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Although the mitochondrial genome is an attribute of all eukaryotes, some yeast species (called petite-positive) can replicate without mitochondrial DNA (mtDNA). Strains without mtDNA (known as rho− mutants or petite mutants) are respiration-deficient and require fermentable carbon sources (such as glucose) for their metabolism. However, they are compromised in many aspects of fitness and competitiveness. Nevertheless, a few research groups have reported that some petite mutants of Candida glabrata and Saccharomyces cerevisiae manifested higher levels of tolerance to the antifungal fluconazole than their wild-type (WT) counterparts. In this study, we show that elevated tolerance to two or three out of four tested antifungals is a generic feature of at least five petite-positive species of yeasts including C. glabrata (higher tolerance of petites to clotrimazole and miconazole), S. bayanus (tolerance to clotrimazole, fluconazole, and miconazole), S. cerevisiae (tolerance to clotrimazole and fluconazole), S. paradoxus (tolerance to clotrimazole, fluconazole, and miconazole), and S. pastorianus (tolerance to clotrimazole and fluconazole). Comparing the levels of tolerance to the antifungals in WT and petite mutants was based on measuring the diameters of the zones of inhibition (ZOIs) using disc diffusion assays. The mode of inhibition in the majority of WT strains by all antifungals was fungicidal; most of the rho− mutants manifested fungistatic inhibition. We observed partial (not complete) inhibition in WT, with four different types of ZOI patterns that were species- and antifungal-specific. The partial inhibition was characterised by the presence of antifungal-tolerant colonies within ZOI areas. The inability of these colonies selected from ZOIs to grow on glycerol, as a single source of carbon, proved that they were rho− mutants spontaneously generated in the WT populations. The results on the elevated tolerance of petite strains to antifungals are discussed in terms of the prospective positive selection of respiratory-deficient mutants and the various implications of such selection. [ABSTRACT FROM AUTHOR]

A series of 5-oxo-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-carboxylic acid derivatives–hydrazones, N-ethylhydrazones, pyrrole, pyrazole, oxadiazole, and triazole were synthesized and evaluated for their anticancer activity using human A549 pulmonary epithelial cells (ATCC CCl-185). The in vitro viability inhibitory effects of the compounds were assessed using the MTT assay. The characterization of the anticancer activity of the synthesized compounds showed that the incorporation of 1,3,4-oxadiazolethione and 4-aminotriazolethione rings into the molecular structures obviously enhances the anticancer activity against human A549 lung epithelial cells, reducing their viability to 28.0% and 29.6%, respectively. The anticancer activity of these azole derivatives was significantly higher than that of cytarabine. Further studies are needed to better optimize 5-oxo-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-carboxylic acid derivatives and enhance their in vitro anticancer activity. [ABSTRACT FROM AUTHOR]

Pyrazole and tetrazole are among the most important heterocyclic members of the azole family. Over the past decade, these N-heterocycles and their derivatives have demonstrated specific properties that give them potent applications in several fields such as pharmacology, technology, and agriculture. Combining these two azoles in single hybrid architecture has given rise to highly potent molecules in terms of efficacy and specificity, with enhanced and scalable properties. In this context, the present paper deals with the literature of the last 10 years describing the synthesis protocols for pyrazole-tetrazole-based molecules. Their biological activities as well as their energetic properties are also reported. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a major threat to global health as the number of efficient antimicrobials decreases and the number of resistant pathogens rises. Our research group has been actively involved in the design of novel antimicrobial drugs. The blueprints of these compounds were azolic heterocycles, particularly thiazole. Starting with oxadiazolines, our research group explored, one by one, the other five-membered heterocycles, developing more or less potent compounds. An overview of this research activity conducted by our research group allowed us to observe an evolution in the methodology used (from inhibition zone diameters to minimal inhibitory concentrations and antibiofilm potential determination) correlated with the design of azole compounds based on results obtained from molecular modeling. The purpose of this review is to present the development of in-house azole compounds with antimicrobial activity, designed over the years by this research group from the departments of Pharmaceutical and Therapeutical Chemistry in Cluj-Napoca. [ABSTRACT FROM AUTHOR]

Fungal resistance is a public health concern due to the limited availability of antifungal resources and the complexities associated with treating persistent fungal infections. Azoles are thus far the primary line of defense against fungi. Specifically, azoles inhibit the conversion of lanosterol to ergosterol, producing defective sterols and impairing fluidity in fungal plasmatic membranes. Studies on azole resistance have emphasized specific point mutations in CYP51/ERG11 proteins linked to resistance. Although very insightful, the traditional approach to studying azole resistance is time-consuming and prone to errors during meticulous alignment evaluation. It relies on a reference-based method using a specific protein sequence obtained from a wild-type (WT) phenotype. Therefore, this study introduces a machine learning (ML)-based approach utilizing molecular descriptors representing the physiochemical attributes of CYP51/ERG11 protein isoforms. This approach aims to unravel hidden patterns associated with azole resistance. The results highlight that descriptors related to amino acid composition and their combination of hydrophobicity and hydrophilicity effectively explain the slight differences between the resistant non-wild-type (NWT) and WT (nonresistant) protein sequences. This study underscores the potential of ML to unravel nuanced patterns in CYP51/ERG11 sequences, providing valuable molecular signatures that could inform future endeavors in drug development and computational screening of resistant and nonresistant fungal lineages. [ABSTRACT FROM AUTHOR]

A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the target compounds have been tested. A microbiological assessment of the obtained compounds was carried out on strains of pathogenic fungi C. albicans, C. non-albicans, multidrug-resistant C. auris, Rhizopus arrhizus, Aspergillus spp. and some dermatophytes and other yeasts. The lowest obtained MIC values for target compounds lie between 0.003 µg/mL and 0.5 µg/mL and therefore the compounds are not inferior or several times better than commercial azole drugs. The length of the acylpiperazine linker has a limited effect on antifungal activity. Some bioisosteric analogues were tested in microbiological analysis, but turned out to be weaker than the leader in activity. The highest activity was demonstrated by a compound with para-chlorobenzylidene substituent in the thiazolidine fragment. Molecular modelling was used to predict binding modes of synthesized molecules and rationalize experimentally observed SAR. The leader compound is twice more effective in inhibiting the formation of germ tubes by Candida albicans yeast cells compared to voriconazole. An increased level of Pdr5, an azoles drug efflux pump was observed, but the increase is lower than that caused by azoles. The results can be useful for further development of more powerful and safe antifungal agents. [ABSTRACT FROM AUTHOR]

Microbial contamination poses a threat to both the preservation of library and archival collections and the health of staff and users. This study investigated the microbial communities and potential health risks associated with the UNESCO-classified Norwegian Sea Trade Archive (NST Archive) collection exhibiting visible microbial colonization and staff health concerns. Dust samples from book surfaces and the storage environment were analysed using culturing methods, qPCR, Next Generation Sequencing, and mycotoxin, cytotoxicity, and azole resistance assays. Penicillium sp., Aspergillus sp., and Cladosporium sp. were the most common fungi identified, with some potentially toxic species like Stachybotrys sp., Toxicladosporium sp., and Aspergillus section Fumigati. Fungal resistance to azoles was not detected. Only one mycotoxin, sterigmatocystin, was found in a heavily contaminated book. Dust extracts from books exhibited moderate to high cytotoxicity on human lung cells, suggesting a potential respiratory risk. The collection had higher contamination levels compared to the storage environment, likely due to improved storage conditions. Even though overall low contamination levels were obtained, these might be underestimated due to the presence of salt (from cod preservation) that could have interfered with the analyses. This study underlines the importance of monitoring microbial communities and implementing proper storage measures to safeguard cultural heritage and staff well-being. [ABSTRACT FROM AUTHOR]

The wheat scab caused by Fusarium graminearum (F. graminearum) has seriously affected the yield and quality of wheat in China. In this study, gallic acid (GA), a natural polyphenol, was used to synthesize three azole-modified gallic acid derivatives (AGAs1–3). The antifungal activity of GA and its derivatives against F. graminearum was studied through mycelial growth rate experiments and field efficacy experiments. The results of the mycelial growth rate test showed that the EC50 of AGAs–2 was 0.49 mg/mL, and that of AGAs–3 was 0.42 mg/mL. The biological activity of AGAs–3 on F. graminearum is significantly better than that of GA. The results of field efficacy tests showed that AGAs–2 and AGAs–3 significantly reduced the incidence rate and disease index of wheat scab, and the control effect reached 68.86% and 72.11%, respectively. In addition, preliminary investigation was performed on the possible interaction between AGAs–3 and F. graminearum using density functional theory (DFT). These results indicate that compound AGAs–3, because of its characteristic of imidazolium salts, has potential for use as a green and environmentally friendly plant-derived antifungal agent for plant pathogenic fungi. [ABSTRACT FROM AUTHOR]

The incidence of infections caused by Candida species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in drug resistance. These are mostly drug- and isolate-specific. Here, we characterized three different genetically modified strains of C. albicans that were multi-drug-resistant (MDR) and deciphered a uniform mechanism responsible for resistance. DNA polymerase epsilon (Polε) is a leading strand-specific polymerase consisting of four subunits, namely, Pol2, Dpb2, Dpb3, and Dpb4. The deletion of one or both of the Dpb3 and Dpb4 subunits in C. albicans rendered multi-drug resistance. A detailed characterization of these strains revealed that acquired mutagenesis, drug efflux pumps, and other known mechanisms did not play a significant role because the complemented strain showed drug sensitivity. More importantly, the function of heat shock protein 90 (Hsp90) in these knockout strains is critical for reducing susceptibility to several antifungal drugs. Cell wall deformity and composition in these strains can add to such a phenotype. The inhibition of Hsp90 function by geldanamycin and tricostatin A sensitized the MDR strains to antifungals. Considering our earlier research and this report, we suggest that replication stress induces Hsp90 expression and activity in order to orchestrate a cellular stress response circuit and thus develop fungal drug resistance. Thus, Hsp90 is an important drug target for use in combinatorial therapy. [ABSTRACT FROM AUTHOR]

(1) Background: Despite being considered a non-pathogenic yeast, recently, a growing occurrence of Saccharomyces cerevisiae infections has been noted. There is little knowledge about the drug susceptibility of this species. Therefore, the objective of this research was to expand it and determine the drug susceptibility profile of a local collection of clinical isolates of this species. (2) Methods: This study contained 55 clinical isolates identified as Saccharomyces cerevisiae using the MALDI-TOF method. The susceptibility of Saccharomyces cerevisiae was tested to 10 antifungals (amphotericin B, flucytosine, fluconazole, voriconazole, posaconazole, micafungin, anidulafungin, caspofungin, and itraconazole) using MICRONAUT-AT tests and manogepix, a new drug, using the microdilution method according to EUCAST. (3) Results: Overall, most strains were classified as sensitive to amphotericin B and flucytosine (MIC ranges of ≤0.03–1 and ≤0.06–0.125, respectively) and also to echinocandins. However, five isolates expressed high MIC values for all of the tested azoles, indicating cross-resistance. The MIC range for manogepix was 0.001–0.125 mg/L, with an MIC50 of 0.03 mg/L and an MIC90 of 0.06 mg/L. (4) Conclusions: The occurrence of resistance to azoles may be a concerning problem and therefore should be investigated further. However, the new antifungal manogepix appears to be an interesting new therapeutic option for treating such infections. [ABSTRACT FROM AUTHOR]

Antifungal therapy, especially with the azoles, could promote the incidence of less susceptible isolates of Cryptococcus neoformans and C. gattii species complexes (SC), mostly in developing countries. Given that these species affect mostly the immunocompromised host, the infections are severe and difficult to treat. This review encompasses the following topics: 1. infecting species and their virulence, 2. treatment, 3. antifungal susceptibility methods and available categorical endpoints, 4. genetic mechanisms of resistance, 5. clinical resistance, 6. fluconazole minimal inhibitory concentrations (MICs), clinical outcome, 7. environmental influences, and 8. the relevance of host factors, including pharmacokinetic/pharmacodynamic (PK/PD) parameters, in predicting the clinical outcome to therapy. As of now, epidemiologic cutoff endpoints (ECVs/ECOFFs) are the most reliable antifungal resistance detectors for these species, as only one clinical breakpoint (amphotericin B and C. neoformans VNI) is available. [ABSTRACT FROM AUTHOR]

A new series of trifluoromethylated pyrimido[1,2-b]indazol-4(1H)-one derivatives was synthesized with good to excellent yields through a simple condensation of 3-aminoindazole derivatives with ethyl 4,4,4-trifluoro 3-oxobutanoate. The functionalization of the corresponding chlorinated fused tricyclic scaffolds via Suzuki-Miyaura and aromatic nucleophilic substitution reactions led to the synthesis of highly diverse trifluoromethylated pyrimido[1,2-b]indazole derivatives with good yields. [ABSTRACT FROM AUTHOR]

In order to look for the origins of tautomeric preferences in neutral creatinine in vacuo, we examined prototropic conversions for model azoles, namely mono-hydroxy and mono-amino imidazoles, and also for their selected 1-methyl derivatives. All possible isomeric forms of creatinine and model compounds, resulting from intramolecular proton transfer (prototropy), conformational isomerism about –OH, and configurational isomerism about =NH, were studied in the gas phase (model of non-polar environment) by means of quantum-chemical methods. Because the bond-length alternation is a consequence of the resonance phenomenon, it was measured for all DFT-optimized structures by means of the harmonic oscillator model of electron delocalization (HOMED) index. Important HOMED analogies were discussed for investigated azoles and compared with those for previously studied cyclic azines, including pyrimidine nucleic acid bases. The internal effects were taken into account, and the stabilities of the investigated tautomers-rotamers were analyzed. Significant conclusions on the favored factors that can dictate the tautomeric preferences in creatinine were derived. [ABSTRACT FROM AUTHOR]

Fluconazole resistance is commonly encountered in Candida auris, and the yeast frequently displays resistance to other standard drugs, which severely limits the number of effective therapeutic agents against this emerging pathogen. In this study, we aimed to investigate the effect of acquired azole resistance on the viability, stress response, and virulence of this species. Fluconazole-, posaconazole-, and voriconazole- resistant strains were generated from two susceptible C. auris clinical isolates (0381, 0387) and compared under various conditions. Several evolved strains became pan-azole-resistant, as well as echinocandin-cross-resistant. While being pan-azole-resistant, the 0381-derived posaconazole-evolved strain colonized brain tissue more efficiently than any other strain, suggesting that fitness cost is not necessarily a consequence of resistance development in C. auris. All 0387-derived evolved strains carried a loss of function mutation (R160S) in BCY1, an inhibitor of the PKA pathway. Sequencing data also revealed that posaconazole treatment can result in ERG3 mutation in C. auris. Despite using the same mechanisms to generate the evolved strains, both genotype and phenotype analysis highlighted that the development of resistance was unique for each strain. Our data suggest that C. auris triazole resistance development is a highly complex process, initiated by several pleiotropic factors. [ABSTRACT FROM AUTHOR]

Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic Candida species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in Candida species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: tac1 and mrr1; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent Candida species. Notably, N. glabrata, P. kudriavzevii and C. auris demonstrate fluconazole resistance. [ABSTRACT FROM AUTHOR]

The mitochondrial translocase Bcs1 is required for the correct assembly of complex III of the mitochondrial respiratory chain. Because of its importance, Bcs1 was recently proposed as a target for antifungal agents. The function of this AAA (ATPase Associated with diverse cellular Activities) protein has been extensively characterized in Saccharomyces cerevisiae. This yeast as well as previously studied mammals each encode only one homolog. In contrast, the pathogenic mold Aspergillus fumigatus encodes three putative Bcs1 homologs, none of which have been characterized to date. To study the role of these three homologs in A. fumigatus, conditional and deletion mutants of the respective genes AFUA_3G13000 (bcs1A), AFUA_4G01260 (bcs1B), and AFUA_2G14760 (bcs1C) were generated. A deletion or downregulation of bcs1A resulted in drastically reduced growth and sporulation rates and in a significantly altered susceptibility to azole antifungals. In contrast, mutants lacking Bcs1B or Bcs1C did not show any phenotypes differing from the wild type. Salicylhydroxamic acid—an inhibitor of the alternative oxidase that allows the respiratory chain to bypass complex III in some species—caused a complete growth arrest of the bcs1A deletion mutant. In a Galleria mellonella infection model, the deletion of bcs1A resulted in significantly decreased virulence. Only Bcs1A was able to partially complement a deletion of BCS1 in S. cerevisiae. The subcellular localization of Bcs1B and Bcs1C outside of mitochondria suggests that these Bcs1 homologs exert cellular functions different from that of Bcs1. Our data demonstrate that Bcs1A is the sole Bcs1 ortholog in A. fumigatus. [ABSTRACT FROM AUTHOR]

The results of this research on the electrochemical behavior of Cu24Zn5Al alloy in a 0.1 mol/dm3 sodium sulfate (Na2SO4) solution containing 1-phenyl-5-mercaptotetrazole (PMT) are presented in this paper. The influence of PMT concentration, chloride ion concentration, and pre-treatment were examined. The influence of pre-treatment was studied in terms of the effect of the immersion time of the electrode in the appropriate inhibitor solution. After selecting the optimal immersion time, its effect on the behavior of the Cu24Zn5Al alloy was tested in a 0.1 mol/dm3 solution of sodium sulfate in the presence of different concentrations of chloride ions. Research shown that with the increase of PMT concentration, the anodic current density around the corrosion potential decreases, indicating that PMT behaves as a corrosion inhibitor for Cu24Zn5Al alloy. [ABSTRACT FROM AUTHOR]

We analyzed the virulence traits and azole resistance mechanisms of 104 Candida auris isolates collected from 13 Korean hospitals from 1996 to 2022. Of these 104 isolates, 96 (5 blood and 91 ear isolates) belonged to clade II, and 8 (6 blood and 2 other isolates) belonged to clade I. Fluconazole resistance (minimum inhibitory concentration ≥32 mg/L) was observed in 68.8% of clade II and 25.0% of clade I isolates. All 104 isolates were susceptible to amphotericin B and three echinocandins. In 2022, six clade I isolates indicated the first nosocomial C. auris cluster in Korea. Clade II C. auris isolates exhibited reduced thermotolerance at 42 °C, with diminished in vitro competitive growth and lower virulence in the Galleria mellonella model compared to non-clade II isolates. Of the 66 fluconazole-resistant clade II isolates, several amino acid substitutions were identified: Erg11p in 14 (21.2%), Tac1Ap in 2 (3.0%), Tac1Bp in 62 (93.9%), and Tac1Bp F214S in 33 (50.0%). Although there were a limited number of non-clade II isolates studied, our results suggest that clade II C. auris isolates from Korean hospitals might display lower virulence traits than non-clade II isolates, and their primary fluconazole resistance mechanism is linked to Tac1Bp mutations. [ABSTRACT FROM AUTHOR]

Background: We sought to characterize the outcomes of patients with primary pulmonary coccidioidomycosis whose post-treatment complement fixation (CF) titer increased by more than 2 dilutions (serologic rebound) after discontinuation of antifungal treatment. Methods. We conducted a retrospective chart review of patients with primary pulmonary coccidioidomycosis and identified immunocompetent, non-pregnant adults who received antifungal treatment and then experienced a serologic rebound after treatment discontinuation. We compared these to matched controls similarly treated who did not have serologic rebound. Results. Fifty-eight patients experienced serologic rebound. Thirty (52%) of these were associated with symptoms. Nine were associated with radiographic progression. The median time to serologic rebound was 3.5 months. Antifungal treatment was reinitiated in 37 (63.7%) patients. Four of the 58 (6.9%) with rebounded serology subsequently developed extra-thoracic dissemination. Compared with matched controls, patients with rebounded serology were more likely to have post-treatment symptoms, reinitiation of antifungal therapy, and a longer duration of clinical follow-up. However, they were not more likely to experience extra-thoracic dissemination. Conclusion: Serological rebound, manifested in at least 2-dilution rise of CF titer following antifungal treatment of primary pulmonary coccidioidomycosis, was uncommon, but resulted in longer clinical follow-up. Continued monitoring of such patients is important to identify the patients who develop subsequent symptoms, as well as extra-thoracic dissemination. [ABSTRACT FROM AUTHOR]

Vulvovaginal candidiasis (VVC) is a common condition associated with discomfort in affected women. Due to the presence of different forms of the disease, diverse treatment regimens are developed; the newest ones include oteseconazole and ibrexafungerp. Here, we focus on the most up-to-date recommendations regarding VVC treatment, as well as novel treatment options. Topical and oral azoles are the drugs of choice in uncomplicated mycosis. The efficacy of probiotics and substances such as TOL-463 and chlorhexidine is indicated as satisfactory; however, there are no relevant guidelines. Although the majority of researchers agree that the treatment of non-albicans VVC should be long-lasting, the recommendations are inconsistent. Another clinical problem is the treatment of VVC with azole intolerance or resistance, for which literature proposes the use of several drugs including oteseconazole, ibrexafungerp, and voriconazole. The treatment schedules for recurrent VVC include mainly fluconazole; however, alternative options such as immunotherapeutic vaccine (NDV-3A) or designed antimicrobial peptides (dAMPs) were also described. We also focused on VVC affecting pregnant women, which is a substantial challenge in clinical practice, also due to the heterogeneous relevant guidelines. Thus far, few precise recommendations are available in the literature. Future studies should focus on atypical VVC forms to elucidate the inconsistent findings. [ABSTRACT FROM AUTHOR]

A new protocol for the synthesis of N-vinyl azoles using vinyl selenones and azoles in the presence of potassium hydroxide was developed. This reaction proceeded under mild and transition metal-free conditions through an addition/elimination cascade process. Both aromatic and aliphatic vinyl selenones and various mono-, bi- and tri-cyclic azoles can be tolerated and give terminal N-vinyl azoles in moderate to high yields. A plausible mechanism is also proposed. [ABSTRACT FROM AUTHOR]

The Antifungal Susceptibility Testing method of the European Committee on Antimicrobial Susceptibility Testing (EUCAST-AFST) is a reference technique for the determination of the Minimum Inhibitory Concentration (MIC) of antifungals for Aspergillus fumigatus. However, it is time-consuming and requires expertise. Micronaut-AM (M-AM) is a fast, simple, time-saving, and ready-to-use new colorimetric method using an indicator (resazurin) to facilitate the visual reading. The aim of this retrospective study was to evaluate the performance of the M-AM system and compare it with the EUCAST broth microdilution reference method to determine the susceptibility of 77 A. fumigatus clinical strains to amphotericin B, itraconazole, voriconazole, and posaconazole. Overall, the essential agreements within ±2 dilutions were 100%, 62%, 58%, and 30% and the categorical agreements were 100%, 97%, 91%, and 87% for amphotericin B, itraconazole, voriconazole, and posaconazole, respectively. No categorical discrepancy was found for amphotericin B, but several categorical discordances were observed with azole antifungals. However, only 2 of the 16 azole-resistant strains confirmed by the cyp51A sequencing would have been misclassified by M-AM. The use of M-AM is probably suitable for the determination of the MICs of amphotericin B, but further evaluations are needed to confirm its usefulness for the determination of the MICs of azoles for A. fumigatus. [ABSTRACT FROM AUTHOR]

The instability and volatility of iodine is high, however, effective iodine biocidal species can be readily stored in iodinated azoles and then be released upon decomposition or detonation. Iodine azoles with high iodine content and high thermal stability are highly desired. In this work, the strategy of methylene bridging with asymmetric structures of 3,4,5-triiodo-1-H-pyrazole (TIP), 2,4,5-triiodo-1H-imidazol (TIM), and tetraiodo-1H-pyrrole (TIPL) are proposed. Two highly stable fully iodinated methylene-bridged azole compounds 3,4,5-triiodo-1-((2,4,5-triiodo-1H-imidazol-1-yl)methyl)-1H-pyrazole (3) and 3,4,5-triiodo-1-((tetraiodo-1H-pyrrol-1-yl)methyl)-1H-pyrazole (4) were obtained with high iodine content and excellent thermal stability (iodine content: 84.27% for compound 3 and 86.48% for compound 4; Td: 3: 285 °C, 4: 260 °C). Furthermore, their composites with high-energy oxidant ammonium perchlorate (AP) were designed. The combustion behavior and thermal decomposition properties of the formulations were tested and evaluated. This work may open a new avenue to develop advanced energetic biocidal materials with well-balanced energetic and biocidal properties and versatile functionality. [ABSTRACT FROM AUTHOR]

Trichosporon spp. endocarditis is a severe and hard-to-treat infection. Immunosuppressed subjects and carriers of prosthetic valves or intracardiac devices are at risk. This article presents the case of an immunocompetent 74-year-old man affected by endocarditis of the prosthetic aortic valve. After Bentall surgery, cultures of the removed valve demonstrated Trichosporon ashaii as the etiological agent. The patient was treated with amphotericin B at first and subsequently with fluconazole. Given the fragility of the patient and the aggressiveness of the pathogen, life-long prophylactic therapy with fluconazole was prescribed. After 5 years follow-up, no drug-related toxicities were reported and the patient never showed any signs of recurrence. The review of the literature illustrates that Trichosporon spp. endocarditis may present even many years after heart surgery, and it is often associated with massive valve vegetations, severe embolic complications, and unfavorable outcome. Due to the absence of international guidelines, there is no unanimous therapeutic approach, but amphotericin B and azoles are usually prescribed. Additionally, a prompt surgical intervention seems to be of paramount importance. When dealing with a life-threatening disease, such as mycotic endocarditis of prosthetic valves, it is essential to consider and treat even rare etiological agents such as Trichosporon spp. [ABSTRACT FROM AUTHOR]

Concern about the global emergence of multidrug-resistant fungal pathogens led us to explore the use of combination therapy to combat azole resistance in Candida auris. Clorgyline had previously been shown to be a multi-target inhibitor of Cdr1 and Mdr1 efflux pumps of Candida albicans and Candida glabrata. A screen for antifungal sensitizers among synthetic analogs of Clorgyline detected interactions with the C. auris efflux pump azole substrates Posaconazole and Voriconazole. Of six Clorgyline analogs, M19 and M25 were identified as potential sensitizers of azole resistance. M19 and M25 were found to act synergistically with azoles against resistant C. auris clade I isolates and recombinant Saccharomyces cerevisiae strains overexpressing C. auris efflux pumps. Nile Red assays with the recombinant strains showed M19 and M25 inhibited the activity of Cdr1 and Mdr1 efflux pumps that are known to play key roles in azole resistance in C. auris clades I, III, and IV. While Clorgyline, M19 and M25 uncoupled the Oligomycin-sensitive ATPase activity of Cdr1 from C. albicans and C. auris, their mode of action is yet to be fully elucidated. The experimental combinations described herein provides a starting point to combat azole resistance dominated by overexpression of CauCdr1 in C. auris clades I and IV and CauMdr1 in C. auris clade III. [ABSTRACT FROM AUTHOR]

Azole resistance in Aspergillus fumigatus (AFM) is mainly associated with mutations in CYP51A and its promoter region or its homologue CYP51B. We evaluated the in vitro activity of isavuconazole, itraconazole, posaconazole, and voriconazole against 660 AFM collected during 2017–2020. Isolates were tested via CLSI broth microdilution. CLSI epidemiological cutoff values were applied. Non-wildtype (NWT) isolates to azoles were screened for alterations in the CYP51 sequences using whole genome sequencing. Azoles had similar activities against 660 AFM isolates. Overall, AFM displayed WT MIC values to isavuconazole (92.7%), itraconazole (92.9%), posaconazole (97.3%), and voriconazole (96.7%). Only 66 isolates (10.0%) were NWT to 1 or more of the azoles, and 32 harbored one or more alterations in the CYP51 sequences. Of these, 29/32 (90.1%) were NWT to itraconazole, 25/32 (78.1%) were NWT to isavuconazole, 17/32 (53.1%) were NWT to voriconazole, and 11/32 (34.4%) were NWT to posaconazole. The most frequent alteration was CYP51A TR34/L98H, carried by 14 isolates. Four isolates carried the alteration I242V in CYP51A, and G448S; A9T, or G138C was carried by one isolate each. Multiple alterations in CYP51A were detected in five isolates. Alterations in CYP51B were noted in seven isolates. Among 34 NWT isolates without -CYP51 alterations, WT rates to isavuconazole, itraconazole, voriconazole, and posaconazole were 32.4%, 47.1%, 85.3%, and 82.4%, respectively. Ten different CYP51 alterations were detected in 32/66 NWT isolates. Alterations in AFM CYP51 sequences can have variable effects on the in vitro activity of the azoles that are best delineated by testing all triazoles. [ABSTRACT FROM AUTHOR]

Compounds composed of [Cu(HIm, metIm)2–3L] ∙ nH2O (n = 0, 2) were obtained during the interaction of slightly soluble tartrate and copper(II) salicylate composed of CuL ∙ nH2O (n = 1–2, L2−—Tar2−, Sal2−) with imidazole (HIm) and 2-methylimidazole (metIm). Mono- and bi-ligand salts were analyzed; the process of their thermal decomposition was studied. The solubility constants KS of the CuC4H4O6 ∙ 2H2O tartrate and CuC7H4O3 ∙ H2O salicylate of copper(II) with at ionic strength of 0.3 were determined. The IR spectroscopy method showed the participation in complexation of the nitrogen atom N(3) of imidazole and the oxygen atoms of the carboxyl groups of oxyacids, as well as the hydroxyl group of salicylic acid in the mixed-ligand salts of copper(II). The compositions and stability of the imidazole-tartrate(salicylate) copper(II) complexes in an aqueous solution were determined by performing photometry and spectrophotometry and of the monoligand complexes [CuTar] and [CuSal] were determined by solubility and isomolar series methods. [ABSTRACT FROM AUTHOR]

Triazole and imidazole fungicides are an emerging class of contaminants with an increasing and ubiquitous presence in the environment. In mammals, their reproductive toxicity has been reported. Concerning male reproduction, a combinatorial activity of tebuconazole (TEB; triazole fungicide) and econazole (ECO; imidazole compound) in inducing mitochondrial impairment, energy depletion, cell cycle arrest, and the sequential activation of autophagy and apoptosis in Sertoli TM4 cells (SCs) has recently been demonstrated. Given the strict relationship between mitochondrial activity and reactive oxygen species (ROS), and the causative role of oxidative stress (OS) in male reproductive dysfunction, the individual and combined potential of TEB and ECO in inducing redox status alterations and OS was investigated. Furthermore, considering the impact of cyclooxygenase (COX)-2 and tumor necrosis factor-alpha (TNF-α) in modulating male fertility, protein expression levels were assessed. In the present study, we demonstrate that azoles-induced cytotoxicity is associated with a significant increase in ROS production, a drastic reduction in superoxide dismutase (SOD) and GSH-S-transferase activity levels, and a marked increase in the levels of oxidized (GSSG) glutathione. Exposure to azoles also induced COX-2 expression and increased TNF-α production. Furthermore, pre-treatment with N-acetylcysteine (NAC) mitigates ROS accumulation, attenuates COX-2 expression and TNF-α production, and rescues SCs from azole-induced apoptosis, suggesting a ROS-dependent molecular mechanism underlying the azole-induced cytotoxicity. [ABSTRACT FROM AUTHOR]

Trichosporon asahii is an opportunistic pathogen that can cause severe or even fatal infections in patients with low immune function. sPLA2 plays different roles in different fungi and is also related to fungal drug resistance. However, the mechanism underlying its drug resistance to azoles has not yet been reported in T. asahii. Therefore, we investigated the drug resistance of T. asahii PLA2 (TaPLA2) by constructing overexpressing mutant strains (TaPLA2OE). TaPLA2OE was generated by homologous recombination of the recombinant vector pEGFP-N1-TaPLA2, induced by the CMV promoter, with Agrobacterium tumefaciens. The structure of the protein was found to be typical of sPLA2, and it belongs to the phospholipase A2_3 superfamily. TaPLA2OE enhanced antifungal drug resistance by upregulating the expression of effector genes and increasing the number of arthrospores to promote biofilm formation. TaPLA2OE was highly sensitive to sodium dodecyl sulfate and Congo red, indicating impaired cell wall integrity due to downregulation of chitin synthesis or degradation genes, which can indirectly affect fungal resistance. In conclusion, TaPLA2 overexpression enhanced the resistance to azoles of T. asahii by enhancing drug efflux and biofilm formation and upregulating HOG-MAPK pathway genes; therefore, it has promising research prospects. [ABSTRACT FROM AUTHOR]

Throughout human history, bacteria and fungi have caused infections that are difficult to combat. For this reason, countless research groups have developed novel compounds to solve this problem. Thiazole and benzothiazole are present in different structures with interesting biological effects and are used to develop new effective antimicrobial agents. Moreover, nitrogen atoms that are present in this heterocycle allow for coordination with various metals, forming metal complexes that enhance the biological activity of organic ligands that are often used as commercial drugs. This bibliographical review summarizes the copper complexes that use thiazole and benzothiazole as ligands and that report efficient antimicrobial activity against different bacteria and fungi. [ABSTRACT FROM AUTHOR]

Reboxetine (REB) and sertraline (SER) are antidepressants. The antifungal potential of these drugs against planktonic Candida has been recently reported with limited data about their effects on Candidal biofilms. Biofilms are self-derived extracellular matrixes produced by the microbial population that is attached to biotic surfaces, such as vaginal and oral mucosa, or abiotic surfaces, such as biomedical devices, resulting in persistent fungal infections. The commonly prescribed antifungals, azoles, are usually less effective when biofilms are formed, and most of the prescribed antifungals are only fungistatic. Therefore, the current study investigates the antifungal potentials of REB and SER, alone and in combination with fluconazole (FLC) and itraconazole (ITR) against Candidal biofilms. Using proper controls, Candida species (Candida albicans, C. albicans; Candida krusei, C. krusei; and Candida glabrata, C. glabrata) were used to form biofilms in 96-well microplates. Serial dilutions corresponding to concentrations ranging from 2 to 4096 µg/mL of the target drugs (REB, SER, FLC, ITR) were prepared and added to the plates. Impairment of the biofilm biomass and biofilm metabolic viability was detected using the crystal violet (CV) assay and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, respectively. In the checkerboard assay, the sessile fractional inhibitory concentration index (SFICI) was calculated to evaluate the effects of drug combinations. SER was more effective in reducing the biomass than REB for C. albicans and C. glabrata, but both were equal for C. krusei. For the reduction in metabolic activity in C. albicans and C. glabrata, SER had a slight advantage over REB. In C. krusei, REB was slightly more potent. Overall, FLC and ITR were almost equal and produced more significant reductions in metabolic activity when compared to SER and REB, except for C. glabrata, where SER was almost equal to FLC. Synergism was detected between REB + FLC and REB + ITR against biofilm cells of C. albicans. Synergism was detected between REB + ITR against biofilm cells of C. krusei. Synergism was detected between REB + FLC and REB + ITR against biofilm cells of C. albicans, C. krusei, and C. glabrata. The results of the present study support the potential of SER and REB as anti-Candidal biofilm agents that are beneficial as a new antifungal to combat Candidal resistance. [ABSTRACT FROM AUTHOR]

Azole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We reported a synthesis of novel monoterpene-containing azoles with high antifungal activity and low cytotoxicity. These hybrids demonstrated broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against both fluconazole-susceptible and fluconazole-resistant strains of Candida spp. Compounds 10a and 10c with cuminyl and pinenyl fragments demonstrated up to 100 times lower MICs than fluconazole against clinical isolates. The results indicated that the monoterpene-containing azoles had much lower MICs against fluconazole-resistant clinical isolates of Candida parapsilosis than their phenyl-containing counterpart. In addition, the compounds did not exhibit cytotoxicity at active concentrations in the MTT assay, indicating potential for further development as antifungal agents. [ABSTRACT FROM AUTHOR]

Human AKR 7A2 broadly participates in the metabolism of a number of exogenous and endogenous compounds. Azoles are a class of clinically widely used antifungal drugs, which are usually metabolized by CYP 3A4, CYP2C19, and CYP1A1, etc. in vivo. The azole–protein interactions that human AKR7A2 participates in remain unreported. In this study, we investigated the effect of the representative azoles (miconazole, econazole, ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole) on the catalysis of human AKR7A2. The steady-state kinetics study showed that the catalytic efficiency of AKR7A2 enhanced in a dose-dependent manner in the presence of posaconazole, miconazole, fluconazole, and itraconazole, while it had no change in the presence of econazole, ketoconazole, and voriconazole. Biacore assays demonstrated that all seven azoles were able to specifically bind to AKR7A2, among which itraconazole, posaconazole, and voriconazole showed the strongest binding. Blind docking predicted that all azoles were apt to preferentially bind at the entrance of the substrate cavity of AKR7A2. Flexible docking showed that posaconazole, located at the region, can efficiently lower the binding energy of the substrate 2-CBA in the cavity compared to the case of no posaconazole. This study demonstrates that human AKR7A2 can interact with some azole drugs, and it also reveals that the enzyme activity can be regulated by some small molecules. These findings will enable a better understanding of azole–protein interactions. [ABSTRACT FROM AUTHOR]

The trifluoromethyl group is widely recognized for its significant role in the fields of medicinal chemistry and material science due to its unique electronic and steric properties that can alter various physiochemical properties of the parent molecule, such as lipophilicity, acidity, and hydrogen bonding capabilities. Compared to the well-established C-trifluoromethylation, N-trifluoromethylation has received lesser attention. Considering the extensive contribution of nitrogen to drug molecules, it is predicted that constructing N-trifluoromethyl (N-CF3) motifs will be of great significance in pharmaceutical and agrochemical industries. This review is mainly concerned with the synthesis of heterocycles containing this motif. In three-membered heterocycles containing the N-CF3 motif, the existing literature mostly demonstrated the synthetic strategy, as it does for four- and larger-membered heterocycles. Certain structures, such as oxaziridines, could serve as an oxidant or building blocks in organic synthesis. In five-membered heterocycles, it has been reported that N-CF3 azoles showed a higher lipophilicity and a latent increased metabolic stability and Caco-2-permeability compared with their N-CH3 counterparts, illustrating the potential of the N-CF3 motif. Various N-CF3 analogues of drugs or bioactive molecules, such as sildenafil analogue, have been obtained. In general, the N-CF3 motif is developing and has great potential in bioactive molecules or materials. Give the recent development in this motif, it is foreseeable that its synthesis methods and applications will become more and more extensive. In this paper, we present an overview of the synthesis of N-CF3 heterocycles, categorized on the basis of the number of rings (three-, four-, five-, six- and larger-membered heterocycles), and focus on the five-membered heterocycles containing the N-CF3 group. [ABSTRACT FROM AUTHOR]

The effectiveness of current antifungal therapies is hampered by the emergence of drug resistance strains, highlighting an urgent need for new alternatives such as adjuvant antifungal treatments. This study aims to examine the synergism between propranolol and antifungal drugs, based on the premise that propranolol is known to inhibit fungal hyphae. In vitro studies demonstrate that propranolol potentiates the antifungal activity of azoles and that the effect is more pronounced for propranolol–itraconazole combination. Using an in vivo murine systemic candidemia model, we show that propranolol–itraconazole combination treatment resulted in a lower rate of body weight loss, decreased kidney fungal bioburden and renal inflammation when compared to propranolol and azole treatment alone or untreated control. Altogether, our findings suggest that propranolol increases the efficacy of azoles against C. albicans, offering a new therapeutic strategy against invasive fungal infections. [ABSTRACT FROM AUTHOR]

Background and Objectives: Vulvovaginal candidiasis (VVC) is a mucous membrane infection, with an increased rate of antifungal resistance of Candida species. In this study, the in vitro efficacy of farnesol alone or in combination with traditional antifungals was assessed against resistant Candida strains recovered from women with VVC. Materials and Methods: Eighty Candida isolates were identified by multiplex polymerase chain reaction (PCR), and the antifungal susceptibility to amphotericin B (AMB), fluconazole (FLU), itraconazole (ITZ), voriconazole (VOR), clotrimazole (CTZ), and farnesol was tested by the standard microdilution method. The combinations of farnesol with each antifungal were calculated based on the fractional inhibitory concentration index (FICI). Result: Candida glabrata was the predominant species (48.75%) isolated from vaginal discharges, followed by C. albicans (43.75%), C. parapsilosis (3.75%), a mixed infection of C. albicans and C. glabrata (2.5%) and C. albicans and C. parapsilosis (1%). C. albicans and C. glabrata isolates had lower susceptibility to FLU (31.4% and 23.0%, respectively) and CTZ (37.1% and 33.3%, respectively). Importantly, there was "synergism" between farnesol–FLU and farnesol–ITZ against C. albicans and C. parapsilosis (FICI = 0.5 and 0.35, respectively), reverting the original azole-resistant profile. Conclusion: These findings indicate that farnesol can revert the resistance profile of azole by enhancing the activity of FLU and ITZ in resistant Candida isolates, which is a clinically promising result. [ABSTRACT FROM AUTHOR]

Our research group has made incursions into the scarcely known coordination chemistry of rhenium(II). The literature shows that Re(II) mononuclear complexes are attractive in molecular magnetism due to high magnetic anisotropy because of a significant spin-orbit coupling, making them a potential source for new molecule-based magnets. In this work, we present the preparation of four novel Re(II) compounds of general formula NBu4[Re(NO)Br4(L)] [NBu4+ = tetra-n-butylammonium: L = imidazole (1), pyrazole (2), 1,2,4-triazole (3) and 1H-tetrazole (4)]. The four compounds were fully characterized by single-crystal X-ray diffraction, infrared spectroscopy, and cryomagnetic measurements in the temperature range of 1.8–300 K. Their crystal structures consist of mononuclear [Re(NO)Br4(L)]− complex anions and NBu4+ cations. Each Re(II) ion is six-coordinate with a linear nitrosyl group and one monodentate nitrogen-donor (L), which are trans-positioned, plus four bromide groups, building a tetragonally distorted octahedral surrounding. The inter-anionic contacts were thoroughly analyzed using Hirshfeld surface analyses (plots over the dnorm, shape index, and 2D fingerprints). Cryomagnetic measurements show that these complexes behave as quasi-magnetically isolated spin doublets with weak antiferromagnetic interactions at low temperatures. The magnetic behavior of Re(II) was modeled by the influence of the ligand field, tetragonal distortion, spin-orbit coupling, and covalence effects. In addition, the antiferromagnetic exchange coupling was correlated to the nature of the intermolecular interactions. [ABSTRACT FROM AUTHOR]

A small set of twelve compounds of a nitrofuran carboxamide chemotype was elaborated from a readily available 2,6-diazaspiro[3.4]octane building block, exploring diverse variants of the molecular periphery, including various azole substituents. The in vitro inhibitory activities of the synthesized compounds were assessed against Mycobacterium tuberculosis H37Rv. As a result, a remarkably potent antitubercular lead displaying a minimal inhibitory concentration of 0.016 μg/mL was identified. [ABSTRACT FROM AUTHOR]

We reported herein efficient economic high-pressure synthesis procedures for the synthesis of bis(azoles) and bis(azines) by utilizing the bis(enaminone) intermediate. Bis(enaminone) reacted with hydrazine hydrate, hydroxylamine hydrochloride, guanidine hydrochloride, urea, thiourea, and malononitrile to form the desired bis azines and bis azoles. A combination of elemental analyses and spectral data was used to confirm the structures of the products. Compared with conventional heating, the high-pressure Q-Tube method promotes reactions in a short period of time and provides high yields. [ABSTRACT FROM AUTHOR]

Life-threatening Candida infections have increased with the COVID-19 pandemic, and the already limited arsenal of antifungal drugs has become even more restricted due to its side effects associated with complications after SARS-CoV-2 infection. Drug combination strategies have the potential to reduce the risk of side effects without loss of therapeutic efficacy. The aim of this study was to evaluate the combination of ent-hardwickiic acid with low concentrations of amphotericin B against Candida strains. The minimum inhibitory concentration (MIC) values were determined for amphotericin B and ent-hardwickiic acid as isolated compounds and for 77 combinations of amphotericin B and ent-hardwickiic acid concentrations that were assessed by using the checkerboard microdilution method. Time–kill assays were performed in order to assess the fungistatic or fungicidal nature of the different combinations. The strategy of combining both compounds markedly reduced the MIC values from 16 µg/mL to 1 µg/mL of amphotericin B and from 12.5 µg/mL to 6.25 µg/mL of ent-hardwickiic acid, from isolated to combined, against C. albicans resistant to azoles. The combination of 1 µg/mL of amphotericin B with 6.25 µg/mL of ent-hardwickiic acid killed all the cells of the same strain within four hours of incubation. [ABSTRACT FROM AUTHOR]

Isavuconazole is the only US FDA-approved antifungal for treating invasive mucormycosis. We evaluated isavuconazole activity against a global collection of Mucorales isolates. Fifty-two isolates were collected during 2017–2020 from hospitals located in the USA, Europe, and the Asia-Pacific. Isolates were identified by MALDI-TOF MS and/or DNA sequencing and susceptibility tested by the broth microdilution method following CLSI guidelines. Isavuconazole (MIC50/90, 2/>8 mg/L) inhibited 59.6% and 71.2% of all Mucorales isolates at ≤2 mg/L and ≤4 mg/L, respectively. Among comparators, amphotericin B (MIC50/90, 0.5/1 mg/L) displayed the highest activity, followed by posaconazole (MIC50/90, 0.5/8 mg/L). Voriconazole (MIC50/90, >8/>8 mg/L) and the echinocandins (MIC50/90, >4/>4 mg/L) had limited activity against Mucorales isolates. Isavuconazole activity varied by species and this agent inhibited at ≤4 mg/L 85.2%, 72.7%, and 25% of Rhizopus spp. (n = 27; MIC50/90, 1/>8 mg/L), Lichtheimia spp. (n = 11; MIC50/90, 4/8 mg/L), and Mucor spp. (n = 8; MIC50, >8 mg/L) isolates, respectively. Posaconazole MIC50/90 values against Rhizopus, Lichtheimia, and Mucor species were 0.5/8 mg/L, 0.5/1 mg/L, and 2/- mg/L, respectively; amphotericin B MIC50/90 values were 1/1 mg/L, 0.5/1 mg/L, and 0.5/- mg/L, respectively. As susceptibility profiles varied among Mucorales genera, species identification and antifungal susceptibility testing are advised whenever possible to manage and monitor mucormycosis. [ABSTRACT FROM AUTHOR]

Candida auris infections are difficult to treat due to acquired drug resistance against one or multiple antifungal drug classes. The most prominent resistance mechanisms in C. auris are overexpression and point mutations in Erg11, and the overexpression of efflux pump genes CDR1 and MDR1. We report the establishment of a novel platform for molecular analysis and drug screening based on acquired azole-resistance mechanisms found in C. auris. Constitutive functional overexpression of wild-type C. auris Erg11, Erg11 with amino acid substitutions Y132F or K143R and the recombinant efflux pumps Cdr1 and Mdr1 has been achieved in Saccharomyces cerevisiae. Phenotypes were evaluated for standard azoles and the tetrazole VT-1161. Overexpression of CauErg11 Y132F, CauErg11 K143R, and CauMdr1 conferred resistance exclusively to the short-tailed azoles Fluconazole and Voriconazole. Strains overexpressing the Cdr1 protein were pan-azole resistant. While CauErg11 Y132F increased VT-1161 resistance, K143R had no impact. Type II binding spectra showed tight azole binding to the affinity-purified recombinant CauErg11 protein. The Nile Red assay confirmed the efflux functions of CauMdr1 and CauCdr1, which were specifically inhibited by MCC1189 and Beauvericin, respectively. CauCdr1 exhibited ATPase activity that was inhibited by Oligomycin. The S. cerevisiae overexpression platform enables evaluation of the interaction of existing and novel azole drugs with their primary target CauErg11 and their susceptibility to drug efflux. [ABSTRACT FROM AUTHOR]

The review presents extensive data (from the author's work and the literature) on the stereochemical structure of functionalized organophosphorus azoles (pyrroles, pyrazoles, imidazoles and benzazoles) and related compounds, using multinuclear 1H, 13C, 31P NMR spectroscopy and quantum chemistry. 31P NMR spectroscopy, combined with high-level quantum-chemical calculations, is the most convenient and reliable approach to studying tetra-, penta-, and hexacoordinated phosphorus atoms of phosphorylated N-vinylazoles and evaluating their Z/E isomerization. [ABSTRACT FROM AUTHOR]

Sulfonamides are the basic motifs for a whole generation of drugs from a large group of antibiotics. Currently, research in the field of the new sulfonamide synthesis has received a "second wind", due to the increase in the synthetic capabilities of organic chemistry and the study of their medical and biological properties of a wide spectrum of biological activity. New reagents and new reactions make it possible to significantly increase the number of compounds with a sulfonamide fragment in combination with other important pharmacophore groups, such as, for example, a wide class of N-containing heterocycles. The result of these synthetic possibilities is the extension of the activity spectrum—along with antibacterial activity, many of them exhibit other types of biological activity. Antiviral activity is also observed in a wide range of sulfonamide derivatives. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against coxsackievirus B, enteroviruses, encephalomyocarditis viruses, adenoviruses, human parainfluenza viruses, Ebola virus, Marburg virus, SARS-CoV-2, HIV and others. Since over the past three years, viral infections have become a special problem for public health throughout the world, the development of new broad-spectrum antiviral drugs is an extremely important task for synthetic organic and medicinal chemistry. Sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. Another approach involves the use of sulfonamides as the reagents for building a nitrogen-containing framework. [ABSTRACT FROM AUTHOR]

Allergic asthma has traditionally been treated with inhaled and systemic glucocorticosteroids. A continuum of allergic fungal airways disease associated with Aspergillus fumigatus colonization and/or atopic immune responses that encompasses fungal asthma, severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis is now recognized along a phenotypic severity spectrum of T2-high immune deviation lung disease. Oral triazoles have shown clinical, anti-inflammatory and microbiologic efficacy in this setting; in the future inhaled antifungals may improve the therapeutic index. Humanized monoclonal antibody biologic agents targeting T2-high disease also show efficacy and promise of improved control in difficult cases. Developments in these areas are highlighted in this overview. [ABSTRACT FROM AUTHOR]

Candida parapsilosis is the second most common Candida species isolated in Asia, Southern Europe, and Latin America and is often involved in invasive infections that seriously impact human health. This pathogen is part of the psilosis complex, which also includes Candida orthopsilosis and Candida metapsilosis. C. parapsilosis infections are particularly prevalent among neonates with low birth weights, individuals who are immunocompromised, and patients who require prolonged use of a central venous catheter or other indwelling devices, whose surfaces C. parapsilosis exhibits an enhanced capacity to adhere to and form biofilms. Despite this well-acknowledged prevalence, the biology of C. parapsilosis has not been as extensively explored as that of Candida albicans. In this paper, we describe the molecular mechanistic pathways of virulence in C. parapsilosis and show how they differ from those of C. albicans. We also describe the mode of action of antifungal drugs used for the treatment of Candida infections, namely, polyenes, echinocandins, and azoles, as well as the resistance mechanisms developed by C. parapsilosis to overcome them. Finally, we stress the importance of the ongoing search for species-specific features that may aid the development of effective control strategies and thus reduce the burden on patients and healthcare costs. [ABSTRACT FROM AUTHOR]

The enantiomeric separation of antifungal compounds is an arduous task in pharmaceutical and biomedical fields due to the different properties that each diastereoisomer presents. The enantioseparation of a group of fungicides (sulconazole, bifonazole, triadimefon and triadimenol) using supercritical fluid chromatography was achieved in this work. For this goal, four different chiral columns based on polysaccharide derivatives, as well as the effect of different chromatographic parameters such as temperature, type and percentage of organic modifier (methanol, ethanol and isopropanol), were thoroughly investigated. The inversion of the elution order of enantiomers as a result of a change in the stationary phase or organic modifier was also evaluated by employing a circular dichroism detector. The best separation conditions, in terms of the enantioresolution and analysis time, were obtained with the Lux® Cellulose-2 column using isopropanol as the organic modifier. [ABSTRACT FROM AUTHOR]

Catecholamines–dopamine, noradrenaline and adrenaline are important biomarkers of neurotransmitter metabolism, indicating neuroendocrine tumors and neurodegenerative diseases. Surface-enhanced Raman spectroscopy (SERS) is a promising analytical technique with unprecedented multiplexing capabilities. However, not all important analytes exhibit strong SERS signals on stable and robust nanostructured substrates. In this work, we propose a novel indicator system based on the formation of mixed ligand complexes with bispidine-based bis-azole ligands which can serve as pliers to trap Cu(II) ions and stabilize its complexes with catecholamines. Four synthesized ligands with different functional groups: carboxyl, amino, benzyl, and methoxybenzyl, were applied for forming stable complexes to shift maximum absorbance of catecholamines from the ultraviolet region to 570–600 nm. A new absorbance band in the visible range resonates with the local surface plasmon resonance (LSPR) band of metal nanoparticles and most used laser wavelengths. This match allowed use of Molecular Immobilization and Resonant Raman Amplification by Complex-Loaded Enhancers (MIRRACLE) methodology to measure intense Raman signals on a nanostructured silver-based SERS-active substrate. The synthesized plier-like ligands fixed and stabilized catecholamine complexes with Cu(II) on the SERS sensor surface, which facilitated the determination of dopamine in a 3.2 × 10−12–1 × 10−8 M concentration range. [ABSTRACT FROM AUTHOR]

The palladium-catalyzed direct arylation of azoles with (hetero)aryl halides is nowadays one of the most versatile and efficient procedures for the selective synthesis of heterobiaryls. Although this procedure is, due to its characteristics, also of great interest in the industrial field, the wide use of a reaction medium such as DMF or DMA, two polar aprotic solvents coded as dangerous according to environmental, health, safety (EHS) parameters, strongly limits its actual use. In contrast, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. In this paper we report an unprecedented selective C-5 arylation procedure involving anisole as an EHS green reaction solvent. In addition, the beneficial role of benzoic acid as an additive was also highlighted, a role that had never been previously described. [ABSTRACT FROM AUTHOR]

Candida albicans seriously threatens human health, especially for immunosuppressed groups. The antifungal agents mainly include azoles, polyenes and echinocandins. However, the few types of existing antifungal drugs and their resistance make it necessary to develop new antifungal drugs. Bacillus and its metabolites has antifungal activity against pathogenic fungi. This review introduces the application of Bacillus metabolites in the control of C. albicans in recent years. Firstly, several compounds produced by Bacillus spp. are listed. Then the isolation and identification techniques of Bacillus metabolites in recent years are described, including high-precision separation technology and omics technology for the separation of similar components of Bacillus metabolites. The mechanisms of Bacillus metabolites against C. albicans are distinguished from the inhibition of pathogenic fungi and inhibition of the fungal virulence factors. The purpose of this review is to systematically summarize the recent studies on the inhibition of pathogenic fungi by Bacillus metabolites. The review is expected to become the reference for the control of pathogenic fungi such as C. albicans and the application of Bacillus metabolites in the future. [ABSTRACT FROM AUTHOR]