Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters.
Vila-Farres Xavier,Chu John,Inoyama Daigo,Ternei Melinda A,Lemetre Christophe,Cohen Louis J,Cho Wooyoung,Reddy Boojala Vijay B,Zebroski Henry A,Freundlich Joel S,Perlin David S,Brady Sean F
Journal of the American Chemical Society
Bacterial culture broth extracts have been the starting point for the development of numerous therapeutics. However, only a small fraction of bacterial biosynthetic diversity is accessible using this strategy. Here, we apply a discovery approach that bypasses the culturing step entirely by bioinformatically predicting small molecule structures from the primary sequences of the biosynthetic gene clusters. These structures are then chemically synthesized to give synthetic-bioinformatic natural products (syn-BNPs). Using this approach, we screened syn-BNPs inspired by nonribosomal peptide synthetases against microbial pathogens, and discovered an antibiotic for which no resistance could be identified and an antifungal agent with activity against diverse fungal pathogens.
10.1021/jacs.6b11861
Nanohexaconazole: synthesis, characterisation and efficacy of a novel fungicidal nanodispersion.
Roy Indrani,Thapa Mala,Goswami Arunava
IET nanobiotechnology
Here, the authors describe a simple method to formulate the nanodispersion of hexaconazole (hexa); henceforth, referred to as nanohexaconazole (N-hexa) that is water soluble and effective against several species of . Size and shape of the prepared nanocomposite was determined with high-resolution transmission electron microscopy and field-emission scanning electron microscopy. Nanohexaconazole structure was further confirmed by Fourier-transform infrared spectroscopy and gas chromatography-mass spectrometry. The antifungal efficacy of nanohexaconazole (N-hexa) was studied , compared with micronised hexaconazole (M-hexa) at different doses (5 ppm, 10 ppm and control) against two food pathogenic fungi: (MTCC 282, MTCC 2196 and BDS 113) and through poisoned food technique. A dose-dependent significant growth inhibition was observed in nanohexaconazole (N-hexa) treated fungal sample compared with that of micronised hexaconazole (M-hexa). Micrographic studies for the morphological analysis of control and nanohexaconazole (N-hexa) treated fungal samples were done, exhibited an alternation in fungal morphology. Results showed that nanohexaconazole (N-hexa) is more efficacious than commercially available micronised hexaconazole (M-hexa). In future nanohexaconazole (N-hexa) could be a possible candidate for modern medical science and also reduce damage to the environment from injudicious use of pesticides.
10.1049/iet-nbt.2018.0041
Structure-guided approaches to targeting stress responses in human fungal pathogens.
LeBlanc Emmanuelle V,Polvi Elizabeth J,Veri Amanda O,Privé Gilbert G,Cowen Leah E
The Journal of biological chemistry
Fungi inhabit extraordinarily diverse ecological niches, including the human body. Invasive fungal infections have a devastating impact on human health worldwide, killing ∼1.5 million individuals annually. The majority of these deaths are attributable to species of , and Treating fungal infections is challenging, in part due to the emergence of resistance to our limited arsenal of antifungal agents, necessitating the development of novel therapeutic options. Whereas conventional antifungal strategies target proteins or cellular components essential for fungal growth, an attractive alternative strategy involves targeting proteins that regulate fungal virulence or antifungal drug resistance, such as regulators of fungal stress responses. Stress response networks enable fungi to adapt, grow, and cause disease in humans and include regulators that are highly conserved across eukaryotes as well as those that are fungal-specific. This review highlights recent developments in elucidating crystal structures of fungal stress response regulators and emphasizes how this knowledge can guide the design of fungal-selective inhibitors. We focus on the progress that has been made with highly conserved regulators, including the molecular chaperone Hsp90, the protein phosphatase calcineurin, and the small GTPase Ras1, as well as with divergent stress response regulators, including the cell wall kinase Yck2 and trehalose synthases. Exploring structures of these important fungal stress regulators will accelerate the design of selective antifungals that can be deployed to combat life-threatening fungal diseases.
10.1074/jbc.REV120.013731
Large-Scale Analysis of Antimicrobial Activities in Relation to Amphipathicity and Charge Reveals Novel Characterization of Antimicrobial Peptides.
Wang Chien-Kuo,Shih Ling-Yi,Chang Kuan Y
Molecules (Basel, Switzerland)
It has been unclear to which antimicrobial activities (e.g., anti-gram-positive bacterial, anti-gram-negative bacterial, antifungal, antiparasitic, and antiviral activities) of antimicrobial peptides (AMPs) a given physiochemical property matters most. This is the first computational study using large-scale AMPs to examine the relationships between antimicrobial activities and two major physiochemical properties of AMPs-amphipathicity and net charge. The results showed that among all kinds of antimicrobial activities, amphipathicity and net charge best differentiated between AMPs with and without anti-gram-negative bacterial activities. In terms of amphipathicity and charge, all the AMPs whose activities were significantly associated with amphipathicity and net charge were alike except those with anti-gram-positive bacterial activities. Furthermore, the higher the amphipathic value, the greater the proportion of AMPs possessing both antibacterial and antifungal activities. This dose-response-like pattern suggests a possible causal relationship-dual antibacterial and antifungal activities of AMPs may be attributable to amphipathicity. These novel findings could be useful for identifying potent AMPs computationally.
10.3390/molecules22112037
Epipyrone A, a Broad-Spectrum Antifungal Compound Produced by ICMP 19927.
Molecules (Basel, Switzerland)
We have isolated a filamentous fungus that actively secretes a pigmented exudate when growing on agar plates. The fungus was identified as being a strain of . The fungal exudate presented strong antifungal activity against both yeasts and filamentous fungi, and inhibited the germination of fungal spores. The chemical characterization of the exudate showed that the pigmented molecule presenting antifungal activity is the disalt of epipyrone A-a water-soluble polyene metabolite with a molecular mass of 612.29 and maximal UV-Vis absorbance at 428 nm. This antifungal compound showed excellent stability to different temperatures and neutral to alkaline pH.
10.3390/molecules25245997
Sterol 14α-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis.
Friggeri Laura,Hargrove Tatiana Y,Wawrzak Zdzislaw,Blobaum Anna L,Rachakonda Girish,Lindsley Craig W,Villalta Fernando,Nes W David,Botta Maurizio,Guengerich F Peter,Lepesheva Galina I
Journal of medicinal chemistry
Because of the increase in the number of immunocompromised patients, the incidence of invasive fungal infections is growing, but the treatment efficiency remains unacceptably low. The most potent clinical systemic antifungals (azoles) are the derivatives of two scaffolds: ketoconazole and fluconazole. Being the safest antifungal drugs, they still have shortcomings, mainly because of pharmacokinetics and resistance. Here, we report the successful use of the target fungal enzyme, sterol 14α-demethylase (CYP51), for structure-based design of novel antifungal drug candidates by minor modifications of VNI [( R)- N-(1-(2,4-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)], an inhibitor of protozoan CYP51 that cures Chagas disease. The synthesis of fungi-oriented VNI derivatives, analysis of their potencies to inhibit CYP51s from two major fungal pathogens ( Aspergillus fumigatus and Candida albicans), microsomal stability, effects in fungal cells, and structural characterization of A. fumigatus CYP51 in complexes with the most potent compound are described, offering a new antifungal drug scaffold and outlining directions for its further optimization.
10.1021/acs.jmedchem.8b00641
Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans.
Bioorganic & medicinal chemistry
The design and synthesis of a library of forty novel 2-aminoazole analogues as well as their evaluation as antifungal compounds against Histoplasma capsulatum and Cryptococcus neoformans is described. These structures were derived from N-[5-(1-naphthalenylmethyl)-2-thiazolyl]cyclohexanecarboxamide (41F5), a fungistatic agent previously identified through phenotypic screening (Antimicrob Agents Chemother. 2013;57:4349). Modifications to improve potency and water-solubility of 41F5 focused primarily on the 5-naphthalenyl group, the thiazole core, and the methylene linker between these two structural elements. In general, compounds with lipophilic [5+6] bicyclic ring systems, such as the 7-benzothiophenyl- and 4-indanyl groups, at the 5-position were 2-3 times more active against both fungal species as compared to 41F5. Also, introduction of a carbonyl group at the methylene linker of 41F5 resulted in a 2-3-fold increase in potency. These highly active compounds also showed generally low toxicities against murine P388D1 macrophages resulting in selectivity indices ranging from 63 to >200. Compounds that were highly active against fluconazole-sensitive C. neoformans strains had almost identical activity against fluconazole-resistant variants of this fungus indicating that 14α-demethylase is not their molecular target. Highly active compounds also retained activity against H. capsulatum phagocytosed into P388D1 macrophages.
10.1016/j.bmc.2018.01.024
Chemical Diversity of (Olivi) C. Agardh Headspace Compounds, Volatiles, Fatty Acids and Insight into Its Antifungal Activity.
Jerković Igor,Kranjac Marina,Marijanović Zvonimir,Šarkanj Bojan,Cikoš Ana-Marija,Aladić Krunoslav,Pedisić Sandra,Jokić Stela
Molecules (Basel, Switzerland)
The focus of present study is on collected from the Adriatic Sea. volatiles were identified by gas chromatography and mass spectrometry (GC-FID; GC-MS) after headspace solid-phase microextraction (HS-SPME), hydrodistillation (HD), and supercritical CO₂ extraction (SC-CO₂). The headspace composition of dried (HS-D) and fresh (HS-F) was remarkably different. Dimethyl sulfide, the major HS-F compound was present in HS-D only as a minor constituent and heptadecane percentage was raised in HS-D. The distillate of fresh contained heptadecane and docosane among the major compounds. After air-drying, a significantly different composition of the volatile oil was obtained with ()-phytol as the predominant compound. It was also found in SC-CO₂ extract of freeze-dried (FD-CB) as the major constituent. Loliolide (3.51%) was only identified in SC-CO₂ extract. Fatty acids were determined from FD-CB after derivatisation as methyl esters by GC-FID. The most dominant acids were palmitic (25.4%), oleic (36.5%), linoleic (11.6%), and stearic (9.0%). FD-CB H₂O extract exhibited better antifungal effects against spp., while dimethyl sulfoxide (DMSO) extract was better for the inhibition of , and spp. The extracts showed relatively good antifungal activity, especially against (for DMSO extract MIC was at 50 µg/mL).
10.3390/molecules24050842
Membrane damage mechanism contributes to inhibition of trans-cinnamaldehyde on Penicillium italicum using Surface-Enhanced Raman Spectroscopy (SERS).
Huang Fei,Kong Jie,Ju Jian,Zhang Ying,Guo Yahui,Cheng Yuliang,Qian He,Xie Yunfei,Yao Weirong
Scientific reports
The antifungal mechanism of essential oils against fungi remains in the shallow study. In this paper, antifungal mechanism of trans-cinnamaldehyde against Penicillium italicum was explored. Trans-cinnamaldehyde exhibited strong mycelial growth inhibition against Penicillium italicum, with minimum inhibitory concentration of 0.313 μg/mL. Conventional analytical tests showed that trans-cinnamaldehyde changed the cell membrane permeability, which led to the leakage of some materials. Meanwhile, the membrane integrity and cell wall integrity also changed. Surface-enhanced Raman spectroscopy, an ultrasensitive and fingerprint method, was served as a bran-new method to study the antifungal mechanism. Characteristic peaks of supernatant obviously changed at 734, 1244, 1330, 1338 and 1466 cm. The Raman intensity represented a strong correlation with results from conventional methods, which made SERS an alternative to study antifungal process. All evidences implied that trans-cinnamaldehyde exerts its antifungal capacity against Penicillium italicum via membrane damage mechanism.
10.1038/s41598-018-36989-7
Discovery of Chitin Deacetylase Inhibitors through Structure-Based Virtual Screening and Biological Assays.
Journal of microbiology and biotechnology
Chitin deacetylase (CDA) inhibitors were developed as novel antifungal agents because CDA participates in critical fungal physiological and metabolic processes and increases virulence in soilborne fungal pathogens. However, few CDA inhibitors have been reported. In this study, 150 candidate CDA inhibitors were selected from the commercial Chemdiv compound library through structure-based virtual screening. The top-ranked 25 compounds were further evaluated for biological activity. The compound J075-4187 had an IC50 of 4.24 ± 0.16 μM for CDA. Molecular docking calculations predicted that compound J075-4187 binds to the amino acid residues, including active sites (H101, D48). Furthermore, compound J075-4187 inhibited food spoilage fungi and plant pathogenic fungi, with minimum inhibitory concentration (MIC) at 260 μg/ml and minimum fungicidal concentration (MFC) at 520 μg/ml. Therefore, compound J075-4187 is a good candidate for use in developing antifungal agents for fungi control.
10.4014/jmb.2201.01009
Cyclization Reaction of Acyl Thiourea Chitosan: Enhanced Antifungal Properties via Structural Optimization.
Molecules (Basel, Switzerland)
In this study, 3-methyl-1,2,4-triazolyl chitosan (MTACS) and 3-chloromethyl-1,2,4-triazolyl chitosan (CMTACS) were prepared via cyclization of acyl thiourea chitosan (TUCS). Their structures were confirmed by FT-IR, ¹H-NMR, elemental analysis, DSC, XRD, and SEM. The conformations were predicted using the Gaussian 09 program. Additionally, the antifungal properties of MTACS and CMTACS against weber (), (), and () were assayed in vitro and ranged from 250 μg/mL to 1000 μg/mL. The results showed that MTACS and CMTACS exhibited enhanced inhibitory effect on the selected fungi compared to the original chitosan and TUCS. In particular, they displayed better antifungal activities against and than that of the positive control, Triadimefon. The findings described here may lead to them being used as antifungal agents for crop protection.
10.3390/molecules23030594
One-pot three component synthesis of substituted dihydropyrimidinones using fruit juices as biocatalyst and their biological studies.
Gulati Susheel,Singh Rajvir,Prakash Ram,Sangwan Suman
PloS one
New and facile one-pot three component approach for the synthesis of substituted dihydropyrimidinones derivatives (4a-4h) from reaction of equimolar substituted aldehydes (1a-1h), methyl acetoacetate (2a) and urea (3a) in presence of nature derived catalyst viz. Cocos nucifera L. juice, Solanum lycopersicum L. juice and Citrus limetta juice, commonly known as coconut juice, tomato juice and musambi juice respectively, at room temperature has been carried out. All synthesized compounds were evaluated for in vitro herbicidal activity against Raphanus sativus L. (Radish seeds). The compounds (4a-4h) were also screened for their antifungal activity against Rhizoctonia solani and Colletotrichum gloeosporioides by poisoned food techniques method. Antibacterial activity was also studied against Erwinia cartovora and Xanthomonas citri by inhibition zone method. From activity data, it was found that compounds 4g and 4d were most active against Raphanus sativus L. (root) and Raphanus sativus L. (shoot) respectively. Compounds 4f and 4c was found most active against Rhizoctonia solani and Colletotrichum gloeosporioides fungus respectively at highest concentration. Compound 4g has shown maximum inhibition zone i.e. 1.00-5.50 mm against Erwinia cartovora at 2000 μg/mL concentration. Maximum Xanthomonas citrii growth was inhibited by compounds 4f showing inhibition zone 4.00-12.00 mm at highest concentration. Short reaction time, high yields, mild reaction condition and simple work-up are some merits of present methodology.
10.1371/journal.pone.0238092
New 2-aryl-7,8-dimethoxy-3,4-dihydroisoquinolin-2-ium salts as potential antifungal agents: synthesis, bioactivity and structure-activity relationships.
Zhu Lifei,Zhou Bohang,Zhang Bingyu,Xu Mingxuan,Geng Huiling,Zhou Le
Scientific reports
The title compounds can be considered as simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs). In order to develop potent QBA-like antifungal agents, as our continuing study, a series of new title compounds were synthesized and evaluated for bioactivity against five plant pathogenic fungi by the mycelium growth rate method in this study. The SAR were also derived. The majority of the compounds showed good to excellent inhibition activity with average EC values of 7.87-20.0 μM for the fungi, superior to sanguinarine and cherythrine (two QBAs) and the commercial fungicide azoxystrobin. Part of the compounds were more active than commercial fungicides thiabendazole or carbendazim against F. solani, F. graminearum and C. gloeosporioides. Six compounds with average EC of 3.5-5.1 μg/mL possessed very great potential for development of new antifungal agents. SAR found that substitution patterns of the two aryl-rings significantly affect the activity. There exists a complex interaction effect between substituents of the two aryl-rings on the activity. Generally, the presence of electron-withdrawing groups on the C-ring can significantly increase the activity. These findings will be of great importance for the design of more potent antifungal isoquinoline agents.
10.1038/s41598-017-07303-8
Rapid synthesis of BiO nano-needles via 'green route' and evaluation of its anti-fungal activity.
Indurkar Abhishek R,Sangoi Viraj D,Patil Prashant B,Nimbalkar Mansingraj S
IET nanobiotechnology
Here, the authors report a rapid, simple, and eco-friendly process for synthesis of BiO nano-needles. tuber extract was used as both reducing and capping agent for the first time. These nanoparticles were characterised by X-ray diffraction, field emission scanning electron microscope, and Fourier transform infrared (FTIR) spectrometry, the nano-structured BiO needles have an average diameter of 158 nm with the lengths in the range of 1-3 μm. CLSI M27-A2 standard was followed for evaluation of anti-fungal activity. BiO nano-needles show remarkable activity against . It exhibits four time greater activity than bulk BiO powder and two time greater activity than itraconazole, which makes it a potent anti-fungal drug.
10.1049/iet-nbt.2017.0070
Trehalose pathway as an antifungal target.
Virulence
With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.
10.1080/21505594.2016.1195529
Synthesis, Antifungal Activities and Molecular Docking Studies of Benzoxazole and Benzothiazole Derivatives.
Luo Bo,Li Ding,Zhang An-Ling,Gao Jin-Ming
Molecules (Basel, Switzerland)
Based on benzoxazole and benzothiazole scaffold as an important pharmacophore, two series of 2-(aryloxymethyl) benzoxazole and benzothiazole derivatives were synthesized and their antifungal effects against eight phytopathogenic fungi were evaluated. Compounds , , , and exhibited significant antifungal activities against most of the pathogens tested. Especially , , , , , and inhibited the growth of with IC of 4.34⁻17.61 μg/mL, which were stronger than that of the positive control, hymexazol (IC of 38.92 μg/mL). was the most potent inhibitor (IC of 4.34 μg/mL) against , which was about nine times more potent than hymexazol. Most of the test compounds displayed significant antifungal effects against (IC of 19.92⁻77.41 μg/mL), among them, was the best one (IC of 19.92 μg/mL). The structure-activity relationships (SARs) were compared and analyzed. The result indicates that the electron-drawing ability and position of the substituents have a significant impact on biological activities. Furthermore, docking studies were carried out on the lipid transfer protein sec14p from , and preliminarily verified the antifungal activities. Taken together, these results provide 2-(phenoxymethyl)benzo[d]oxazole as an encouraging framework that could lead to the development of potent novel antifungal agents.
10.3390/molecules23102457
Assessment of Chemical Composition and Anti-Penicillium Activity of Vapours of Essential Oils from Abies Alba and Two Melaleuca Species in Food Model Systems.
Molecules (Basel, Switzerland)
The possibilities of the practical utilization of essential oils (EOs) from various plant species in the food industry have attracted the attention of the scientific community. Following our previous studies, the antifungal activities of three further commercial EOs, Melaleuca armillaris subsp. armillaris (rosalina; REO), Melaleuca quinquenervia (niaouli; NEO), and Abies alba (fir; FEO), were evaluated in the present research in respect to their chemical profiles, over four different concentrations, 62.5 μL/L, 125 μL/L, 250 μL/L, and 500 μL/L. The findings revealed that the major compounds of REO, NEO, and FEO were linalool (47.5%), 1,8-cineole (40.8%), and α-pinene (25.2%), respectively. In vitro antifungal determinations showed that the inhibition zones of a Penicillium spp. mycelial growth ranged from no inhibitory effectiveness (00.00 ± 00.00 mm) to 16.00 ± 1.00 mm, indicating a very strong antifungal activity which was detected against P. citrinum after the highest REO concentration exposure. Furthermore, the in situ antifungal efficacy of all EOs investigated was shown to be dose-dependent. In this sense, we have found that the highest concentration (500 µL/L) of REO, NEO, and FEO significantly reduced (p < 0.05) the growth of all Penicillium strains inoculated on the bread, carrot, and potato models. These results indicate that the investigated EOs may be promising innovative agents in order to extend the shelf life of different types of food products, such as bread, carrot and potato.
10.3390/molecules27103101
Synthesis, Structure, and Activity of the Antifungal Plant Defensin D.
Skalska Julia,Andrade Vitor M,Cena Gabrielle L,Harvey Peta J,Gaspar Diana,Mello Érica O,Henriques Sónia T,Valle Javier,Gomes Valdirene M,Conceição Katia,Castanho Miguel A R B,Andreu David
Journal of medicinal chemistry
Available treatments for invasive fungal infections have limitations, including toxicity and the emergence of resistant strains. Therefore, there is an urgent need for alternative solutions. Because of their unique mode of action and high selectivity, plant defensins (PDs) are worthy therapeutic candidates. Chemical synthesis remains a preferred method for the production of many peptide-based therapeutics. Given the relatively long sequence of PDs, as well as their complicated posttranslational modifications, the synthetic route can be considered challenging. Here, we describe a total synthesis of D, the defensin from the common bean . Analytical, structural, and functional characterization revealed that both natural and synthetic peptides fold into a canonical CSαβ motif stabilized by conserved disulfide bonds. Moreover, synthetic D retained the biological activity against four different species and showed no toxicity . Adding the high resistance of synthetic D to proteolytic degradation, we claim that conditions are now met to consider PDs druggable biologicals.
10.1021/acs.jmedchem.0c00543
Characterization of a novel cysteine-rich antifungal protein from Fusarium graminearum with activity against maize fungal pathogens.
Patiño Belén,Vázquez Covadonga,Manning James M,Roncero María Isabel G,Córdoba-Cañero Dolores,Di Pietro Antonio,Martínez-Del-Pozo Álvaro
International journal of food microbiology
Filamentous fungi are an invaluable source for biocontrol strategies and for production and development of different antifungal polypeptides. Within this context, cysteine-rich antifungal AFP-like peptides stand out among many different antimicrobial compounds given their production easiness, stability, versatility, and efficacy. AFP from Aspergillus giganteus represents the hallmark of this still increasing family of antifungal polypeptides. Close in silico analyses of the Fusarium graminearum genome revealed the presence of an AFP-like peptide, here designated as FgAFP. This new peptide was cloned, produced in the yeast Pichia pastoris, and characterized. The results obtained showed its strong and specific antifungal activity against several well-recognized maize pathogens, but inefficacy against F. oxysporum, which has not been described as a natural biological competitor of other fungal pathogens assayed. All results together suggest that this small peptide is an important factor for the fungal interplays involved in maize infection and reveals unforeseen potential biotechnological applications for FgAFP in maize production and storage.
10.1016/j.ijfoodmicro.2018.06.017
Biosynthesis of Sinapigladioside, an Antifungal Isothiocyanate from Burkholderia Symbionts.
Chembiochem : a European journal of chemical biology
Sinapigladioside is a rare isothiocyanate-bearing natural product from beetle-associated bacteria (Burkholderia gladioli) that might protect beetle offspring against entomopathogenic fungi. The biosynthetic origin of sinapigladioside has been elusive, and little is known about bacterial isothiocyanate biosynthesis in general. On the basis of stable-isotope labeling, bioinformatics, and mutagenesis, we identified the sinapigladioside biosynthesis gene cluster in the symbiont and found that an isonitrile synthase plays a key role in the biosynthetic pathway. Genome mining and network analyses indicate that related gene clusters are distributed across various bacterial phyla including producers of both nitriles and isothiocyanates. Our findings support a model for bacterial isothiocyanate biosynthesis by sulfur transfer into isonitrile precursors.
10.1002/cbic.202100089
Structure-activity relationship studies of ultra-short peptides with potent activities against fluconazole-resistant Candida albicans.
Ng Siew Mei Samantha,Yap Jia Mao,Lau Qiu Ying,Ng Fui Mee,Ong Esther Hong Qian,Barkham Timothy,Teo Jeanette Woon Pei,Alfatah Mohammad,Kong Kiat Whye,Hoon Shawn,Arumugam Prakash,Hill Jeffrey,Brian Chia Cheng San
European journal of medicinal chemistry
Vulvovaginal candidiasis (VVC) is a genital fungal infection afflicting approximately 75% of women globally and is primarily caused by the yeast Candida albicans. The extensive use of fluconazole, the first-line antifungal drug of choice, has led to the emergence of fluconazole-resistant C. albicans, creating a global clinical concern. This, coupled to the lack of new antifungal drugs entering the market over the past decade, has made it imperative for the introduction of new antifungal drug classes. Peptides with antifungal properties are deemed potential drug candidates due to their rapid membrane-disrupting mechanism of action. By specifically targeting and rapidly disrupting fungal membranes, they reduce the chances of resistance development and treatment duration. In a previous screening campaign involving an antimicrobial peptide library, we identified an octapeptide (IKIKIKIK-NH) with potent activity against C. albicans. Herein, we report a structure-activity relationship study on this peptide with the aim of designing a more potent peptide for further development. The lead peptide was then tested against a panel of fluconazole-resistant C. albicans, subjected to a fungicidal/static determination assay, a human dermal fibroblast viability assay and a homozygous profiling assay to gain insights into its mechanism of action and potential for further development as a topical antifungal agent.
10.1016/j.ejmech.2018.03.027
Synthesis of Water-Soluble Sulfonated Chitin Derivatives for Potential Antioxidant and Antifungal Activity.
Marine drugs
Chitin is a natural renewable and useful biopolymer limited by its insolubility; chemical derivatization can enhance the solubility and bioactivity of chitin. The purpose of this study was to synthesize novel water-soluble chitin derivatives, sulfo-chitin (SCT) and sulfopropyl-chitin (SPCT), as antioxidant and antifungal agents. The target derivatives were characterized by means of elemental analysis, FTIR, 13C NMR, TGA and XRD. Furthermore, the antioxidant activity of the chitin derivatives was estimated by free radical scavenging ability (against DPPH-radical, hydroxyl-radical and superoxide-radical) and ferric reducing power. In addition, inhibitory effects against four fungi were also tested. The findings show that antioxidant abilities and antifungal properties were in order of SPCT > SCT > CT. On the basis of the results obtained, we confirmed that the introduction of sulfonated groups on the CT backbone would help improve the antioxidant and antifungal activity of CT. Moreover, its efficacy as an antioxidant and antifungal agent increased as the chain length of the substituents increased. This derivatization strategy might provide a feasible way to broaden the utilization of chitin. It is of great significance to minimize waste and realize the high-value utilization of aquatic product wastes.
10.3390/md20110668
Inhibition of Growth and Aflatoxins Production by Natural Essential Oils and Phenolic Acids.
Toxins
Aflatoxins represent a significant risk to food safety, and strategies are being implemented to reduce their entry into the food chain. The aim of this study was to evaluate the in vitro effect of four essential oils (EOs) (lavandins Grosso and Abrial, Origanum virens, and Rosmarinus officinalis) and four natural phenolic acids (PAs) (caffeic, chlorogenic, ferulic, and p-coumaric) on the growth and aflatoxins (B1, B2, G1, and G2) production by Aspergillus parasiticus. Minimal inhibitory concentration (MIC) and minimal fungicide concentration (MFC) were determined by the broth macrodilution method. Additionally, the mycelia weight was determined at concentration levels lower than MIC. The antiaflatoxigenic activity was evaluated in the two concentrations of the EOs right before MIC and at concentrations below the MIC value for the PAs. To this end, in-house validated methodology based on high-performance liquid chromatography with post-column photochemical derivatization and fluorescence detection (HPLC-PHRED-FLD) was used. EOs of O. virens and lavandins (Grosso and Abrial) completely inhibited mold growth. In addition, a significant reduction in mycelial mass (p < 0.05) was observed for all EOs and PAs at different concentrations. In all cases except for lavandin Abrial, EO concentrations just before the MIC value strongly reduced (p < 0.05) aflatoxins synthesis. Aflatoxins production was completely inhibited by all PAs at a concentration of 20 mM; although at low concentrations, mycotoxin production was stimulated in some cases. The present study provides a scientific basis for further study of the inhibiting mechanisms.
10.3390/toxins14060384
Antifungal Activity of Hexahydropyrimidine Derivatives against the Causative Agents of Dermatomycosis.
Martins Francislene J,Caneschi César A,Senra Mônica P,Carvalho Gustavo S G,da Silva Adilson D,Raposo Nádia R B
TheScientificWorldJournal
Nitrogenated heterocyclic compounds are present in both natural and synthetic drugs, and hexahydropyrimidine derivatives may prove to be efficient in treating dermatomycosis causing fungi. This study evaluated the antifungal activity of four hexahydropyrimidine derivatives against the dermatomycosis causing fungi. These derivatives were synthesized, characterized, and assessed in terms of their activity against , , , , , and between concentrations 7.8 and 1,000 g mL. Scanning electron micrographs were assessed for the active derivatives and reference drugs, and these micrographs revealed that new agents cause morphological changes in fungi. The derivatives HHP1, HHP3, and HHP4 revealed poor activity against the four fungal strains (MICs range 500-1000 g mL). Compound HHP3 was found to be the best potential antifungal agent among those tested and was the most effective among all the active derivatives that caused morphological changes in the susceptible strains.
10.1155/2017/1207061
Assessment of the nail penetration of antifungal agents, with different physico-chemical properties.
Davies-Strickleton Heather,Cook Julie,Hannam Sally,Bennett Rhys,Gibbs Alan,Edwards David,Ridden Christine,Ridden John,Cook David
PloS one
Onychomycosis, or fungal nail infection, is a common fungal infection largely caused by dermatophyte fungi, such as Trichophyton rubrum or Trichophyton mentagrophytes, which affects a significant number of people. Treatment is either through oral antifungal medicines, which are efficacious but have significant safety concerns, or with topical antifungal treatments that require long treatment regimens and have only limited efficacy. Thus, an efficacious topical therapy remains an unmet medical need. Among the barriers to topical delivery through the nail are the physico-chemical properties of the antifungal drugs. Here, we explore the ability of a range of antifungal compounds with different hydrophilicities to penetrate the nail. Human nail discs were clamped within static diffusion (Franz) cells and dosed with equimolar concentrations of antifungal drugs. Using LC-MS/MS we quantified the amount of drug that passed through the nail disc and that which remained associated with the nail. Our data identified increased drug flux through the nail for the more hydrophilic compounds (caffeine as a hydrophilic control and fluconazole, with LogP -0.07 and 0.5, respectively), while less hydrophilic efinaconazole, amorolfine and terbinafine (LogP 2.7, 5.6 and 5.9 respectively) had much lower flux through the nail. On the other hand, hydrophilicity alone did not account for the amount of drug associated with/bound to the nail itself. While there are other factors that are likely to combine to dictate nail penetration, this work supports earlier studies that implicate compound hydrophilicity as a critical factor for nail penetration.
10.1371/journal.pone.0229414
Composition and Antifungal Activity of the Alkaloidal Fraction of Leaves: A Biochemometrics-Based Exploration.
Molecules (Basel, Switzerland)
plants are well-recognized due to their significant alkaloid content, which has made them the subject of several studies. However, the lack of chemical and biological information on the Colombian species remains a fact. Therefore, the alkaloidal fractions from the leaves of L. obtained by conventional solvent and ultrasound-assisted extraction (CSE and UAE, respectively) at different time frames were analyzed. Sparteine () was the main component in all cases; however, its relative abundance showed large variability, ranging from 64.7% to 80.6%. Minor constituents were also affected by the extraction conditions. In general, prolonged times gave a higher proportion of alkaloids under CSE, while only a slight decrease was observed under UAE. Both the method and extraction time appeared to equally affect the ratios of particular alkaloids, leading to variations in their effect on the mycelial growth of . Holistic analysis through multiple-covariate statistical methods as an approach to integrating chemical and bioactivity datasets allowed inferring the compounds most likely responsible for the changes in mycelial growth inhibition. 13α-Hydroxylupanine () might represent a promising compound to be included in further studies against this phytopathogen.
10.3390/molecules27092832
Chemical Composition and Antifungal Activity of Fruit Essential Oil against .
Molecules (Basel, Switzerland)
Pathogenic plant oomycetes cause devastating damage to fruits and vegetables worldwide. Plant essential oils (EOs) are known to be promising candidates for the development of fungicides. In this study, we isolated twelve EOs from , , , , , and leaves and fruits. We then investigated their chemical composition and antifungal activity against phytopathogenic oomycetes. Our results demonstrated that fruit essential oil (ZFO) in particular substantially inhibited the mycelial growth of . Similarly, ZFO also strongly suppressed spore production and germination of , and the application of ZFO significantly reduced disease symptoms caused by in pepper. Furthermore, results from microscopic and biochemical studies indicated that ZFO damaged the ultrastructure and destroyed the membrane integrity of , leading to the leakage of the cellular contents and ultimately causing cell death. It was concluded that ZFO could enhance the activities of defense-related enzymes in pepper fruits, which may also be responsible for the inhibition of phytophthora disease. Moreover, linalool and -limonene were proven to be the primary effective components of ZFO. Our results collectively indicate that ZFO could be a potential candidate for the management of disease caused by .
10.3390/molecules27238636
Molecules and Metabolites from Natural Products as Inhibitors of Biofilm in Candida spp. pathogens.
Current topics in medicinal chemistry
BACKGROUND:Biofilm is a critical virulence factor associated with the strains of Candida spp. pathogens as it confers significant resistance to the pathogen against antifungal drugs. METHODS:A systematic review of the literature was undertaken by focusing on natural products, which have been reported to inhibit biofilms produced by Candida spp. The databases explored were from PubMed and Google Scholar. The abstracts and full text of the manuscripts from the literature were analyzed and included if found significant. RESULTS:Medicinal plants from the order Lamiales, Apiales, Asterales, Myrtales, Sapindales, Acorales, Poales and Laurales were reported to inhibit the biofilms formed by Candida spp. From the microbiological sources, lactobacilli, Streptomyces chrestomyceticus and Streptococcus thermophilus B had shown the strong biofilm inhibition potential. Further, the diverse nature of the compounds from classes like terpenoids, phenylpropanoid, alkaloids, flavonoids, polyphenol, naphthoquinone and saponin was found to be significant in inhibiting the biofilm of Candida spp. CONCLUSION:Natural products from both plant and microbial origins have proven themselves as a goldmine for isolating the potential biofilm inhibitors with a specific or multi-locus mechanism of action. Structural and functional characterization of the bioactive molecules from active extracts should be the next line of approach along with the thorough exploration of the mechanism of action for the already identified bioactive molecules.
10.2174/1568026619666191025154834
Screening Effective Antifungal Substances from the Bark and Leaves of by the Bioactivity-Guided Isolation Method.
Xiong Yongtong,Huang Guan,Yao Zongli,Zhao China,Zhu Xiang,Wu Qinglai,Zhou Xudong,Li Junkai
Molecules (Basel, Switzerland)
To find good antifungal substances by the bioactivity-guided isolation method, we tracked down the effective antifungal substances in the bark and leaves of , and isolated three antifungal compounds , , and The structures were identified as xanthyletin, luvangetin, and avicennin by H-NMR, C-NMR, and HRMS spectra. Particularly, compound had several isomers, and the H-NMR spectra of in different solvents showed a significant difference. To determine the stereo structure of 2, a single crystal was prepared and identified by X-ray diffraction as Luvangetin. Moreover, the difference of H-NMR data of between in solvent dimethyl sulfoxide-d (DMSO-d) and deuterated chloroform (CDCl), and other reported isomers were discussed for the first time. The bioassay results indicated that the three compounds , , and displayed low to high antifungal activities against tested phytopathogenic fungi. In particular, all compounds , , and showed excellent antifungal activities against Pyricularia oryzae and , with the values of half maximal effective concentration (EC) ranging from 31 to 61 mg/L, and compound was also identified as a more potent inhibitor against Fusaium graminearum (EC = 43.26 ± 1.76 mg/L) compared with fungicide PCA (phenazine-1-carboxylic acid) (EC = 52.34 ± 1.53 mg/L). The results revealed that compounds and were the main antifungal substances of Z. avicennae, and can be used as lead compounds of a fungicide, which has good development value and prospect.
10.3390/molecules24234207
Syntheses of Novel 4-Substituted N-(5-amino-1H-1,2,4-triazol-3-yl)pyridine-3-sulfonamide Derivatives with Potential Antifungal Activity.
Szafrański Krzysztof,Sławiński Jarosław,Kędzia Anna,Kwapisz Ewa
Molecules (Basel, Switzerland)
Candidiasis represent a serious threat for patients with altered immune responses. Therefore, we have undertaken the synthesis of compounds comprising a pyridine-3-sulfonamide scaffold and known antifungally active 1,2,4-triazole substituents. Thus a series of novel 4-substituted -(5-amino-1-1,2,4-triazol-3-yl)pyridine-3-sulfonamides have been synthesized by multistep reactions starting from 4-chloropyridine-3-sulfonamide via '-cyano--[(4-substitutedpyridin-3-yl)sulfonyl]carbamimidothioates which were further converted with hydrazine hydrate to the corresponding 1,2,4-triazole derivatives -. The final compounds were evaluated for antifungal activity against strains of the genera , , , and isolated from patients with mycosis. Many of them show greater efficacy than fluconazole, mostly towards and species, with MIC values ≤ 25 µg/mL. A docking study of the most active compounds 26, 34 and 35 was performed showing the potential mode of binding to lanosterol 14α-demethylase. Also in vitro cytotoxicity of selected compounds have been evaluated on the NCI-60 cell line panel.
10.3390/molecules22111926
Synthesis and Anticandidal Activity of New Imidazole-Chalcones.
Osmaniye Derya,Kaya Çavuşoğlu Betül,Sağlık Begüm Nurpelin,Levent Serkan,Acar Çevik Ulviye,Atlı Özlem,Özkay Yusuf,Kaplancıklı Zafer Asım
Molecules (Basel, Switzerland)
In the present work, 15 new 1-(4-(1-imidazol-1-yl)phenyl)-3-(4-substituedphenyl)prop-2-en-1-one derivatives (–) were synthesized to evaluate their antifungal activity. Structures of newly synthesized imidazole derivatives (–) were characterized by IR, ¹H-NMR, C-NMR, and LCMSMS spectroscopic methods. The anticandidal activity of compounds (–) against (ATCC 24433), (ATCC 6258), (ATCC 22019), and (ATCC 90030) was elucidated according to the EUCAST definitive (EDef 7.1) method. Consistent with the activity studies, – were found to be more potent derivatives with their MIC values (0.78 µg/mL–3.125 µg/mL) against strains. Compound indicated similar antifungal activity to ketoconazole against all species and was evaluated as the most active derivative in the series. Effects of the most potent derivatives – on ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of the ergosterol level in . Moreover, these compounds were subjected to a cytotoxicity test for the preliminary toxicological profiles and were found as non-cytotoxic. Furthermore, docking studies for the most active derivative were performed to evaluate its binding modes on lanosterol 14-α-demethylase. In addition to in vitro tests, docking studies also revealed that Compound is a potential ergosterol biosynthesis inhibitor.
10.3390/molecules23040831
Design, Synthesis, and Fungicidal Activity of Novel Thiosemicarbazide Derivatives Containing Piperidine Fragments.
Zhang Xuebo,Lei Peng,Sun Tengda,Jin Xiaoyu,Yang Xinling,Ling Yun
Molecules (Basel, Switzerland)
In order to discover novel eco-friendly lead compounds for plant pathogenic fungi control, a series of benzaldehyde thiosemicarbazide derivatives with a piperidine moiety have been designed and synthesized. Fungicidal activities of all the synthesized compounds were evaluated in vitro. The results indicated that all the title compounds exhibited moderate to good fungicidal activities. Compound displayed excellent activities against , , , and , with EC values lower than 10 μg/mL. Especially, in the case of , its activity (EC = 1.6 μg/mL) is superior to the commercial azoxystrobin (EC = 16.9 μg/mL) and close to fluopicolide (EC = 1.0 μg/mL). Initial structure-activity relationship (SAR) analysis showed that the heterocyclic piperidine group can influence the biological activities of the title compounds significantly. The fungicidal activity of compounds with piperidine is better than that of compounds without piperidine. The highly-active compound , with its simple structure and easy synthetic route, is worthy to be further studied as a new lead fungicide.
10.3390/molecules22122085
Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters.
Huang Min,Duan Wen-Gui,Lin Gui-Shan,Li Kun,Hu Qiong
Molecules (Basel, Switzerland)
A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two - stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures of all the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, ESI-MS, and elemental analysis. The antifungal activity of the target compounds was preliminarily evaluated by the in vitro method against f. sp. , , , , , , and at 50 µg/mL. The target compounds exhibited best antifungal activity against , in which compounds ()- (R = -pyridyl), ()- (R = -thienyl), ()- (R = -F Ph), ()- (R = -Me Ph), ()- (R = -Me Ph), and ()- (R = -furyl) had inhibition rates of 97.1%, 87.4%, 87.4%, 85.0%, 81.9%, and 77.7%, respectively, showing better antifungal activity than that of the commercial fungicide chlorothanil. Also, compound ()- (R = -pyridyl) displayed remarkable antifungal activity against all the tested fungi, with inhibition rates of 76.7%, 82.7%, 97.1%, 66.3%, 74.7%, 93.9%, 76.7% and 93.3%, respectively, showing better or comparable antifungal activity than that of the commercial fungicide chlorothanil. Besides, the isomers of the target oxime esters were found to show obvious differences in antifungal activity. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents.
10.3390/molecules22091538
Screening of Ionic Liquids against Bamboo Mildew and Its Inhibition Mechanism.
Molecules (Basel, Switzerland)
Ionic liquids are a class of organic molten salts that consist entirely of cations and anions. They are characterized by their low vapor pressure, low viscosity, low toxicity, high thermal stability, and strong antifungal potential. In this study, the inhibitory performance of ionic liquid cations against Penicillium citrinum, Trichoderma viride, and Aspergillus niger was investigated, along with the mechanism of cell membrane disruption. The Oxford cup method, SEM, and TEM were employed to examine the extent of damage and the specific site of action of ionic liquids on the mycelium and cell structure of these fungi. The results showed that 1-decyl-3-methylimidazole had a strong inhibitory effect on ; benzyldimethyldodecylammonium chloride had a weak inhibitory effect on , , , and a mixed culture; while dodecylpyridinium chloride exhibited significant inhibitory effects on , , , and Mix, with more prominent effects observed on and Mix, exhibiting MIC values of 5.37 mg/mL, 5.05 mg/mL, 5.10 mg/mL, and 5.23 mg/mL, respectively. The mycelium of the mildews showed drying, partial loss, distortion, and uneven thickness. The cell structure showed separation of the plasma wall. The absorbance of the extracellular fluid of and reached the maximum after 30 min, while that of reached the maximum after 60 min. The pH of the extracellular fluid decreased initially and then increased within 60 min, followed by a continuous decrease. These findings provide important insights for the application of ionic liquid antifungal agents in bamboo, medicine, and food.
10.3390/molecules28083432
Xanthone synthetic derivatives with high anticandidal activity and positive mycostatic selectivity index values.
Scientific reports
With the current massive increases in drug-resistant microbial infection as well as the significant role of fungal infections in the death toll of COVID-19, discovering new antifungals is extremely important. Natural and synthetic xanthones are promising derivatives, although only few reports have demonstrated their antifungal mechanism of action in detail. Newly synthetized by us xanthone derivative 44 exhibited strong antifungal activity against reference and fluconazole resistant C. albicans strains. Our results indicate that the most active compounds 42 and 44 are not substrates for fungal ABC transporters (Cdr1p and Cdr2p) and Mdr1p, the main representative of the major facilitator superfamily efflux pumps, membrane proteins that are responsible for the development of resistance. Moreover, fungicidal mode of action reduces the probability of persistent or recurrent infections and resistance development. In this light, the demonstrated killing activity of the examined derivatives is their undoubted advantage. Novel synthesized compounds exhibited moderate cytotoxicity against human cell lines, although the selectivity index value for human pathogenic strains remained favourable. Our results also indicate that novel synthetized compounds 42 and 44 with antifungal activity target yeast topoisomerase II activity. In summary, further validation of xanthones applicability as antifungals is highly valuable.
10.1038/s41598-023-38963-4
Influence of α-FeO, CuO and GO 2D nano-fillers on the structure, physical properties and antifungal activity of Na-CMC-PAAm blend.
Scientific reports
The present work aims to improve the uses of the carboxymethyl cellulose-polyacrylamide (Na-CMC-PAAm) blend for energy storage, optoelectronic applications, biological control, and plant disease management. Nano-sized materials (α-FeO nanoplates (NP), CuO NP, and GO nanosheets (NS), were synthesized and incorporated into the blend. The phase purity and morphologies of the used fillers were studied by XRD and HR-TEM. The interactions and complexation between the nano-fillers and the blend chains were investigated using XRD and FTIR spectra. The chemical composition and surface morphology of the nanocomposites were studied using EDS and FE-SEM analysis. UV-vis-NIR spectra revealed that the blend shows about 95% transmittance, reduced by 10-30% after doping. The absorption and refractive indices, as well as the optical gaps of the blend, were greatly affected by the doping. The dielectric constant and loss depend on the type of filler and the applied frequency. The maximum ac conductivity of the blend at 303 K and 4.0 MHz is 21.5 × 10 S/m and increased to 23.5 × 10 S/m after doping with CuO NP. The thermal stability, activation energy, stress-strain curves, and tensile strength are dependent on the filler type. All nanocomposite solutions except the blend exhibited a wide range of antifungal properties against pre- and post-harvest phytopathogenic fungi. Aspergillus niger among the examined fungi showed high sensitivity to the tested nanocomposite solutions. Furthermore, the CuO/blend nanocomposite had the highest antifungal activity against all tested fungi. Based on that, we suggest the use of CuO/blend and GO/blend nanocomposites to control and combat pre- and post-harvest fungal plant diseases.
10.1038/s41598-023-39056-y
Selective Metal Chelation by a Thiosemicarbazone Derivative Interferes with Mitochondrial Respiration and Ribosome Biogenesis in Candida albicans.
Microbiology spectrum
Metal chelation is generally considered as a promising antifungal approach but its specific mechanisms are unclear. Here, we identify 13 thiosemicarbazone derivatives that exert broad-spectrum antifungal activity with potency comparable or superior to that of fluconazole by screening a small compound library comprising 89 thiosemicarbazone derivatives as iron chelators. Among the hits, 19ak exhibits minimal cytotoxicity and potent activity against either azole-sensitive or azole-resistant fungal pathogens. Mechanism investigations reveal that 19ak inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation, and further reduces mitochondrial membrane potential and ATP synthesis in Candida albicans. In addition, 19ak inhibits fungal ribosome biogenesis mainly by disrupting intracellular zinc homeostasis. 19ak also stimulates the activities of antioxidant enzymes and decreases reactive oxygen species formation in C. albicans, resulting in an increase in detrimental intracellular reductive stress. However, 19ak has minor effects on mammalian cells in depleting intracellular iron and zinc. Moreover, 19ak exhibits low capacity to induce drug resistance and efficacy in a Galleria mellonella infection model. These findings uncover retarded fungal mitochondrial respiration and ribosome biogenesis as downstream effects of disruption of iron and zinc homeostasis in C. albicans and provide a basis for the thiosemicarbazone 19ak in antifungal application. The increasing incidence of fungal infections and resistance to existing antifungals call for the development of broad-spectrum antifungals with novel mechanisms of action. In this study, we demonstrate that a thiosemicarbazone derivative 19ak selectively inhibits mitochondrial respiration mainly by retarding mitochondrial respiratory chain complex I activity through iron chelation and inhibits ribosome biogenesis mainly by disrupting intracellular zinc homeostasis in C. albicans. In addition, 19ak exhibits low capacity to induce fungal resistance, minimal cytotoxicity, and antifungal efficacy. This study provides the basis of thiosemicarbazone derivative 19ak as a metal chelator for the treatment of fungal infections.
10.1128/spectrum.01951-21
L. and Its Secondary Metabolites in the Management of Different Fungal Pathogens.
Chahal Rubal,Nanda Arun,Akkol Esra Küpeli,Sobarzo-Sánchez Eduardo,Arya Ashwani,Kaushik Deepak,Dutt Rohit,Bhardwaj Rashmi,Rahman Md Habibur,Mittal Vineet
Molecules (Basel, Switzerland)
L. (Family-Asteraceae) is an annual aromatic invasive herb, mainly distributed over the tropical and subtropical regions of the world. It owns a reputed history of indigenous remedial uses, including as a wound dressing, an antimicrobial, and mouthwash as well as in treatment of dysentery, diarrhea, skin diseases, etc. In this review, the core idea is to present the antifungal potential of the selected medicinal plant and its secondary metabolites against different fungal pathogens. Additionally, toxicological studies (safety profile) conducted on the amazing plant L. are discussed for the possible clinical development of this medicinal herb. Articles available from 2000 to 2020 were reviewed in detail to exhibit recent appraisals of the antifungal properties of . Efforts were aimed at delivering evidences for the medicinal application of by using globally recognized scientific search engines and databases so that an efficient approach for filling the lacunae in the research and development of antifungal drugs can be adopted. After analyzing the literature, it can be reported that the selected medicinal plant effectively suppressed the growth of numerous fungal species, such as , , , , , and , owing to the presence of various secondary metabolites, particularly chromenes, terpenoids, flavonoids and coumarins. The possible mechanism of action of different secondary metabolites of the plant against fungal pathogens is also discussed briefly. However, it was found that only a few studies have been performed to demonstrate the plant's dosage and safety profile in humans. Considered all together, extract and its constituents may act as a promising biosource for the development of effective antifungal formulations for clinical use. However, in order to establish safety and efficacy, additional scientific research is required to explore chronic toxicological effects of , to determine the probability of interactions when used with different herbs, and to identify safe dosage. The particulars presented here not only bridge this gap but also furnish future research strategies for the investigators in microbiology, ethno-pharmacology, and drug discovery.
10.3390/molecules26102933
Molecular Epidemiology of Azole-Resistant in France Shows Patient and Healthcare Links to Environmentally Occurring Genotypes.
Frontiers in cellular and infection microbiology
Resistance of the human pathogenic fungus to antifungal agents is on the rise. However, links between patient infections, their potential acquisition from local environmental sources, and links to global diversity remain cryptic. Here, we used genotyping analyses using nine microsatellites in , in order to study patterns of diversity in France. In this study, we genotyped 225 local isolates, 112 azole susceptible and 113 azole resistant, collected from the Bourgogne-Franche-Comté region (Eastern France) and sampled from both clinical ( = 34) and environmental ( = 191) sources. Azole-resistant clinical isolates ( = 29) were recovered mainly from cystic fibrosis patients and environmental isolates ( = 84) from market gardens and sawmills. In common with previous studies, the TR/L98H allele predominated and comprised 80% of resistant isolates. The genotypes obtained for these local TR/L98H isolates were integrated into a broader analysis including all genotypes for which data are available worldwide. We found that dominant local TR/L98H genotypes were isolated in different sample types at different dates (different patients and types of environments) with hospital air and patient's isolates linked. Therefore, we are not able to rule out the possibility of some nosocomial transmission. We also found genotypes in these same environments to be highly diverse, emphasizing the highly mixed nature of populations. Identical clonal genotypes were found to occur both in the French Eastern region and in the rest of the world (notably Australia), while others have not yet been observed and could be specific to our region. Our study demonstrates the need to integrate patient, healthcare, and environmental sampling with global databases in order to contextualize the local-scale epidemiology of antifungal resistant aspergillosis.
10.3389/fcimb.2021.729476
Novel 6a,12b-Dihydro-6,7-chromeno[3,4-c] chromen-6-ones: Synthesis, Structure and Antifungal Activity.
Bao Jin-Ping,Xu Cui-Lian,Yang Guo-Yu,Wang Cai-Xia,Zheng Xin,Yuan Xin-Xin
Molecules (Basel, Switzerland)
A new series of coumarin derivatives, 7-hydroxy-7-(trifluoromethyl)-6a,12b-dihydro-6,7-chromeno[3,4-c]chromen-6-ones -, were synthesized via Michael addition, transesterification and nucleophilic addition from the reaction of 3-trifluoroacetyl coumarins and phenols in the presence of an organic base. The products were characterized by infrared spectroscopy (IR), hydrogen nuclear magnetic resonance spectroscopy (H-NMR), carbon nuclear magnetic resonance spectroscopy (C-NMR) and high-resolution mass spectrometer (HRMS). Single crystal X-ray analysis of compounds and clearly confirmed their assigned chemical structures and their twisted conformations. Compound crystallized in the orthorhombic system, Pbca, in which a = 8.6244(2) Å, b = 17.4245(4) Å, c = 22.5188(6) Å, α = 90°, β = 90°, γ = 90°, v = 3384.02(14) Å, and z = 8. In addition, the mycelial growth rate method was used to examine the in vitro antifungal activities of the title compounds - against and at 500 µg/mL. The results showed that compound exhibited significant anti- activity with inhibitory index of 84.6%.
10.3390/molecules24091745
Antifungal Activities of Phytochemically Characterized Hydroethanolic Extracts of Leaves and Stem Bark against Fluconazole-Resistant Strains.
BioMed research international
The study evaluated the antifungal activities of the 70% ethanol extracts of leaves (SBL) and stem bark (SBB) against strains and fluconazole-resistant isolates, their antifungal effects in combination with conventional antifungals as well as their effects on the biofilms of the strains and isolates. UPLC-QTOF-MS/MS analysis was then carried out to investigate the metabolite profile of the extracts and UPLC fingerprints developed for their routine identification as part of quality control measures. The extracts exhibited considerable antifungal activity with MIC ranging from 12.21 to 97.66 g/mL and MFC from 12.21 to 390.63 g/mL against the strains and isolates. The antifungal activity of the stem bark extract was higher than the leaf extract. SBL and SBB also significantly inhibited biofilm formation (IC = 12.49 to 164.42 g/mL) and the mature biofilms (IC = 91.50 to 685.20 g/mL) of the strains and isolates of the and demonstrated potential for their use in combination therapies with currently used antifungals especially the stem bark extract with nystatin. Metabolite profiling identified the presence of polyphenolic compounds in both leaves and stem bark mostly flavonoids, their derivatives, and proanthocyanidins, which contribute in part to the bioactivity of the plant. Whereas flavonoids like quercetin, myricetin, and their derivatives were abundant in the leaves, epicatechin monomers with their condensed tannins, including procyanidin B2 and procyanidin C, were abundant in the stem bark. Fingerprints of SBL and SBB were developed and validated and could be used as qualitative tools to authenticate the plant. The outcomes of the study show the promise of the leaf and stem bark extracts of to be studied further and developed as antifungal agents.
10.1155/2022/4261741
Biosynthesis of the Polycyclic System in the Antifungal HSAF and Analogues from Lysobacter enzymogenes.
Li Yaoyao,Wang Haoxin,Liu Yan,Jiao Yujie,Li Shanren,Shen Yuemao,Du Liangcheng
Angewandte Chemie (International ed. in English)
The biocontrol agent Lysobacter enzymogenes produces polycyclic tetramate macrolactams (PoTeMs), including the antifungal HSAF. To elucidate the biosynthesis of the cyclic systems, we identified eleven HSAF precursors/analogues with zero, one, two, or three rings through heterologous expression of the HSAF gene cluster. A series of combinatorial gene expression and deletion experiments showed that OX3 is the "gatekeeper" responsible for the formation of the first 5-membered ring from lysobacterene A, OX1 and OX2 are responsible for formation of the second ring but with different selectivity, and OX4 is responsible for formation of the 6-membered ring. In vitro experiments showed that OX4 is an NADPH-dependent enzyme that catalyzes the reductive cyclization of 3-dehydroxy alteramide C to form 3-dehydroxy HSAF. Thus, the multiplicity of OX genes is the basis for the structural diversity of the HSAF family, which is the only characterized PoTeM cluster that involves four redox enzymes in the formation of the cyclic system.
10.1002/anie.201802488
Discovery of metal-based complexes as promising antimicrobial agents.
Liang Jing,Sun Dejuan,Yang Yueying,Li Mingxue,Li Hua,Chen Lixia
European journal of medicinal chemistry
The antimicrobial resistance (AMR) is an intractable problem for the world. Metal ions are essential for the cell process and biological function in microorganisms. Many metal-based complexes with the potential for releasing ions are more likely to be absorbed for their higher lipid solubility. Hence, this review highlights the clinical potential of organometallic compounds for the treatment of infections caused by bacteria or fungi in recent five years. The common scaffolds, including antimicrobial peptides, N-heterocyclic carbenes, Schiff bases, photosensitive-grand-cycle skeleton structures, aliphatic amines-based ligands, and special metal-based complexes are summarized here. We also discuss their therapeutic targets and the risks that should be paid attention to in the future studies, aiming to provide information for researchers on metal-based complexes as antimicrobial agents and inspire the design and synthesis of new antimicrobial drugs.
10.1016/j.ejmech.2021.113696
A Label-Free Cellular Proteomics Approach to Decipher the Antifungal Action of DiMIQ, a Potent Indolo[2,3-]Quinoline Agent, against Biofilms.
Zarnowski Robert,Jaromin Anna,Zagórska Agnieszka,Dominguez Eddie G,Sidoryk Katarzyna,Gubernator Jerzy,Andes David R
International journal of molecular sciences
forms extremely drug-resistant biofilms, which present a serious threat to public health globally. Biofilm-based infections are difficult to treat due to the lack of efficient antifungal therapeutics, resulting in an urgent demand for the development of novel antibiofilm strategies. In this study, the antibiofilm activity of DiMIQ (5,11-dimethyl-5-indolo[2,3-]quinoline) was evaluated against biofilms. DiMIQ is a synthetic derivative of indoquinoline alkaloid neocryptolepine isolated from a medicinal African plant, . Antifungal activity of DiMIQ was determined using the XTT assay, followed by cell wall and extracellular matrix profiling and cellular proteomes. Here, we demonstrated that DiMIQ inhibited biofilm formation and altered fungal cell walls and the extracellular matrix. Cellular proteomics revealed inhibitory action against numerous translation-involved ribosomal proteins, enzymes involved in general energy producing processes and select amino acid metabolic pathways including alanine, aspartate, glutamate, valine, leucine and isoleucine. DiMIQ also stimulated pathways of cellular oxidation, metabolism of carbohydrates, amino acids (glycine, serine, threonine, arginine, phenylalanine, tyrosine, tryptophan) and nucleic acids (aminoacyl-tRNA biosynthesis, RNA transport, nucleotide metabolism). Our findings suggest that DiMIQ inhibits biofilms by arresting translation and multidirectional pathway reshaping of cellular metabolism. Overall, this agent may provide a potent alternative to treating biofilm-associated infections.
10.3390/ijms22010108
Aureobasidium pullulans volatilome identified by a novel, quantitative approach employing SPME-GC-MS, suppressed Botrytis cinerea and Alternaria alternata in vitro.
Yalage Don S M,Schmidtke L M,Gambetta J M,Steel C C
Scientific reports
Volatile organic compounds (VOCs) produced by Aureobasidium pullulans were investigated for antagonistic actions against Alternaria alternata and Botrytis cinerea. Conidia germination and colony growth of these two phytopathogens were suppressed by A. pullulans VOCs. A novel experimental setup was devised to directly extract VOCs using solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) from antagonist-pathogen culture headspace. The proposed system is a robust method to quantify microbial VOCs using an internal standard. Multivariate curve resolution-alternating least squares deconvolution of SPME-GC-MS spectra identified fourteen A. pullulans VOCs. 3-Methyl-1-hexanol, acetone, 2-heptanone, ethyl butyrate, 3-methylbutyl acetate and 2-methylpropyl acetate were newly identified in A. pullulans headspace. Partial least squares discriminant analysis models with variable importance in projection and selectivity ratio identified four VOCs (ethanol, 2-methyl-1-propanol, 3-methyl-1-butanol and 2-phenylethanol), with high explanatory power for discrimination between A. pullulans and pathogen. The antifungal activity and synergistic interactions of the four VOCs were evaluated using a Box-Behnken design with response surface modelling. Ethanol and 2-phenylethanol are the key inhibitory A. pullulans VOCs against both B. cinerea and A. alternata. Our findings introduce a novel, robust, quantitative approach for microbial VOCs analyses and give insights into the potential use of A. pullulans VOCs to control B. cinerea and A. alternata.
10.1038/s41598-020-61471-8
Quest for the Molecular Basis of Improved Selective Toxicity of Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics.
Borzyszkowska-Bukowska Julia,Górska Justyna,Szczeblewski Paweł,Laskowski Tomasz,Gabriel Iwona,Jurasz Jakub,Kozłowska-Tylingo Katarzyna,Szweda Piotr,Milewski Sławomir
International journal of molecular sciences
Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled photochemical isomerization. The obtained isomers demonstrated substantially improved in vitro selective toxicity in the cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.
10.3390/ijms221810108
In Vitro Antifungal Activity of New and Known Geranylated Phenols against Rands.
Chavez María I,Soto Mauricio,Cimino Franco A,Olea Andrés F,Espinoza Luis,Díaz Katy,Taborga Lautaro
International journal of molecular sciences
A series of new and known geranylated phenol/methoxyphenol derivatives has been tested in vitro as inhibitor agents of mycelial growth of . The activity of tested compounds is correlated with the nature, number, and position of the substituent group on the aromatic ring. Results indicate that the most active geranylated derivatives are those having two hydroxyl groups (or one ⁻OH and one ⁻OCH₃) attached to the aromatic ring. Interestingly, these derivatives are as active as Metalaxil, a commonly used commercial fungicide. Thus, our results suggest that some of these compounds might be of agricultural interest due to their potential use as fungicides against . The effect of structure on fungicide activity is discussed in terms of electronic distribution on both the aromatic ring and side geranyl chain. All tested compounds have been synthesized by direct coupling of geraniol and the respective phenol. Interestingly, new digeranylated derivatives were obtained by increasing the reaction time.
10.3390/ijms19061601
Design, synthesis, mechanistic studies and in silico ADME predictions of benzimidazole derivatives as novel antifungal agents.
Morcoss Martha M,Abdelhafez El Shimaa M N,Ibrahem Reham A,Abdel-Rahman Hamdy M,Abdel-Aziz Mohamed,Abou El-Ella Dalal A
Bioorganic chemistry
Herein, novel three series of benzimidazole scaffold bearing hydrazone, 1,2,4-triazole and 1,3,4-oxadiazole moieties 1-3, 4a-j, 6a-c and 7 derivatives were designed, synthesized and evaluated for their antimicrobial activity. The structures of the prepared compounds were assigned using different spectroscopic techniques such as IR, H NMR, C NMR and elemental analyses. Compounds 3, 4a, 4e and 4f exhibited remarkable antifungal activity against C. albicans and C. neoformans var. grubii with MIC values ranging from 4 to 16 μg/mL. Furthermore, they were not cytotoxic against red blood cells and human embryonic kidney cells at concentration up to 32 μg/mL. The study was expanded to forecast the mechanism of action of the prepared compounds and determine sterol quantitation method (SQM) by spectrophotometric assay. On the other hand, compound 4e showed the highest inhibitory activity against lanosterol 14α-demethylase (CYP51) with IC value = 0.19 μg/mL compared to fluconazole as reference IC value = 0.62 μg/mL. Also, compounds 4d and 4f exhibited mild to moderate antibacterial activity. Moreover, molecular docking of the active target compound 4e in active site of lanosterol 14α-demethylase (CYP51) revealed that docking scores and binding mode are comparable to that of co-crystallized ligand confirming their antifungal activity. In silico ADME prediction investigations also forecasting the drug-like characters of these compounds.
10.1016/j.bioorg.2020.103956
Structural Characterization, DFT Calculation, NCI, Scan-Rate Analysis and Antifungal Activity against of ()-2-{[(2-Aminopyridin-2-yl)imino]-methyl}-4,6-di--butylphenol (Pyridine Schiff Base).
Carreño Alexander,Páez-Hernández Dayán,Cantero-López Plinio,Zúñiga César,Nevermann Jan,Ramírez-Osorio Angélica,Gacitúa Manuel,Oyarzún Poldie,Sáez-Cortez Felipe,Polanco Rubén,Otero Carolina,Fuentes Juan A A
Molecules (Basel, Switzerland)
is a ubiquitous necrotrophic filamentous fungal phytopathogen that lacks host specificity and can affect more than 1000 different plant species. In this work, we explored [(E)-2-{[(2-aminopyridin-2-yl)imino]-methyl}-4,6-di-tert-butylphenol], a pyridine Schiff base harboring an intramolecular bond (IHB), regarding their antifungal activity against Botrytis cinerea. Moreover, we present a full characterization of the L1 by NMR and powder diffraction, as well as UV-vis, in the presence of previously untested different organic solvents. Complementary time-dependent density functional theory (TD-DFT) calculations were performed, and the noncovalent interaction (NCI) index was determined. Moreover, we obtained a scan-rate study on cyclic voltammetry of L1. Finally, we tested the antifungal activity of L1 against two strains of Botrytis cinerea (B05.10, a standard laboratory strain; and A1, a wild type strains isolated from Chilean blueberries). We found that L1 acts as an efficient antifungal agent against Botrytis cinerea at 26 °C, even better than the commercial antifungal agent fenhexamid. Although the antifungal activity was also observed at 4 °C, the effect was less pronounced. These results show the high versatility of this kind of pyridine Schiff bases in biological applications.
10.3390/molecules25122741
Synthesis and Evaluation of New 1,3,4-Thiadiazole Derivatives as Potent Antifungal Agents.
Karaburun Ahmet Çağrı,Acar Çevik Ulviye,Osmaniye Derya,Sağlık Begüm Nurpelin,Kaya Çavuşoğlu Betül,Levent Serkan,Özkay Yusuf,Koparal Ali Savaş,Behçet Mustafa,Kaplancıklı Zafer Asım
Molecules (Basel, Switzerland)
With the goal of obtaining a novel bioactive compound with significant antifungal activity, a series of 1,3,4-thiadiazole derivatives (⁻) were synthesized and characterized. Due to thione-thiol tautomerism in the intermediate compound , type of substitution reaction in the final step was determined by two-dimensional (2D) NMR. In vitro antifungal activity of the synthesized compounds was evaluated against eight species. The active compounds and displayed very notable antifungal effects. The probable mechanisms of action of active compounds were investigated using an ergosterol quantification assay. Docking studies on 14-α-sterol demethylase enzyme were also performed to investigate the inhibition potency of compounds on ergosterol biosynthesis. Theoretical absorption, distribution, metabolism, and excretion (ADME) predictions were calculated to seek their drug likeness of final compounds. The results of the antifungal activity test, ergosterol biosynthesis assay, docking study, and ADME predictions indicated that the synthesized compounds are potential antifungal agents, which inhibit ergosterol biosynthesis probably interacting with the fungal 14-α-sterol demethylase.
10.3390/molecules23123129
Synthesis of promising antimicrobial agents: hydrazide-hydrazones of 5-nitrofuran-2-carboxylic acid.
Popiołek Łukasz,Rysz Bernadetta,Biernasiuk Anna,Wujec Monika
Chemical biology & drug design
In this research, we synthesized and evaluated for in vitro antimicrobial activity a new series of hydrazide-hydrazones obtained from 5-nitrofuran-2-carboxylic acid. New compounds were identified and characterized by spectral methods ( H NMR and C NMR). All tested hydrazide-hydrazones proved to be promising antimicrobial agents. Antimicrobial activity and antifungal activity of new derivatives of 5-nitrofuran-2-carboxylic acid were revealed in many cases to be higher than the activity of reference substances (nitrofurantoin, cefuroxime and ampicillin).
10.1111/cbdd.13639
Analysis and Evaluation of the Flagellin Activity of Ba168 Antimicrobial Proteins against .
Molecules (Basel, Switzerland)
Blue mold caused by Penicillium expansum is one of the most common apple diseases, and it is becoming a serious threat in apple production. The strain Ba168 showed high levels of antimicrobial activity in our previous study. To analyze the antimicrobial protein of Ba168, a high-resolution LC-MS/MS proteomic analysis was performed. A total of 1155 proteins were identified from 5233 unique peptides. A total of 16 potential antimicrobial-activity-related proteins were identified; 10 of these proteins have direct antimicrobial effects, while 6 of these proteins are associated with the formation of antimicrobial substances. Then, an antifungal protein of Ba168 was isolated and purified by the sequential chromatography of DEAE Bio-sep FF anion exchange and Sephadex G-75. The single protein, named BP8-2, showed antifungal activity towards . The peptide mass fingerprinting of the protein band of BP8-2 had a high similarity with the amino acid sequences of flagellin protein. The results showed that BP8-2 significantly inhibited the growth of and slowed the spread of apple blue mold. The results indicated that flagellin is one of the important antimicrobial substances from Ba168.
10.3390/molecules27134259
Discovery of an Octahedral Silicon Complex as a Potent Antifungal Agent.
Fu Chen,Fu Bin,Peng Xixi,Liao Guojian
Molecules (Basel, Switzerland)
Octahedral transition metal complexes have been shown to have tremendous applications in chemical biology and medicinal chemistry. Meanwhile, structural transition metals can be replaced by inert octahedral silicon in a proof-of-principle study. We here introduce the first example of octahedral silicon complexes, which can very well serve as an efficient antimicrobial agent. The typical silicon arenediolate complex {[(phen)₂Si(OO)](PF₆)₂, with phen = 1,10-phenanthroline, OO = 9,10-phenanthrenediolate} exhibited significant inhibition towards the growth of with MIC and MFC values of 4.5 and 11.3 μM, respectively. Moreover, it was fungicidal against both proliferative and quiescent Cryptococcus cells. This work may set the stage for the development of novel antifungal drugs based upon hexacoodinate silicon scaffolds.
10.3390/molecules22040637
Broadening antifungal spectrum and improving metabolic stablity based on a scaffold strategy: Design, synthesis, and evaluation of novel 4-phenyl-4,5-dihydrooxazole derivatives as potent fungistatic and fungicidal reagents.
Yin Wenbo,Cui Hengxian,Jiang Hong,Zhang Yuxin,Liu Lei,Wu Tianxiao,Sun Yin,Zhao Liyu,Su Xin,Zhao Dongmei,Cheng Maosheng
European journal of medicinal chemistry
5-phenylthiophene derivatives exhibited excellent antifungal activity against Candida albicans, Candida tropicalis and Cryptococcus neoformans. However, optimal compound 7 was inactive against Aspergillus fumigatus and unstable in human liver microsomes in vitro with a half-life of 18.6 min. To discover antifungal agents with a broad spectrum and improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of 4-phenyl-4,5-dihydrooxazole derivatives were designed and synthesized. It was especially encouraging that compound 22a displayed significant antifungal activities against eight susceptible strains and seven FLC-resistant strains. Furthermore, the potent compound 22a could prevent the formation of fungalbiofilms and displayed satisfactory fungicidal activity. In addition, the metabolic stability of compound 22a was improved significantly, with the half-life of 70.5 min. Compound 22a was almost nontoxic to mammalian A549, MCF-7, HepG2, and 293T cells. Moreover, pharmacokinetic studies in SD rats showed that compound 22a exhibited pharmacokinetic properties with a bioavailability of 15.22% and a half-life of 4.44 h, indicating that compound 22a is worthy of further study.
10.1016/j.ejmech.2021.113955