating Fungal Infections: A Comprehensive Review on the Development of Azole Hybrid Antifungals.

In this review, we have summarized antifungal agents containing potent azole analogues. The provided literature is related to the development and application of azole derivatives and has been accessed from electronic data bases such as Science direct, Google Scholar, and Pubmed using keywords such as "design, synthesis and evaluation", "azole hybrids", "diazole hybrids", "indazole derivatives", "imidazole derivatives", "triazole derivatives", "tetrazole derivatives" and related combinations. From this review, it was identified that azole derivatives with promising antifungal activity play a vital role in drug discovery and development. The literature revealed that azole derivatives can effectively fight several types of microorganisms, such as Candida albicans, Aspergillus niger, and others. The rational design and structure‒activity relationship of these compounds are discussed in this paper, highlighting their potential as effective therapeutic options against various fungal pathogens. Moreover, this work addresses the challenges and future directions in the development of azole hybrids. The results of docking studies of several of the hybrids that the researchers provided are also summarized. The current work attempts to review such innovations, which may lead to the preparation of novel therapeutics. More research is required to confirm their safety and effectiveness in clinical practices.

Novel benzylidene derivatives: Synthesis and their antimicrobial and anticancer studies and in silico investigations

Given the importance of carbohydrate-based drugs, this study focused on the synthesis of five novel analogs (3–7) of methyl 4,6-O-benzylidene-α-D-glucopyranoside (2, MBDG). In vitro antimicrobial screening revealed that these MBDG derivatives possess promising antifungal activity against Aspergillus niger and moderate antibacterial activity. Compound 4 exhibited an MIC of 0.68–2.7 mg/mL and an MBC of 1.35–5.4 mg/mL against five different bacterial strains. The insertion of various acyl groups, particularly (CH3(CH2)3CO-) and (CH3(CH2)4CO-) at the second and third positions of MBDG (2), increased the antimicrobial effectiveness. Compound 6 was found to reduce EAC (Ehrlich ascites carcinoma) cell proliferation by 30.17% at 500 μg/mL, with an IC50 value of 852.47 μg/mL. Furthermore, frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) analyses were conducted to investigate the physicochemical properties and relative reactivities of the newly synthesized MBDGs. Molecular docking analysis revealed that compounds 4 and 5 bind efficiently with binding affinities of -7.2 kcal/moL and -5.7 kcal/moL against Bacillus subtilis and A. niger, respectively, compared with the standard drug azithromycin. The stability of the protein‒ligand complexes were ascertained via MMPBSA binding free energy calculations and molecular dynamics (MD) simulations. These findings demonstrate that compounds 4 and 5 may be useful antimicrobial medications. An in silico ADMET assay was employed to evaluate the pharmacological and toxicological properties of the MBDGs.

Comparative phytochemical, antioxidant and antifungal evaluation of successive extracts of Bombax ceiba L. thorns

This study aims to analyze the comprehensive qualitative and quantitative phytochemical analyses, antioxidant potential, and antifungal activity of successive extracts from Bombax ceiba thorn. The assessment of antioxidant activities was performed by two methods, the phosphomolybdate assay and the reducing power assay. In vitro anti-fungal activity was evaluated by the agar well diffusion method. The results of phytochemical screening revealed the presence of various phytoconstituents like flavonoids, sterols, and tannins. Antioxidant potential and antifungal activity against Candida albicans were also found to be higher in ethyl acetate extract. All the successive extracts showed dose-dependent antioxidant potential. This study indicates that B. ceiba thorn has promising antioxidant and antifungal activity due to the presence of phenolics and flavonoids. B. ceiba can be used as potential antioxidant and antifungal agents, and resources for the development of new molecules.

Synthesis, Characterization, Bioactivity Evaluation, and POM/DFT/Docking Analysis of Novel Thiazolidine Derivatives as Potent Anticancer and Antifungal Agents

AbstractA series of 2,2′‐(1,4‐phenylene)bis(N‐substituted phenylthiazolidine‐4‐amide) derivatives, denoted as (A3–9), were synthesized, and characterized for their potential applications against prostate cancer cells (PC3), and Candida albicans fungi. These compounds incorporate various substituents on the phenyl ring such as 4‐NO2, 3‐NO2, 4‐COCH3, 4‐H, 4‐OCH3, 4‐OCH2CH3, and 4‐Cl. The chemical structures of these derivatives were confirmed by NMR, FTIR, and mass spectroscopy. Biological assays, utilizing the MTT assay for prostate cancer cells (PC3) and the disk diffusion assay for Candida albicans fungi, were conducted to evaluate the bioactivity of these compounds. The results revealed promising cytotoxic and antifungal activities. Specifically, compounds A3 (IC50=69.74±0.96), A4 (IC50=63.64±0.950), and A9 (IC50=57.14±0.88 μg/mL) exhibited notable potency against PC3 cells, while A7 and A8 exhibited considerable antifungal efficacy against Candida albicans with MIC of 312 μg/mL. Moreover, density functional theory (DFT) simulations were used to study electronic properties and reactivity descriptors such as energy gap (Eg), ionization potential (IP), electron affinity (EA), chemical potential (μ), chemical hardness (η), global softness (σ), electronegativity (χ), and electrophilicity (ω) to gain a better understanding of the Structure‐Activity Relationship (SAR). Molecular docking analysis against DNA Gyrase and EGFR tyrosine kinase enzymes revealed strong binding interactions of the investigated molecules within their active sites, making them valuable candidates for further development as therapeutic agents against prostate cancer and fungal infections. POM analysis indicates the presence of two antifungal pharmacophore sites (O1δ−, O2δ−) and (O3δ−, O4δ−), as well as two antitumor pharmacophore sites (O1δ−, NH1δ+) and (O4δ−, NH2δ+).

Biocontrol potential of Bevibacillus brevis HK544 for fungal plant diseases

Chemical fungicides have been widely used to control plant diseases caused by fungal pathogens. Still, the overuse of these fungicides has led to concerns about the hazards to humans, animals, and the environment and an increase in fungicide resistance. Interest in biocontrol agents with strong antimicrobial activity has significantly increased to counteract the escalating risks of chemical fungicides. Our previous study found that a soil-born microbe, Brevibacillus brevis HK544, exhibited a promising antifungal activity against a plant pathogen, Fusarium graminearum, with edeine B1 identified as the active compound. Herein, we extended our study to investigate the in vitro and in vivo antifungal spectrum of B. brevis HK544, including edeine B1, against various plant pathogenic fungi and evaluated the possibility that B. brevis HK544 could be used in combination with chemical fungicides to enhance the disease control efficacy. With an in vitro broad-spectrum antifungal activity, the B. brevis HK544 culture filtrate, culture broth, and metabolite edeine B1 exhibited a promising disease control efficacy against tomato gray mold and tomato late blight among the tested fungal diseases. Based on the in vitro antifungal activity against Botrytis cinerea, when edeine B1 was combined with various chemical fungicides, the highest average synergy score among the tested combinations was observed in the edeine B1 and benomyl combination. The co-application of the B. brevis HK544 culture filtrate and benomyl improved the disease control efficacy against gray mold disease, supporting the in vitro result. Taken together, our results show that B. brevis HK544 has potential as a biological control agent for controlling plant pathogenic fungi and also that B. brevis HK544 could be combined with chemical fungicides to enhance the efficacy of antifungal agents.

Unveiling the potential of novel Metschnikowia yeast biosurfactants: triggering oxidative stress for promising antifungal and anticancer activity

BackgroundSophorolipids are glycolipid biosurfactants with potential antibacterial, antifungal, and anticancer applications, rendering them promising for research. Therefore, this study hypothesizes that sophorolipids may have a notable impact on disrupting membrane integrity and triggering the production of reactive oxygen species, ultimately resulting in the eradication of pathogenic microbes.ResultsThe current study resulted in the isolation of two Metschnikowia novel yeast strains. Sophorolipids production from these strains reached maximum yields of 23.24 g/l and 21.75 g/l, respectively, at the bioreactors level. Biosurfactants sophorolipids were characterized using FTIR and LC–MS techniques and found to be a mixture of acidic and lactonic forms with molecular weights of m/z 678 and 700. Our research elucidated sophorolipids’ mechanism in disrupting bacterial and fungal membranes through ROS generation, confirmed by transmission electron microscopy and FACS analysis. The results showed that these compounds disrupted the membrane integrity and induced ROS production, leading to cell death in Klebsiella pneumoniae and Fusarium solani. In addition, the anticancer properties of sophorolipids were investigated on the A549 lung cancer cell line and found that sophorolipid-11D (SL-11D) and sophorolipid-11X (SL-11X) disrupted the actin cytoskeleton, as evidenced by immunofluorescence microscopy. The A549 cells were stained with Acridine orange/Ethidium bromide, which showed that they underwent necrosis. This was confirmed by flow cytometric analysis using Annexin/PI staining. The SL-11D and SL-11X molecules exhibited low levels of haemolytic activity and in-vitro cytotoxicity in HEK293, Caco-2, and L929 cell lines.ConclusionIn this work, novel yeast species CIG-11DT and CIG-11XT, isolated from the bee’s gut, produce significant yields of sophorolipids without needing secondary oil sources, indicating a more economical production method. Our research shows that sophorolipids disrupt bacterial and fungal membranes via ROS production. They suggest they may act as chemo-preventive agents by inducing apoptosis in lung cancer cells, offering the potential for enhancing anticancer therapies.

Homoleptic Co(II) and Ni(II) complexes with promising anticancer and antimicrobial activities; Synthesis, X-ray structure, and DFT studies

The antimicrobial and anticancer potentials of the newly synthesized homoleptic [M(BPPT)2](ClO4)2 complexes, where M = Co or Ni, were reported. Their molecular structure aspects were investigated with the aid of elemental analysis, FTIR spectra, and X-ray crystallography. The s-triazine functional ligand (BPPT) worked as a tridentate N-chelate. With two BPPT molecules in the coordination sphere, the Co(II) and Ni(II) are hexa-coordinated with distorted octahedral configuration. The important supramolecular structural aspects were investigated using Hirshfeld topology analysis. The red spots in the dnorm map are related to the short O···H, N···H, C···H, and C···O contacts. 1 and 2 have promising antibacterial and antifungal activities against P.vulgaris (MIC = 2.5 μg/mL) and A. fumigatus (2.5 μg/mL), respectively exceeding the medications gentamycin (MIC= 5.0 μg/mL) and ketoconazole (5 μg/mL) as positive controls, respectively. In addition, 1 is better anticancer agent against HCT-116 (IC50 = 2.44±0.32 µg/mL) and A-549 (3.88±0.38 µg/mL) cell lines compared to the Ni(II) analogue (3.54±0.39 and 6.37±0.54 µg/mL, respectively). Their cytotoxic activity exceeded the efficiency of cis-platin versus both carcinoma cells (HCT-116; 8.4 ± 0.8 and A-549; 19.3 ± 0.8 µg/mL). The selectivity indices of 1 and 2 are exceeding unity indicating their availability for use as anticancer therapeutic agents.

MBX-7591: a promising drug candidate against drug-resistant fungal infections.

Invasive fungal infections (IFIs) caused by pathogenic fungi pose a significant public health concern, particularly for immunocompromised individuals. Mortality rates for IFIs remain high, and currently available treatment options are limited. Existing antifungal agents often suffer from limited clinical efficacy, poor fungicidal activity within the host, potential toxicity, and increasing ineffectiveness due to emerging resistance, especially against triazole drugs, the current mainstay of antifungal treatment. A recent study has identified MBX-7591, a small molecule with promising antifungal activity against Aspergillus fumigatus and other pathogenic fungi, including strains resistant to triazoles (C. Gutierrez-Perez, C. Puerner, J. T. Jones, S. Vellanki, E. M. Vesely, et al., mBio e01166-24, 2024, https://doi.org/10.1128/mbio.01166-24). This novel compound appears to inhibit stearoyl-CoA 9-desaturase, a key enzyme involved in fungal fatty acid biosynthesis. By disrupting the conversion of saturated fatty acids to oleic acid, MBX-7591 offers a unique mechanism of action, potentially reducing the risk of resistance development. Here, we now discuss the implications of these groundbreaking findings for overcoming antifungal drug resistance.

Synthesis and Biological Activities of C1-Substituted Acylhydrazone β-Carboline Analogues as Antifungal Candidates.

In our ongoing work to create potential antifungal agents, we synthesized and tested a group of C1-substituted acylhydrazone β-carboline analogues 9a-o and 10a-o for their effectiveness against Valsa mali, Fusarium solani, Fusarium oxysporum, and Fusarium graminearum. Their compositions were analyzed using different spectral techniques, such as 1H/13C NMR and HRMS, with the structure of 9l being additionally confirmed through X-ray diffraction. The antifungal evaluation showed that, among all the target β-carboline analogues, compounds 9n and 9o exhibited more promising and broad-spectrum antifungal activity than the commercial pesticide hymexazol. Several intriguing findings regarding structure-activity relationships (SARs) were examined. In addition, the cytotoxicity test showed that these acylhydrazone β-carboline analogues with C1 substitutions exhibit a preference for fungi, with minimal harm to healthy cells (LO2). The reported findings provide insights into the development of β-carboline analogues as new potential antifungal agents.

Degradation-Risk-Inspired Optimization of the Antifungal Oxazolinyl Aniline Lead by a Fusion of Triazole with Nicotinamide.

The discovery of readily available and easily modifiable new models is a crucial and practical solution for agrochemical innovation. Antifungal function-oriented fusion of triazole with the prevalidated lead (R)-LE001 affords a novel framework with a broad and enhanced antifungal spectrum. Characterized by the easy accessibility and adjustability of [1,2,4]triazolo[4,3-a]pyridine, modular fine-tuning provided a set of unprecedented leads (e.g., Z23, Z25, Z26, etc.) with superior antifungal potentials than the positive control boscalid. Candidate Z23 exhibited a more promising antifungal activity against Sclerotinia sclerotiorum, Botrytis cinerea, and Phytophthora capsici with EC50 values of 0.7, 0.6, and 0.5 μM, respectively. This candidate could effectively control boscalid-resistant B. cinerea strains and also exhibit good vivo efficacy in controlling gray mold. Noteworthily, both the SDH-inhibition and the efficiency against Oomycete P. capsici are quite distinct from that of the positive control boscalid. A molecular docking simulation also differentiates Z23 from boscalid. These findings highlight the potential of [1,2,4]triazolo[4,3-a]pyridine amide as a novel antifungal model.

Discovery, Optimization, and Biological Evaluation of Novel Pyrazol-5-yl-phenoxybenzamide Derivatives as Potent Succinate Dehydrogenase Inhibitors.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali, Gaeumannomyces graminis, and Botrytis cinerea, with EC50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC50 = 0.82 mg/L) and Rhizoctonia solani (EC50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum, respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (ΔGcal = -46.8 kcal/mol, IC50 = 1.22 mg/L, compared to ΔGcal = -41.1 kcal/mol, IC50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

Anti-Sporothrix Activity of Novel Copper-Itraconazole Complexes.

A series of new metal complexes, [Cu(ITZ)2Cl2] ⋅ 5H2O (1), [Cu(NO3)2(ITZ)2] ⋅ 3H2O ⋅ C4H10O (2) and [Cu(ITZ)2)(PPh3)2]NO3 ⋅ 5H2O (3) were synthesized by a reaction of itraconazole (ITZ) with the respective copper salts under reflux. The metal complexes were characterized by elemental analyses, molar conductivity, 1H and 13C{1H} nuclear magnetic resonance, UV-Vis, infrared and EPR spectroscopies. The antifungal activity of these metal complexes was evaluated against the main sporotrichosis agents: Sporothrix brasiliensis, Sporothrix schenkii, and Sporothrix globosa. All three new compounds inhibited the growth of S. brasiliensis and S. schenckii at lower concentrations than the free azole, with complex 2 able to kill all species at 4 μM and induce more pronounced alterations in fungal cells. Complexes 2 and 3 exhibited higher selectivity and no mutagenic effect at the concentration that inhibited fungal growth and affected fungal cells. The strategy of coordinating itraconazole (ITZ) to copper was successful, since the corresponding metal complexes were more effective than the parent drug. Particularly, the promising antifungal activity of the Cu-ITZ complexes makes them potential candidates for the development of an alternative drug to treat mycoses.

Discovery of a novel series of phenylthiazole thioether (sulfone) compounds based on natural thiasporine A as potential candidates for controlling rice fungal and bacterial diseases

AbstractHalf of the world's population depends on rice for their calories. Protecting rice in the growth period from damage caused by phytopathogens is faced with a great challenge under the frequent extreme climate. To find novel fungicides to control rice diseases, 35 novel phenylthiazole‐1,3,4‐oxadiazole‐thioether (sulfone) derivatives were synthesized and evaluated for their efficacy against destructive fungal and bacterial diseases of rice. Bioassay results demonstrated that most of G‐series compounds possessed excellent antifungal and antibacterial activities. In particular, compounds G1 (EC50 = 2.22 μg/mL, R.s) and G7 (EC50 = 2.76 μg/mL, R.s) showed the most promising antifungal activities in vitro and exhibited superior protective and curative activities against rice sheath blight in vivo compared with commercial carbendazim. Surprisingly, compound G2 exhibited the remarkable antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo) with an EC50 value of 1.98 μg/mL, and demonstrated superior protective activity (88.08%) than thiodiazole copper (79.39%) against rice bacterial leaf blight at 200 μg/mL. The abovementioned results fully manifested that the phenylthiazole‐1,3,4‐oxadiazole‐sulfone structure, especially compounds G1 and G2, had the potential to develop as commercial agents for controlling rice fungal and bacterial diseases.