Promising Antifungal Candidate Research Articles

Antifungal Activity of Novel Isoindoline-2-Yl Putrescines as Potential Autophagy-Activated Fungicide.

The exacerbation of plant fungal diseases necessitates the development of new fungicides to prevent outbreaks. In this study, five novel isoindoline-2-yl putrescines (ISPs) were synthesized, and their synthetic procedures and gram-scale preparation were explored. When tested at 50 μg mL-1, ISPs did not significantly inhibit mycelial growth on agar plates. However, at 100 μg mL-1, they demonstrated remarkable in vivo efficacy in mitigating Botrytis cinerea infection, especially ISP3 showed curative and protective activities of 91.9 % and 92.6 %, respectively. Moreover, ISP3 also effectively halted lesion expansion of gray mold, Sclerotic rot, and Fusarium scabs, while inducing excessive malformed top mycelial branches of B. cinerea and Sclerotinia sclerotiorum, suppressing sclerotia formation in S. sclerotiorum, and triggering autophagic vacuolization with numerous autophagosomes in the mycelia of these fungi. Molecular docking revealed that ISP3 effectively bound to the active site of BcAtg3, forming hydrogen bonds with Ser279, Gly343, Asp370, and Asp13, along with establishing a stable salt bridge with Asp13. Furthermore, ISP3 possessed favorable ADMET properties. These findings highlight ISP3 as a promising antifungal candidate through autophagy activation.

Action of dithiocarbimates salts on the honey bee and its pathogen Nosema ceranae

Apis mellifera, crucial pollinators for both native and cultivated plants, also yield various products such as honey, wax, royal jelly, and propolis, extensively utilized in the food, pharmaceuticals, and cosmetics industries. Nosema ceranae, a prevalent microsporidian worldwide, stands as a significant pathogen for A. mellifera, showing resistance to conventional antibiotics. Consequently, the exploration of novel compounds for N. ceranae control becomes imperative. Dithiocarbimate derivatives emerge as promising antifungal candidates under evaluation for combating various pathogens, particularly those affecting plants. This study assessed the toxicity profile of six dithiocarbimate derivatives on A. mellifera worker survival and N. ceranae pathogen. Among these, four compounds exhibited minimal bee mortality and proceeded to further evaluation against N. ceranae. In vitro assays demonstrated their inhibitory effects on spore germination. Remarkably, the most potent compound suppressed N. ceranae spores by 62% at a concentration of 20 µmol L−1in vivo. Thus, these dithiocarbimate derivatives represent promising new antifungal agents for combatting nosemosis in honey bee populations.

Design, synthesis and antifungal activity of novel α-methylene-γ-butyrolactone derivatives containing benzothiophene moiety.

The discovery of agricultural fungicide candidates from natural products is one of the key strategies for developing environment friendly agricultural fungicides with high efficiency, high selectivity and unique modes-of-action. Based on previous work, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing benzothiophene moiety were designed and synthesized. The majority of the proposed compounds displayed moderate to considerable antifungal efficacy against the tested pathogenic fungi and oomycetes, some exhibiting broad spectrum antifungal activity. Notably, compounds 2 (3-F-Ph) and 7 (4-Cl-Ph) showed excellent antifungal activity against Rhizoctonia with half maximal effective concentration (EC50) values of 0.94 and 0.99 mg L-1, respectively, comparable to the commercial fungicide tebuconazole (EC50 = 0.96 mg L-1), and also displayed significant inhibitory effects against V alsa mali with EC50 values of 2.26 and 1.67 mg L-1, respectively - better than famoxadone and carabrone. The in vivo protective and curative effects against R. solani of compound 2 were 57.2% and 53.7% at 100 mg L-1, respectively, which were equivalent to tebuconazole (51.6% and 52.4%). Further investigations found that compound 2 altered the ultrastructure of R. solani cell, significantly increased the relative conductivity of the cells, and reduced the activity of complex III in a dose-dependent manner. Molecular docking results showed that compound 2 matched well with the Qo pocket. The results revealed that MBL derivatives containing benzothiophene moiety are promising antifungal candidates and provide a new backbone structure for further optimization of novel fungicides. © 2024 Society of Chemical Industry.

Antifungal drug discovery for targeting Candida albicans morphogenesis through structural dynamics study

In response to the escalating threat of drug-resistant fungi to human health, there is an urgent need for innovative strategies. Our focus is on addressing this challenge by exploring a previously untapped target, yeast casein kinase (Yck2), as a potential space for antifungal development. To identify promising antifungal candidates, we conducted a thorough screening of the diverse-lib drug-like molecule library, comprising 99,288 molecules. Five notable drug-like compounds with diverse-lib IDs 24334243, 24342416, 17516746, 17407455, and 24360740 were selected based on their binding energy scores surpassing 11 Kcal/mol. Our investigation delved into the interaction studies and dynamic stability of these compounds. Remarkably, all selected molecules demonstrated acceptable RMSD values during the 200 ns simulation, indicating their stable nature. Further analysis through Principal Component Analysis (PCA)-based Free Energy Landscape (FEL) revealed minimal energy transitions for most compounds, signifying dynamic stability. Notably, the two compounds exhibited slightly different behaviour in terms of energy transitions. These findings mark a significant breakthrough in the realm of antifungal drugs against C. albicans by targeting the Yck2 protein. However, it is crucial to note that additional experimental validation is imperative to assess the efficacy of these molecules as potential antifungal candidates. This study serves as a promising starting point for further exploration and development in the quest for effective antifungal solutions. Communicated by Ramaswamy H. Sarma

Enhancing oral bioavailability of an antifungal thiazolylhydrazone derivative: Development and characterization of a self-emulsifying drug delivery system

RN104 (2-[2-(cyclohexylmethylene)hydrazinyl)]-4-phenylthiazole) is a thiazolylhydrazone derivative with prominent antifungal activity. This work aimed to develop a self-emulsifying drug delivery system (SEDDS) loaded with RN104 to improve its biopharmaceutical properties and enhance its oral bioavailability. Medium chain triglycerides, sorbitan monooleate, and polysorbate 80 were selected as components for the SEDDS formulation based on solubility determination and a pseudo-ternary phase diagram. The formulation was optimized using the central composite design in response surface methodology. The optimized condition consisted of medium chain triglycerides, sorbitan monooleate, and polysorbate 80 in a mass ratio of 65.5:23.0:11.5, achieving maximum drug loading (10 mg/mL) and minimum particle size (118.4 ± 0.7 nm). The developed RN104-SEDDS was fully characterized using dynamic light scattering, in vitro release studies, stability assessments, polarized light microscopy, and transmission electron microscopy. In vivo pharmacokinetic studies in mice demonstrated that RN104-SEDDS significantly improved oral bioavailability compared to free RN104 (the relative bioavailability was 2133 %). These results clearly indicated the successful application of SEDDS to improve the pharmacokinetic profile and to enhance the oral bioavailability of RN104, substantiating its potential as a promising antifungal drug candidate.

Unveiling the Cell Wall-Targeting Mechanisms and Multifaceted Virulence Modulation by a Eugenol Glycoconjugate against Aspergillus fumigatus: Insights from in vitro and in ovo Studies.

The primary objective of this study was to elucidate the putative cell wall-associated targets of compound 6i, a glycoconjugate of eugenol, in Aspergillus fumigatus, while also evaluating its toxicity and assessing histopathologic alterations in the liver, heart, and kidney of compound 6i-treated embryos using an in ovo model. To achieve this aim, compound 6i was synthesized, and a series of biochemical assays were performed to determine its impact on the fungal cell wall. Additionally, qRT-PCR and LC-MS/MS analyses were conducted to investigate changes in gene and protein expression profiles associated with melanin biosynthesis, conidiation, siderophore production, transcriptional regulation of β-glucan biosynthesis, and calcineurin activity in A. fumigatus. The experimental findings revealed that compound 6i exhibited notable antifungal activity against A. fumigatus by perturbing cell wall integrity, hindering ergosterol, glucan, and chitin biosynthesis, and inhibiting catalase production. Moreover, relative gene expression and proteomic analyses demonstrated that compound 6i exerted both down-regulatory and up-regulatory effects on several crucial genes and proteins involved in the aforementioned fungal processes. Furthermore, increased expression of oxidative stress-related proteins was observed in the presence of compound 6i. Notably, the glycoconjugate of eugenol did not elicit cytotoxicity in the liver, heart, and kidney of chick embryos. The current investigation elucidated the multifaceted mechanisms by which compound 6i exerts its antifungal effects against A. fumigatus, primarily through targeting cell wall components and signaling pathways. These findings underscore the potential of the eugenol glycoconjugate as a promising antifungal candidate, warranting further exploration and development for combating A. fumigatus infections.

Imidazole derivatives as novel and potent antifungal agents: Synthesis, biological evaluation, molecular docking study, molecular dynamic simulation and ADME prediction

Fungal infections have become a serious threat to human health due to their high incidence and mortality. In this study, a new set of imidazole derivatives (7a-f) were synthesized and their chemical structures were characterized using spectroscopic techniques including IR, 1H-NMR, 13C-NMR and Mass. In the following, the antifungal activities of these derivatives were evaluated against several yeasts, aspergillus and dermatophyte species using the CLSI method. In addition, to check the safety of the synthesized compounds, the in vitro cytotoxicity activity of these compounds was investigated towards normal human fibroblasts cell line (MRC-5) using MTT assay. The obtained biological results indicated that these compounds acted as the most potential antifungal agents. In particular, compounds 7c, 7d and 7f exhibited excellent activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei, Candida dubliniensis, Candida parapsilosis, and Cryptococcus neoformans species with MIC50 values in the range of 0.5-16 µg/ml. The cytotoxicity results showed that these compounds have low toxicity against normal human fibroblasts cell line (MRC-5). Additionally, molecular modelling studies and molecular dynamic simulation were carried out to predict the binding energy and possible interaction mode of these compounds in the binding site of lanosterol 14α-demethylase (CYP51) as a conventional target for azole derivatives. In silico ADME study was also performed to investigate the physicochemical features of the synthesized imidazole derivatives. According to the results, these compounds can be considered as promising antifungal candidates for further development.

N-Heterocycle Modified Graphene Quantum Dots as Topoisomerase Targeted Nanoantibiotics for Combating Microbial Infections.

Developing next-generation antibiotics to eliminate multidrug-resistant (MDR) bacteria/fungi and stubborn biofilms is challenging, because of the excessive use of currently available antibiotics. Herein, the fabrication of anti-infection graphene quantum dots (GQDs) is reported, as a new class of topoisomerase (Topo) targeting nanoantibiotics, by modification of rich N-heterocycles (pyridinic N) at edge sites. The membrane-penetrating, nucleus-localizing, DNA-binding GQDs not only damage the cell walls/membranes of bacteria or fungi, but also inhibit DNA-binding proteins, such as Topo I, thereby affecting DNA replication, transcription, and recombination. The obtained GQDs exhibit excellent broad-spectrum antimicrobial activity against non-MDR bacteria, MDR bacteria, endospores, and fungi. Beyond combating planktonic microorganisms, GQDs inhibit the formation of biofilms and can kill live bacteria inside biofilms. RNA-seq further demonstrates the upregulation of riboflavin biosynthesis genes, DNA repair related genes, and transport proteins related genes in methicillin-resistant S. aureus (MRSA) in response to the stress induced by GQDs. In vivo animal experiments indicate that the biocompatible GQDs promote wound healing in MRSA or C. albicans-infected skin wound models. Thus, GQDs may be a promising antibacterial and antifungal candidate for clinical applications in treating infected wounds and eliminating already-formed biofilms.

Screening of alkaloids and withanolides isolated from Solanaceae plants for antifungal properties against non-wild type Sporothrix brasiliensis

Antifungal resistance has often been found in animal sporotrichosis in Southern Brazil. The biological potential of compounds from plants of the Solanaceae family against infectious diseases is known, however, it is still unknown against Sporothrix brasiliensis. This study evaluated the anti-Sporothrix brasiliensis activity, synergism, cytotoxicity, and action mechanism of steroidal lactones (withanolides) and alkaloids isolated from these plants. Pure compounds of withanolide D (WNOD), physalin F (PHYF), withanicandin (WNIC), nicandin B (NICB), solasonine (SSON), and solamargine (SMAR) were tested against 12 Sporothrix brasiliensis isolated from cats (n = 11) and dogs (n = 2) through M38-A2 CLSI. For the compounds with the best activity, a checkerboard assay for synergism, sorbitol protection, and ergosterol effect for action mechanism; and MTT test for cytotoxicity were performed. The withanolides WNOD, PHYF, WNIC, and NICB were not antifungal, but SSON (MIC 0.125–1 mg/mL) and SMAR (MIC 0.5–1 mg/mL) were both fungistatic and fungicidal (MFC 0.5–1 mg/mL for both) against wild-type (WT) and non-WT isolates. The activity of SSON and SMAR was indifferent when combined with itraconazole. In the mechanism of action, cell wall and plasma membrane by complexation with ergosterol seemed to be two target structures of SSON and SMAR. SSON was selected for cytotoxicity, whose cell viability in MDBK cells ranged from 28.85 % to 101.75 %, and was higher than 87.49 % at concentrations ≤0.0015 mg/ml. Only the steroidal alkaloids SSON and SMAR were active against non-WT isolates, being promising antifungal candidates for the treatment of feline and canine sporotrichosis with low susceptibility to itraconazole.

Novel Nitric Oxide Donor-Azole Conjugation Strategy for Efficient Treatment of Cryptococcus neoformans Infections.

Invasive fungal infections (IFIs) such as cryptococcal meningitis (CM) remain a serious health issue worldwide due to drug resistance closely related to biofilm formation. Unfortunately, available antifungal drugs with ideal safety and promising potency are still lacking; thus, the research of new candidate and therapeutic approach is urgently needed. As an important gas messenger molecule, nitric oxide (NO) shows vital inhibition on various microorganism biofilms. Hence, three series of novel NO-donating azole derivatives were designed and synthesized, and the in vitro antifungal activity as well as the mechanism of action was investigated. Among them, 3a and 3e displayed excellent antifungal activity against Cryptococcus neoformans and biofilm depending on the release of NO. Moreover, a more stable analogue 3h of 3a demonstrated markedly anti-CM effects via intranasal dropping, avoiding the first-pass effects and possessing a better brain permeability bypass blood-brain barrier. These results present a promising antifungal candidate and intranasal dropping approach for the treatment of CM, warranting further studies.

Triazine-Based Small Molecules: A Potential New Class of Compounds in the Antifungal Toolbox.

Invasive fungal infections caused by Candida species remain a significant public health problem worldwide. The increasing prevalence of drug-resistant infections and a limited arsenal of antifungal drugs underscore the need for novel interventions. Here, we screened several classes of pharmacologically active compounds against mammalian diseases for antifungal activity. We found that the synthetic triazine-based compound melanogenin (Mel) 56 is fungicidal in Candida albicans laboratory and clinical strains with minimal inhibitory concentrations of 8−16 µg/mL. Furthermore, Mel56 has general antifungal activity in several non-albicans Candida species and the non-pathogenic yeast Saccharomyces cerevisiae. Surprisingly, Mel56 inhibited the yeast-to-hyphae transition at sublethal concentrations, revealing a new role for triazine-based compounds in fungi. In human cancer cell lines, Mel56 targets the inner mitochondrial integral membrane prohibitin proteins, PHB1 and PHB2. However, Mel56 treatment did not impact C. albicans mitochondrial activity, and antifungal activity was similar in prohibitin single, double, and triple homozygous mutant strains compared to the wild-type parental strain. These results suggests that Mel56 has a novel mechanism-of-action in C. albicans. Therefore, Mel56 is a promising antifungal candidate warranting further analyses.

A recyclable and light-triggered nanofibrous membrane against the emerging fungal pathogen Candida auris.

The emerging "super fungus" Candida auris has become an important threat to human health due to its pandrug resistance and high lethality. Therefore, the development of novel antimicrobial strategy is essential. Antimicrobial photodynamic therapy (aPDT) has excellent performance in clinical applications. However, the relevant study on antifungal activity and the mechanism involved against C. auris remains scarce. Herein, a recyclable and biodegradable polylactic acid-hypocrellin A (PLA-HA) nanofibrous membrane is newly developed. In vitro PLA-HA-aPDT could significantly reduce the survival rate of C. auris plankton and its biofilms, and the fungicidal effect of the membrane is still significant after four repeated uses. Simultaneously, PLA-HA exhibits good biocompatibility and low hemolysis. In vivo experiments show that PLA-HA-aPDT can promote C. auris-infected wound healing, reduce inflammatory response, and without obvious toxic side-effects. Further results reveal that PLA-HA-aPDT could increase endogenous reactive oxygen species (ROS) levels, leading to mitochondrial dysfunction, release of cytochrome C, activation of metacaspase, and nuclear fragmentation, thereby triggering apoptosis of C. auris. Compared with HA, PLA-HA shows stronger controllability and reusability, which can greatly improve the utilization efficiency of HA alone. Taken together, the efficacy, safety and antifungal activity make PLA-HA-aPDT a highly promising antifungal candidate for skin or mucous membrane C. auris infection.

Insight into the substrate-dependent anti-aflatoxigenic effects of nanosized ZnO film: Electron transfer directed oxidative stress mechanisms

Exploring new anti-aflatoxigenic materials and their mechanisms are critical to reduce the prevalence of drug-resistant fungi and the contamination of aflatoxins. Zinc oxide nanoparticles (ZnONPs) are promising antifungal candidates but supporting substrates generally affect their antifungal activities. In this study, ZnONPs with a three-dimensional flower-like hierarchical microstructure bound to different substrates as anti-aflatoxigenic composites were prepared using a facile deposition method. It was found that ZnO nanocomposites showed the substrate-dependent anti-aflatoxigenic activities. The antifungal activities of ZnO films toward A. flavus growth and aflatoxin B1 production decreased significantly in the order ZnO@Zn＞ZnO@Sn＞ZnO@Steel＞ZnO@Glass. The electrical conductivity of the substrate should play an important role for antifungal response. When compared with ZnO@Sn and ZnO@Steel, the conductivity value of ZnO@Zn was 2.07-fold and 14.84-fold of them, respectively. The higher the electrical conductivity of the substrate, the better the anti-aflatoxigenic efficiency of the composite. Such anti-aflatoxigenic activity was also due to ROS generation through electron transfer between fungi and the ZnO-substrate system, which could provoke the strength of intracellular oxidative stress. This mechanism was further confirmed using several assays such as hyphal morphology analysis, Zn2+ release, ROS evaluation, lipid peroxidation and antioxidant response. Collectively, improvement in knowledge regarding anti-aflatoxigenic performance of ZnONPs can help develop novel and effective strategies to reduce fungi growth and aflatoxin contamination in the food field.

Discovery of Novel Pyrazole Carboxylate Derivatives Containing Thiazole as Potential Fungicides.

Inspired by commercially established fluxapyroxad as the lead compound of novel efficient antifungal ingredients, novel pyrazole carboxylate derivatives containing a flexible thiazole backbone were successfully designed, synthesized, and detected for their in vitro and in vivo biological activities against eight agricultural fungi. The antifungal bioassay results showed that compound 24 revealed excellent bioactivities against Botrytis cinerea and Sclerotinia sclerotiorum, with median effective concentrations (EC50) of 0.40 and 3.54 mg/L, respectively. Compound 15 revealed remarkable antifungal activity against Valsa mali, with an EC50 value of 0.32 mg/L. For in vivo fungicide control against B. cinerea and V. mali, compounds 3 and 24 at 25 mg/L, respectively, displayed prominent efficacy on cherry tomatoes and apple branches. Molecular docking results demonstrated that compound 15 could form an interaction with several crucial residues of succinate dehydrogenase (SDH), and the in vitro enzyme assay indicated that the target compound 15 displayed an inhibitory effect toward SDH, with an IC50 value of 82.26 μM. The experimental results indicated that phenyl pyrazole carboxylate derivatives displayed a weak antifungal property and low activity compared to the other title substituent pyrazole carboxylate derivatives. Compounds 3, 15, and 24 are promising antifungal candidates worthy of further fungicide development due to their prominent effectiveness.

In vivo and In vitro Antifungal Activity of 2,3-Dimethylquinoxline

Aims: To explore the antifungal activity of 2,3-dimethylquinoxaline.
 Study Design: A preclinical study of a compound against 10 fungal species.
 Backgrounds: Severe fungal infections cause significant clinical problem and need more effort to search for new antifungals.
 Methodology: We evaluated the susceptibility of 2,3-dimethylquinoxaline in vitro against a wide range of pathogenic fungi, including six Candida species, two Aspergillus species, one Cryptococcus species, and one Trichophyton species. Also, we evaluated the susceptibility of 2,3-dimethylquinoxaline in vivo against oral candidiasis using a mice model.
 Results: The highest score of the minimum inhibitory concentration was 9 µg/ml against Cryptococcus neoformans. While, the lowest score was 1125 µg/ml against Candida tropicalis. The oral candidiasis in a mouse model was resolved using 2,3-dimethylquinoxaline 1% gel.
 Conclusion: The 2,3-Dimethyquinoxaline has interesting antifungal activity. Quinoxalines in general need to be further developed as a promising antifungal candidate.

Myco-Fabrication of Copper Nanoparticles and Its Effect on Crop Pathogenic Fungi.

Phytopathogens are responsible for huge losses in the agriculture sector. Amongst them, fungal phytopathogen is quite difficult to control. Many chemicals are available in the market, claiming the high activity against them. However, the development of resistance by the fungal pathogen is the main concern to overcome their menace. Nanotechnology-based products can be a potential alternative to conventional fungicides. Amongst various nanoparticles, Copper nanoparticles (CuNPs) are appearing to be a promising antifungal candidate. It can be synthesized by various methods, but the myco-fabrication appears to be an environmental-friendly approach. Hence, the present study is an attempt to synthesize CuNPs using Aspergillus flavus. The myco-fabricated CuNPs were characterized by UV spectrophotometer, Fourier transform infrared spectroscopy (FTIR), Nanoparticles tracking and analysis system (NTA), Transmission Electron Microscopy (TEM), X-ray diffraction (XRD) and Zeta potential measurement. Myco-fabricated CuNPs showed maximum absorbance at 602 nm and particle size ranging 5-12 nm with the least average size of 8 nm with spherical shape and moderate stability. Myco-fabricated CuNPs tested against selected fungal crop pathogens viz. Aspergillus niger, Fusariumoxysporum, and Alternaria alternata reveal a significant effect. Besides these we have given the hypothetical mechanism depicting the antifungal action of myco-fabricated CuNPs.

Quinolines derivatives as promising new antifungal candidates for the treatment of candidiasis and dermatophytosis.

Fungal infections have emerged as a current serious global public health problem. The main problem involving these infections is the expansion of multidrug resistance. Therefore, the prospection of new compounds with efficacy antifungal becomes necessary. Thus, this study evaluated the antifungal profile and toxicological parameters of quinolines derivatives against Candida spp. and dermatophyte strains. As a result, a selective anti-dermatophytic action was demonstrated by compound 5 (geometric means (GM = 19.14 μg ml−1)). However, compounds 2 (GM = 50 μg ml−1) and 3 (GM = 47.19 μg ml−1) have presented only anti-Candida action. Compounds 3 and 5 did not present cytotoxic action. Compound 5 did not produce dermal and mucosal toxicity. In addition, this compound showed the absence of genotoxic potential, suggesting safety for topical and systemic use. Quinolines demonstrated a potent anti-dermatophytic and anti-yeast action. Moreover, compound 5 presented an excellent toxicological profile, acting as a strong candidate for the development of a new effective and safe compound against dermatophytosis of difficult treatment.Electronic supplementary materialThe online version of this article (10.1007/s42770-020-00348-4) contains supplementary material, which is available to authorized users.

11g, a Potent Antifungal Candidate, Enhances Candida albicans Immunogenicity by Unmasking β-Glucan in Fungal Cell Wall

In the course of optimizing GPI biosynthesis inhibitors, we designed and synthetized a 2-aminonicotinamide derivative named 11g. After evaluating the antifungal activity of compound 11g in vitro, we investigated the influences of 11g on fungi immunogenicity. In addition, we also took advantage of murine systemic candidiasis model to investigate the protective effects of 11g in vivo. Results show that 11g exhibited potent antifungal activity both in vitro and in vivo. Further study shows that 11g caused the unmasking of fungi β-glucan layer, leading to stronger immune responses in macrophages through Dectin-1. These results suggest that 11g is a very promising antifungal candidate, which assists in eliciting stronger immune responses to help host immune system disposing pathogens. The discovery of 11g might expand the toolbox of fungal infection treatment.

8-Hydroxyquinoline-5-sulfonamides are promising antifungal candidates for the topical treatment of dermatomycosis.

The purpose of this study was to uncover insights into the mechanism of action of the 8-hydroxyquinoline derivatives PH151 and PH153. In addition, with the future perspective of developing a topical drug for the treatment of candidiasis and dermatophytosis, the antifungal activity of a nanoemulsion formulation containing the most active compound (PH151) is also presented here. Sorbitol protection assay and scanning electron microscopy indicate that the 8-hydroxyquinoline derivatives act on the cell wall of Candida sp. and dermatophytes and they inhibit the pseudohyphae formation of C. albicans. These findings demonstrate a strong effect of these compounds on C. albicans morphogenesis, which can be considered a potential mode of action for this molecule. Besides, the nanoemulsion formulation MIC values ranged from 0·5 to 4μgml-1 demonstrating the significant antifungal activity when incorporated into a pharmaceutical formulation. Taken together, the results support the potential of these molecules as promising antifungal candidates for the treatment of candidiasis and dermatophytosis. There is an emerging need to fill the pipeline with new antifungal drugs due to the limitations presented by the currently used drugs. In this study, we have described a novel formulation with a 8-hydroxyquinoline-5-sulfonamide derivative which has presented a great potency in providing a finished product. Furthermore, the derivative has shown a selective mechanism of action confirming its potential to be developed into a new drug candidate.

Cinnamaldehyde inhibits Candida albicans growth by causing apoptosis and its treatment on vulvovaginal candidiasis and oropharyngeal candidiasis.

The invasion of Candida albicans is one of the most common fungal infections seen in clinical practice, and serious drug resistance has been reported in recent years. Therefore, new anti-C. albicans drugs must be introduced. In this research, it was demonstrated that cinnamaldehyde (CA) shows strong antimicrobial activity, with 0.26mg/mL CA being the minimum inhibitory concentration to manage C. albicans. Extraordinarily, we detected that CA accumulated the intracellular reactive oxygen species (ROS) and enhanced the calcium concentration in the cytoplasm and mitochondria through flow cytometry. In addition, we observed that C. albicans cells released Cytochrome c from the mitochondria to the cytoplasm, depolarized the mitochondrial membrane potential, and activated the metacaspase when exposed to 0.065, 0.13, 0.26, and 0.52mg/mL CA. Furthermore, to confirm that CA introduces the C. albicans apoptosis, we discovered that when the phosphatidylserine was exposed, DNA damage and chromatin condensation occurred, which were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 4',6-diamidino-2-phenylindole (DAPI) staining. Finally, demonstrations of phenotype investigation, colony-forming unit (CFU) counts, and periodic acid-Schiff (PAS) staining were conducted to prove that CA possessed the ability to treat oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC). From the above, our research indicates that CA is a promising antifungal candidate when applied to C. albicans infections.