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Monocyclic 5‐membered heterocycles including imidazoles, thiazoles, oxazoles, and their related compounds have gained significant attention in medicinal chemistry because of their potent anticancerous activity. These small heterocyclic molecules possess versatile properties, including biological activity, absorption, distribution, metabolism, excretion, and chemical diversity that give them immense potential as anticancer agents. It is also a fact that inherent characteristic of azoles to combine with many biological molecules through hydrogen bond, stacking, and hydrophobic interaction makes them effective against almost all cancer types. In the present paper the author discusses the way which is connected with chemical structure of monocyclic azoles and their anticancer activity namely the ability of these compounds to intercalate with DNA, to inhibit some enzymes and to interfere cellular signaling pathways. Interestingly, several azole derivatives have been seen to be effective in preclinical efficacy studies as well as in clinical trials and are considered to be potent in overcoming the problem of resistance and side effects of the common anticancer agents. As the synthetic chemistry progresses, the structural system of the azoles has diversified and development in the pharmacology has become more specific. This has helped in enhancing the formation of new molecules in the azole class with improved selectivity and efficacy. Furthermore, the comprehensive review explains how computational chemistry and structure‐activity relationship (SAR) approaches are applied to the design of future‐generation azole compounds. In light of these facts, this article is designed to give a broad overview of the current state of monocyclic azole‐based anticancer agents in an attempt to further assert its therapeutic promise and spur further attempts at infusing the said agents into the cancer therapeutics fray. The discoveries made in this study may allow the development the radical different therapeutic approaches, which could lead to improved and targeted treatment of cancer. [ABSTRACT FROM AUTHOR]

Background Outpatient parenteral antimicrobial therapy (OPAT) can deliver extended parenteral treatment of fungal infections in an ambulatory setting, whilst minimizing treatment burden and cost. The extended dosing interval of rezafungin may potentiate the benefits of OPAT. Methods This retrospective cohort study includes all adult patients who received echinocandin therapy in a large OPAT programme between 2012 and 2022. Patient characteristics, treatment and outcomes were studied. Data were analysed to determine the effects of replacing daily dosing with weekly dosing of echinocandin. Results Across the study period, 11% (44/386) of all patients in our Health Service treated with ≥7 days of echinocandin were managed via OPAT. All were Candida and related 'yeast-like' species infections. Nakaseomyces glabrata (20/41; 49%) was the most common pathogen, fungaemia the most common presentation (17/41; 41%) and azole resistance the most frequent indication for echinocandin use (21/41; 51%). In total, 633 days of echinocandin were administered as OPAT. Thirteen patients (13/41; 32%) received concurrent parenteral antibacterials. Treatment success was achieved in 30/41 (73%) patients. If daily echinocandin dosing was replaced with weekly dosing, a potential 52% (633 to 326) reduction in the total number of treatments (for any therapy) delivered by the OPAT team is possible. The ongoing need for daily antibacterial administration mitigated the benefit in some of this cohort. Conclusions Echinocandin therapy can be safely delivered via OPAT with outcomes equivalent to bed-based care. The extended dosing interval of rezafungin will allow for a substantial reduction in the number of treatments required across the patient cohort. [ABSTRACT FROM AUTHOR]

The efficacy and safety of venetoclax in newly diagnosed pediatric acute myeloid leukemia (AML) are not well-established as they are in adults. Children newly diagnosed with AML were recommended for induction therapy with venetoclax and chemotherapy or hypomethylating agents (HMAs) as per for the ChiCTR1900027146 trial. Venetoclax was administered at a consistent dose of 200 mg/m2/day for 28 days, with adjustments when used concurrently with azoles. The study measured both the remission rates and the safety assessments of venetoclax. We enrolled 45 newly diagnosed pediatric patients with AML. The complete remission rates were 94.7% in the low/middle-risk group and 80.8% in the high-risk group; MRD-negative rates were 52.6% and 38.5% in the low/middle-risk group and high-risk group, respectively. Venetoclax based combination therapy was well tolerated by the majority of patients. The median duration of venetoclax dosing was 18 days (range 9–28), with hematological toxicity and infection being the most common adverse events. Venetoclax-based induction regimens demonstrated a high response rate and safety profile in newly diagnosed pediatric AML cases. This underscores the significance of venetoclax as a viable treatment option for untreated AML, extending beyond its role as salvage therapy for refractory/relapsed AML. [ABSTRACT FROM AUTHOR]

The reaction of cyanogen azide with strained‐ring containing primary and secondary amines led to the isolation of energetic molecules deriving their energy content from both strained rings as well as aminotetrazoles. Azo‐coupling of these materials afforded novel high‐nitrogen energetic materials of very high sensitivity. All compounds were chemically characterized by IR, NMR, single‐crystal X‐ray crystallography, and high‐resolution mass spectrometry. Their impact and friction sensitivities were experimentally determined, and their energetic performances were calculated. [ABSTRACT FROM AUTHOR]

Invasive fungal infections pose a serious risk to human health; therefore, it is important to study the dissemination and proliferation of pathogenic fungal species in the environment. This could prove useful in preventing infections in susceptible individuals, such as those who are immune-compromised or suppressed. Pathogenic yeasts belonging to the genera Candida, Cryptococcus and Rhodotorula are commonly found in various water sources that are used for daily activities and are included in the World Health Organization fungal priority pathogens list, further warranting investigation into the possibility that infections may occur through contact with yeast-contaminated water. In addition, the close association between antifungal pollutants and yeast in water may induce acquired antifungal resistance development, further complicating the effective treatment of these infections. Thus, investigating the presence and antifungal susceptibility of yeast found in water and identifying ways to monitor potential fungal pathogens may prove useful in combating invasive fungal infections. This review deals with the occurrence and infection risks posed by pathogenic yeasts in water as well as the possibility of these yeasts acquiring antifungal resistance due to the simultaneous presence of antifungal compounds from medical and agricultural runoff. [ABSTRACT FROM AUTHOR]

Background: Invasive fungal disease (IFD) is a sinister complication encountered in patients with haematological disorders. When occurring in the central nervous system (CNS), IFDs can have catastrophic outcomes. Objectives: To study the clinical presentation, predisposing etiological factors, and prognosis of a CNS‐IFD in a patient with a haematological disorder. Patients and Methods: This is a retrospective study focusing on the clinical profile, diagnosis, treatment strategy and outcomes of 43 patients with an underlying haematological disorder, who were diagnosed with CNS‐IFD between 2018 and 2022. Results: Of the 43 patients, 18 were chemotherapy recipients, while 23 were stem cell transplant (SCT) recipients and 2 presented with CNS‐IFD at diagnosis. AML/MDS (37.2%) and ALL (18.6%) were the predominant underlying diagnoses. A sudden deterioration in sensorium (53.5%) was the earliest clinical sign, while T2 hyperintensities (26.8%), vascular involvement (26.8%) and ring‐enhancing lesions (16.3%) were the commonest radiological findings, with all patients exhibiting diffusion restriction in diffusion‐weighted images. Microbiological evidence of infection was obtained in all patients; however, culture positivity was established in only 25 patients. Rhizopus spp (23.2%) and Aspergillus spp (20.9%) were implicated in most cases. Overall survival of the cohort was 27.9% at a median follow‐up of 6 months. In patients who succumbed, the median time to death was 4 days (0–46). Conclusion: CNS‐IFD is associated with very poor survival in patients undergoing chemotherapy or an SCT, urging the need for prompt diagnosis and initiation of suitable antifungal therapy. [ABSTRACT FROM AUTHOR]

Background New antifungal agents are required to mitigate against azole-resistant Aspergillus and drug-resistant non- Aspergillus moulds. The novel orotomide, olorofim (F2G, Manchester, UK), has potent fungicidal activity against Aspergillus including azole-resistant Aspergillus fumigatus, Lomentospora prolificans and Scedosporium spp. Development of olorofim-specific clinical breakpoints/epidemiological cut-off values requires reliable MIC data. Objectives Determine the in vitro activity of olorofim compared with standard antifungals against mould pathogens at an Australian hospital. Materials and methods Olorofim MICs were determined for 507 clinical mould isolates using the CLSI M38-A3 standard. MICs of amphotericin B, anidulafungin, posaconazole, voriconazole and isavuconazole were obtained using Sensititre™ YeastOne YO10 and AUSNMRCI panels (Thermo-Fisher Scientific). Results A. fumigatus sensu stricto was the commonest species (33.3%) followed by L. prolificans (18.3%), Scedosporium (11.4%) and Fusarium (6%) species. Olorofim modal MICs were ≤0.25 mg/L (MIC90 0.25 mg/L) for all Aspergillus except Aspergillus Section Usti (1 mg/L); MICs for nine azole-resistant/non-wild-type A. fumigatus ranged from 0.008 to 0.125 mg/L. The MIC90 of olorofim for L. prolificans was 0.5 mg/L, 0.25–0.5 mg/L for Scedosporium spp. and 8 mg/L for the F. solani complex but with modal MICs of 0.25 and 0.008 mg/L for F. oxysporum and F. proliferatum complexes, respectively. For Verruconis gallopava (n  = 10), the olorofim MIC90 was 0.06 mg/L (voriconazole MIC90 2 mg/L, isavuconazole MICs of 4–>8 mg/L). Olorofim had little activity against other dematiaceous moulds including Exophiala species. Conclusions Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus , L. prolificans , Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava. [ABSTRACT FROM AUTHOR]

Candidemia is emerging as a significant concern in children, particularly among those with underlying conditions like malignancies or prematurity. The interpretation of epidemiological data on candidemias and their antifungal resistance plays a vital role in aiding diagnosis and guiding clinicians in treatment decisions. From 2014 to 2021, a retrospective analysis was conducted in İstanbul, Turkey; comparing Candida albicans and non-albicans (NAC) spp in both surviving and deceased groups. Furthermore, an examination of Candida parapsilosis and other species was performed, assessing various clinical and laboratory parameters. Among 93 patients, with a median age of 17 months, C. parapsilosis emerged as the predominant isolated species (44%), followed by C. albicans (34.4%). Resistance to fluconazole, voricanozole, and echinocandins, along with a history of broad-spectrum antibiotic use were found to be significantly higher in the non-albicans Candida group compared to C. albicans group. In the C. parapsilosis group, statistically lower age was identified in comparison to the other groups (P  = .018). In addition, high fluconazole and voriconazole resistance was detected in Candida parapsilosis spp. Our study highlights a notable prevalence of C. parapsilosis, particularly in younger children, which is different from similar studies in childhood. This trend may be attributed to the common use of total parenteral nutrition and central venous catheter in gastrointestinal disorders and metabolic diseases. Furthermore, as anticipated, high azole resistance is noted in C. parapsilosis and other non-albicans Candida species. Interestingly, resistance to both amphotericin B and echinocandins within this group has been notably high. It is crucial to emphasize the considerable antifungal resistance seen in C. parapsilosis isolates. [ABSTRACT FROM AUTHOR]

Recently, PEPPSI‐type palladium‐complexes bearing N‐heterocyclic carbene (NHC) ligand have commonly been used as the effective catalysts in the direct arylation of heteroaromatic compounds. In most of previous studies catalyzed by such complexes, unsaturated ring carbene ligands such as benzo[d]imidazol‐2‐ylidene and imidazol‐2‐ylidene were used. However, the use of saturated ring carbene ligands such as 4,5‐dihydro‐imidazol‐2‐ylidene has been highly limited. Therefore, in this study, four novel 4,5‐dihydro‐1H‐imidazolium salts were synthesized as saturated ring carbene precursors. Then, well‐defined air‐ and moisture‐stable four novel PEPPSI‐type palladium‐complexes with 4,5‐dihydro‐imidazol‐2‐ylidene ligands were prepared. All synthesized carbene precursors and palladium‐complexes were structurally characterized by different spectroscopic and analytical techniques. Further structural characterization of two of the palladium‐complexes was performed by single‐crystal X‐ray diffraction. Next, the palladium‐complexes were tested in the direct arylation of azoles such as 4,5‐dimethylthiazole and 1‐methyl‐1H‐imidazole with (hetero)aryl halides in presence of 1 mol% catalyst loading at 120°C. The results showed that these novel palladium complexes are effective catalysts. [ABSTRACT FROM AUTHOR]

This research focused on the synthesis and analysis of two novel Ru(II)-based complexes, cis-[RuCl(Hind)(phen)2]PF6 (FOR022) and cis-[Ru(Hind)2(phen)2](PF6)2 (FOR0E2), where Hind represents indazole and phen stands for 1,10-phenanthroline. These compounds were thoroughly characterized using various methods such as elemental analysis, spectroscopy techniques, and electrochemistry assay, confirming their structures. The research highlights the effectiveness of the compound FOR0E2 in exhibiting strong cytotoxic properties against various tumor cell lines, including HCT116, HepG2, HL-60, LNcaP, and PC-3, with half-maximal inhibitory concentration (IC50) values ranging from 10.7 to 25.2 μmol L−1. Additionally, FOR0E2 showed substantial leishmanicidal capabilities against both the promastigote and amastigote forms of L. amazonensis, with IC50 values of 5.7 μmol L−1 and 1.6 μmol L−1, respectively. These outcomes suggest that the inclusion of indazole in FOR022 and FOR0E2 significantly enhances their biological effectiveness, positioning it as a promising candidate for pharmacological treatments. [ABSTRACT FROM AUTHOR]

Zwitterionic compounds are an emergent class of energetic materials and have gained synthetic interest of many in the recent years. Due to their better packing efficiencies and strong inter/intramolecular electrostatic interactions, they often ensue superior energetic properties than their salt analogues. A systematic review from the perspective of design, synthesis, and physicochemical properties evaluation of the zwitterionic energetic materials is presented. Depending on the parent ring(s) used for the synthesis and the type of moieties bearing positive and negative charges, different classes of energetic materials, such as primary explosives, secondary explosives, heat resistant explosives, oxidizers, etc., may result. The properties of some of the energetic zwitterionic compounds are also compared with analogous energetic salts. This review will encourage readers to explore the possibility of designing new zwitterionic energetic materials. [ABSTRACT FROM AUTHOR]

A new approach to the alkylation of azoles with alkenes catalyzed by the nickel complexes with N-heterocyclic carbenes (Ni/NHC) was developed. The catalytically active Ni/NHC complexes are formed in situ from the air-stable precursors: the nickel chloride complex with pyridine (NiCl2Py2), imidazolium salt IMes•HCl (IMes is 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene) as the carbene source, and sodium tert-butoxide (ButONa). The advantages of the developed approach are availability of the components of the catalytic system, no necessity to apply special agents for the reduction of NiII to Ni0, and simplification of the synthesis procedure. [ABSTRACT FROM AUTHOR]

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Objectives: This study evaluated the role of Upc2 in the development of azole resistance in Candida albicans isolates from Lebanese hospitalized patients and determined a correlation between resistance and virulence. Methods: The UPC2 gene which codes for an ergosterol biosynthesis regulator was sequenced and analysed in two azole-resistant and one azole-susceptible C. albicans isolates. An amino acid substitution screening was carried out on Upc2 with a focus on its ligand binding domain (LBD) known to interact with ergosterol. Then, Upc2 protein secondary structure prediction and homology modelling were conducted, followed by total plasma membrane ergosterol and cell wall chitin quantifications. For virulence, mouse models of systemic infection were generated and an agar adhesion and invasion test was performed. Results: Azole-resistant isolates harboured novel amino acid substitutions in the LBD of Upc2 and changes in protein secondary structures were observed. In addition, these isolates exhibited a significant increase in plasma membrane ergosterol content. Resistance and virulence were inversely correlated while increased cell wall chitin concentration does not seem to be linked to resistance since even though we observed an increase in chitin concentration, it was not statistically significant. Conclusions: The azole-resistant C. albicans isolates harboured novel amino acid substitutions in the LBD of Upc2 which are speculated to induce an increase in plasma membrane ergosterol content, preventing the binding of azoles to their target, resulting in resistance.

Invasive fungal infections are rapidly increasing, and the opportunistic pathogenic Candida species are the fourth most common cause of nosocomial systemic infections. The current antifungal classes, of which azoles are the most widely used, all have shortcomings. Azoles are generally considered fungistatic rather than fungicidal, they do not actively kill fungal cells and therefore resistance against azoles can be rapidly acquired. Combination therapies with azoles provide an interesting therapeutic outlook and agents limiting iron are excellent candidates. We summarize how iron is acquired by the host and transported towards both storage and iron‐utilizing organelles. We indicate whether these pathways alter azole susceptibility and/or tolerance, to finally link these transport mechanisms to mitochondrial iron availability. In this review, we highlight putative novel intracellular iron shuffling mechanisms and indicate that mitochondrial iron dynamics in relation to azole treatment and iron limitation is a significant knowledge gap. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Nakaseomyces glabratus (N. glabratus) formerly known as Candida glabrata (C. glabrata), is an endogenous opportunistic pathogen, which is generally located in the gastrointestinal tract but can spread in immunocompromised patients. N. glabratus is the second most common pathogen that causes candidemia in several countries. N. glabratus virulence factors may increase antifungal resistance and reduce the number of available treatment options. High resistance to azoles and increasing resistance to echinocandins have been previously reported in N. glabratus.To establish the distribution of N. glabratus isolates in Europe and its drug susceptibility/resistance in each country over the last 7 years.The search was performed across three databases: PubMed, Scopus and Scielo, using the MeSH terms: “Candida glabrata”, “Nakaseomyces glabratus”, “Europe”, “resistance” and “Epidemiology” exclusively in English. All available information from January 2002 to December 2022 was included, excluding reviews, meta‐analyses and book chapters.Fifty‐seven articles with information on antifungal susceptibility in Europe were retrieved and analysed with a total of 15,400 reported C. glabrata isolates. Remarkably, nations that presented the maximum number of cases during the study period included the United Kingdom (n = 7241, 47.02%), France (n = 3190, 20.71%), Spain (n = 900, 5.84%), Hungary (n = 745, 4.84%) and Italy (n = 486, 3.16%). C. glabrata isolates presented resistance to azoles [voriconazole (n = 2225, 14.45%), fluconazole (n = 1612, 10.47%), itraconazole (n = 337, 2.19%) and clotrimazole (n = 89, 0.58%)], increased resistance to echinocandins, especially to anidulafungin (n = 138, 0.89%), and high sensitivity to amphotericin B.The number of candidemia cases associated with triazole‐resistant N. glabratus isolates have been increasing in Europe. Therefore, echinocandins and amphotericin B can be considered optional empirical treatments; however, antifungal susceptibility testing is required to determine the best therapeutic options. [ABSTRACT FROM AUTHOR]

The reactivity of imidazole, pyrazole, 1,2,4‐triazole, 1,2,3‐triazole, and tetrazole with acetone (propan‐2‐one) has been studied by 1H and 13C NMR using acetone‐d6 as solvent at temperatures ranging from 173 to 300 K at 10 K intervals. Simultaneously, the reaction has been theoretically calculated at the B3LYP/6‐311++G(d,p) level, and experimental and theoretical results have been compared. The equilibrium constants between azoles and adducts α,α‐dimethyl‐azole‐methanol were analyzed, assuming that the straight part of the plots –R ln Ke vs. 1/T can be used to determine ΔH and ΔS. Calculated and experimental data are related, but the theoretical values are proportionally higher. The tautomerism of triazoles and tetrazole has been considered in order to discuss the reactions. [ABSTRACT FROM AUTHOR]

Plenodomus lingam (Leptosphaeria maculans) and P. biglobosus (L. biglobosa) are fungi causing Phoma leaf spot/stem canker, an international damaging disease of oilseed rape (Brassica napus) and other brassicas. In Europe, fungicides used for disease management are mainly sterol 14α‐demethylase (CYP51) inhibitors (DMIs/azoles); quinone‐outside inhibitors (QoIs) and succinate dehydrogenase inhibitors (SDHIs) are also used. Decreased DMI sensitivity has emerged in Australian and eastern European P. lingam populations and is mediated by CYP51 promoter inserts resulting in target site overexpression. In this study using in vitro sensitivity testing, we report decreased DMI (prothioconazole‐desthio, mefentrifluconazole) sensitivity in modern western European P. lingam isolates (collected 2022–2023) compared to older baseline (1992–2005) isolates. Around 85% of modern western European P. lingam isolates collected, for which the CYP51 promoter region was sequenced, carried a promoter insert, but target site alterations were not detected. Six different CYP51 promoter inserts were identified, most commonly a 237 bp fragment of the Sahana transposable element. Inserts were associated with an approximately 3‐ to 10‐fold decrease in sensitivity to the DMIs tested. In contrast to P. lingam, PCR screening revealed CYP51 promoter inserts were absent in modern western European P. biglobosus isolates (2021–2023). Combined data indicate P. lingam isolates lacking an insert were similarly (or slightly more) sensitive to the DMIs tested for P. biglobosus, whereas those carrying an insert were slightly less sensitive than P. biglobosus. No evidence for substantive sensitivity shifts to the QoI (pyraclostrobin) or SDHI (boscalid) fungicides tested was obtained for either Plenodomus species. [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]

Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11) of the ergosterol biosynthesis pathway. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold Aspergillus fumigatus strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not trigger comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3β,6α-diol, the "toxic diol" responsible for the fungistatic activity against yeasts, is not required for the fungicidal effects in A. fumigatus. While ERG3-lacking yeasts are azole resistant, ERG3-lacking A. fumigatus becomes more susceptible. Mutants lacking mitochondrial complex III functionality, which are much less effectively killed, but strongly inhibited in growth by azoles, convert eburicol more efficiently into the supposedly "toxic diol". We propose that the mode of action of azoles against A. fumigatus relies on accumulation of eburicol which exerts fungicidal effects by triggering cell wall carbohydrate patch formation. Azole antifungals inhibit the ergosterol biosynthesis enzyme CYP51, but their effects on fungal viability and growth vary greatly among fungal species. Here, the authors provide evidence that the mode of action of azoles against Aspergillus fumigatus relies on accumulation of the CYP51 substrate eburicol, which exerts fungicidal effects by triggering cell-wall carbohydrate patch formation. [ABSTRACT FROM AUTHOR]

N,N‐dialkylbenzofuran‐ and N,N‐dialkylbenzothiophene‐2‐carboxamides were readily prepared from bare benzofuran and benzothiophene by deprotocupration followed by trapping with N,N‐dialkylcarbamoyl chlorides. They were reacted with 2‐benzofuryl‐ and 2‐benzothienyllithiums to form symmetrical and unsymmetrical diarylketones, or underwent deprotolithiation‐electrophilic trapping sequences at their 3 position. From 3‐iodinated derivatives, copper‐catalysed N‐arylation of azoles was performed, followed by lithium amide‐promoted cyclisation, to give 'tripentone' analogues. The diarylketones were also iodinated at their 3,3' positions and then engaged in the copper‐promoted double N‐arylation of anilines, giving rise to a family of original pentacyclic derivatives. A preliminary assessment of their electrochemical and biological properties was carried out, showing promising results against the proliferation of melanoma cells. [ABSTRACT FROM AUTHOR]

Background: The resistance of Aspergillus flavus to the azole antifungal drugs is an emerging problem. Mutations in the molecular targets of the azole antifungals ‐ CYP 51 A, B and C ‐ are possible mechanisms of resistance, but data to confirm this hypothesis are scarce. In addition, the behaviour of resistant strains in vitro and in vivo is not yet understood. Objectives: This study had 3 objectives. The first was to compare the sequences of CYP51 A, B and C in resistant and susceptible strains of A. flavus. The second was to look for the existence of a fitness cost associated with resistance. The third was to evaluate the activity of voriconazole and posaconazole on resistant strains in the Galleria mellonella model. Methods: The CYP51 A, B and C sequences of seven resistant strains with those of four susceptible strains are compared. Fitness costs were assessed by growing the strains in RPMI medium and testing their virulence in G. mellonella larvae. In addition, G. mellonella larvae infected with strains of A. flavus were treated with voriconazole and posaconazole. Results: In the CYP51A sequences, we found the A91T, C708T and A1296T nucleotide substitutions only in the resistant strains. The resistant strains showed a fitness cost with reduced in vitro growth and reduced virulence in G. mellonella. In vivo resistance to posaconazole is confirmed in a strain with the highest MIC for this antifungal agent. Conclusions: These results allow to conclude that some substitutions in CYP51 genes, in particular CYP51A, contribute to resistance to azole drugs in A. flavus. The study of the relationship between drug dosage and treatment duration with resistance and the reduction of fitness costs in resistant strains is a major perspective of this study. This work could help to establish recommendations for the treatment of infections with resistant strains of A. flavus. [ABSTRACT FROM AUTHOR]

Background: Candida vulturna is an emerging pathogen belonging to the Metshnikowiaceae family together with Candida auris and Candida haemulonii species complex. Some strains of this species were reported to be resistant to several antifungal agents. Objectives: This study aims to address identification difficulties, evaluate antiungal susceptibilities and explore the molecular mechanisms of azole resistance of Candida vulturna. Methods: We studied five C. vulturna clinical strains isolated in three Colombian cities. Identification was performed by phenotypical, proteomic and molecular methods. Antifungal susceptibility testing was performed following CLSI protocol. Its ERG11 genes were sequenced and a substitution was encountered in azole resistant isolates. To confirm the role of this substitution in the resistance phenotype, Saccharomyces cerevisiae strains with a chimeric ERG11 gene were created. Results: Discrepancies in identification methods are highlighted. Sequencing confirmed the identification as C. vulturna. Antifungal susceptibility varied among strains, with four strains exhibiting reduced susceptibility to azoles and amphotericin B. ERG11 sequencing showed a point mutation (producing a P135S substitution) that was associated with the azole‐resistant phenotype. Conclusions: This study contributes to the understanding of C. vulturna's identification challenges, its susceptibility patterns, and sheds light on its molecular mechanisms of azole resistance. [ABSTRACT FROM AUTHOR]

The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles. [ABSTRACT FROM AUTHOR]

Based on cations of diazo group, imino group and nitrogen-rich azole, the synthetic strategies and properties of az-ole, bis-azoles and fused heterocycle-based zwitterionic energetic materials were reviewed in recent ten years, and the influence of molecular structures on their energetic performance and stability was clarified. Meanwhile, the future directions on the zwitterionic energetic materials based on nitrogen-rich azoles were pointed out: (1) Diazonium zwitterionic energetic materials outperform DDNP in detonation performance, warranting deeper research into heat-resistant explosives, harnessing alkyl-bridged, fused-ring nitrogen-rich azoles. (2) The imino-gem-dinitromethyl zwitterionic energetic materials can alleviate the sensitivity of diazonium salts, but their thermal stability still requires further optimization. (3) The modifiable structure of nitrogen-rich azole cation energetic salts and explosive groups, and synergies with ionic salts, cocrystals should be fully explored, which could effectively expand their applications in high-energy insensitive explosives, high-energy propellants, green gas generators, and heat-resistant energetic materials. [ABSTRACT FROM AUTHOR]

In the realm of energetic materials research, there has been notable interest in energetic coordination compounds (ECCs) owing to their remarkable thermal stability and resistance to mechanical stimuli. This study successfully demonstrated the synthesis of an azole-based C–C bonded ECC1 under ambient conditions. A comprehensive characterization study, employing techniques such as IR, TGA-DSC, NMR and single-crystal X-ray diffraction analysis, was conducted. The bulk compound was investigated by PXRD analysis. In-depth exploration of its physicochemical and energetic performance revealed good detonation properties such as a detonation velocity (VOD) of 8553 m s−1 and a detonation pressure (DP) of 36.2 GPa, which surpass those of heat resistant explosives HNS and TATB. Due to its remarkable high melting and onset decomposition temperature (278/379 °C), it also outperforms the benchmark explosive HMX (279 °C) and the heat-resistant explosive HNS (318 °C) and shows a high impact sensitivity (IS) of 20 J and friction sensitivity (FS) of 360 N. The study also employed Hirshfeld surface and 2D fingerprint analysis to elucidate the close contact of atoms within the molecules. The combination of high detonation properties, thermal stability, and low sensitivity makes the synthesized ECC1 intriguing for further investigations and suggests its potential applications as a safe and high-energy-dense material. [ABSTRACT FROM AUTHOR]

Treatment of 2-methylsulfinylbenzazoles with triflic anhydride in the presence of phenols yields the corresponding 4-(p-hydroxyphenyl)-2-methylsulfanylbenzazoles. This regioselective dehydrative C–H/C–H coupling arylation represents a rare example of functionalizations on the benzene rings of benzo-fused azoles. [ABSTRACT FROM AUTHOR]

Introduction: Fungal diseases are frequently associated with elevated mortality rates in elasmobranchs. Currently, there is a notable absence of scientifically validated therapeutic medications that can ensure both effectiveness and safety when administered to this group of animals. The empirical prescription of azole antifungal agents, particularly voriconazole, has been posited as a potentially efficacious treatment approach for addressing most common mycoses in sharks and rays. However, there are still no published pharmacokinetic studies supporting its use in elasmobranchs and there is a lack of scientific base for its utilization in elasmobranchs. Methods: For this study, voriconazole was administered intravenously (IV) and intramuscularly (IM), at a single dose of 4 mg/kg to six adult undulate skates (Raja undulata). A washout period of 8 weeks was left between each route of administration. Blood samples were collected both before and at ten predetermined intervals after each dosing (0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, and 36 h after drug administration). Plasma concentrations were quantified using a validated high-performance liquid chromatography method, and pharmacokinetic (PK) data was analyzed through non-compartmental methods. Results: The mean extrapolated concentration at 0 h (C0) after IV administration was 27.19 ± 7.15 µg/mL and the mean peak plasma concentrations (Cmax) ± SEM after IM administration resulted 2.98 ± 0.28 µg/mL at a mean time to maximum concentration (T max) of 1.33 ± 0.17 h. Terminal half-lives were calculated and resulted 11.18 ± 1.32 h for IV injections and 9.59 ± 1.38 h for IM injections. The area under the curve extrapolated to infinity was determined as 58.14 ± 2.79 h·µg/ml following IV injections and 37.60 ± 6.67 h·µg/ml following IM injections. The IM-administered voriconazole exhibited a mean absolute bioavailability of 64.67 ± 11.47%. Discussion: These discoveries provide backing for the possible application of voriconazole through the intramuscular route in undulate skates and support using lower dosage regimens compared to those required for oral administration, emphasizing the importance of conducting further pharmacokinetic studies with antifungals in elasmobranchs. [ABSTRACT FROM AUTHOR]

Herein, a series of novel ferrocenyl/phenyl/thiophenyl‐azoles was disclosed by vinylic amination of ferrocenyl/phenyl/thiophenyl substituted β‐chloro cinnamaldehydes and acrylonitriles. A highly economical and robust chalcogen‐stabilized iron selenide carbonyl cluster Fe3Se2(CO)9 worked as an efficient catalyst under aerobic conditions. The amination of ferrocenyl/phenyl/thiophenyl substituted β‐chloro‐vinylic Csp2‐Cl with azole derivatives was fully established and fabrication of the Csp2‐N bond was completely supported by various spectral analysis. Moreover, wide range of substrates with functionally different azoles were investigated for the present reaction and good to excellent transformation was recorded. Some of the selected ferrocenated azole derivatives were screened for anti‐cancer activity against the prostate cancer cells (PC‐3) and found to be highly active at low concentration of 5.77 μM with IC50 value. Furthermore, HOMO and LUMO levels and energy gap of some selected compounds were calculated by the density functional theory (DFT). [ABSTRACT FROM AUTHOR]

Background: The prevalence of Candida glabrata healthcare‐associated infections is on the rise worldwide and in Lebanon, Candida glabrata infections are difficult to treat as a result of their resistance to azole antifungals and their ability to form biofilms. Objectives: The first objective of this study was to quantify biofilm biomass in the most virulent C. glabrata isolates detected in a Lebanese hospital. In addition, other pathogenicity attributes were evaluated. The second objective was to identify the mechanisms of azole resistance in those isolates. Methods: A mouse model of disseminated systemic infection was developed to evaluate the degree of virulence of 41 azole‐resistant C. glabrata collected from a Lebanese hospital. The most virulent isolates were further evaluated alongside an isolate having attenuated virulence and a reference strain for comparative purposes. A DNA‐sequencing approach was adopted to detect single nucleotide polymorphisms (SNPs) leading to amino acid changes in proteins involved in azole resistance and biofilm formation. This genomic approach was supported by several phenotypic assays. Results: All chosen virulent isolates exhibited increased adhesion and biofilm biomass compared to the isolate having attenuated virulence. The amino acid substitutions D679E and I739N detected in the subtelomeric silencer Sir3 are potentially involved— in increased adhesion. In all isolates, amino acid substitutions were detected in the ATP‐binding cassette transporters Cdr1 and Pdh1 and their transcriptional regulator Pdr1. Conclusions: In summary, increased adhesion led to stable biofilm formation since mutated Sir3 could de‐repress adhesins, while decreased azole susceptibility could result from mutations in Cdr1, Pdh1 and Pdr1. [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]

Organic azides are universally important in many areas of chemistry, particularly in organic synthesis. The availability of these azides often depends on specific transfer reagents and reaction conditions, or only work with certain substrates. Customizable transfer reagents offer a safe and direct pathway to desired compounds, thereby increasing the availability of N‐alkyl‐azides. In an effort to streamline the synthesis and broaden the scope of N‐azidoethyl‐containing molecules, three different versatile azidoethyl transfer reagents were synthesized and a uniform reaction protocol with azoles as substrates, including imidazole, pyrazole, 1,2,3‐triazole, 1,2,4‐triazole, and tetrazole was established. The resulting azidoethyl‐azoles were further used as ligands for energetic coordination compounds in an effort to create new lead‐free primary explosives. A comprehensive characterization of the transfer reagents, the azidoethyl‐containing products, and energetic coordination compounds was conducted using multinuclear nuclear magnetic resonance (NMR), elemental analysis, mass spectrometry, and infrared spectroscopy (IR). Furthermore, their thermal stability and sensitivity toward friction and impact were determined as well as the detonation properties were calculated by using the EXPLO5 code. [ABSTRACT FROM AUTHOR]

Two new zinc azole complexes incorporated Strandberg-type cluster-based solids, namely (Hpz)6{Zn(pz)4(H2O)2}[{Zn(pz)2P2Mo5O23}2]·8H2O (1) and (Himi)4{Zn(imi)3P2Mo5O23}·7H2O (2) were crystallized using isomeric azole ligands, i.e., pyrazole (pz) and imidazole (imi), respectively. While solid 1 crystallized in triclinic system with space group P-1 with cell parameters a = 9.5647(15), b = 12.558(2), c = 20.340(3) Å, α = 75.907(7), β = 84.727(6), γ = 87.525(7)°, Z = 1; 2 crystallized in orthorhombic system with space group P212121 having cell parameters a = 12.048(3), b = 19.561(5), c = 20.732(5) Å, Z = 4. Both pyrazole and imidazole can form a complex with zinc centres to form an extended solid in 1 and a derivatized Strandberg-type cluster in 2. Interestingly, 1 is a new supramolecular isomer of previously reported solid viz., (pz)[{Zn(pz)3}3{P2Mo5O23}]·2H2O and 2 is the only example wherein a zinc imidazole complex has derivatized a Strandberg-type cluster. Detailed structure analysis of 1 and 2 was carried out, and the role of tectons in dictating the self-assembly of these solids was evaluated. In addition, a solid-state photoluminescence study was carried out for 1 and 2 at room temperature. Two zinc azole complexes incorporated Strandberg-type cluster-based solids and have been crystallized. While 1 is a new supramolecular isomer of (pz)[{Zn(pz)3}3{P2Mo5O23}]·2H2O; 2 is the only example wherein a zinc imidazole complex has derivatized a Strandberg-type cluster. Apart from detailed structural analysis, solid-state photoluminescence of solids has also been investigated. [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]

Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic system, and recipients of organ transplants. Historically, drug-susceptible strains have been linked to clonal outbreaks. However, worldwide studies started since 2018 have reported severe outbreaks among adults caused by fluconazole-resistant strains. Outbreaks caused by fluconazole-resistant strains are associated with high mortality rates and can persist despite strict infection control strategies. The emergence of resistance threatens the efficacy of azoles, which is the most widely used class of antifungals and the only available oral treatment option for candidaemia. The fact that most patients infected with fluconazole-resistant strains are azole-naive underscores the high potential adaptability of fluconazole-resistant strains to diverse hosts, environmental niches, and reservoirs. Another concern is the multidrug-resistant and echinocandin-tolerant C parapsilosis isolates, which emerged in 2020. Raising awareness, establishing effective clinical interventions, and understanding the biology and pathogenesis of fluconazole-resistant C parapsilosis are urgently needed to improve treatment strategies and outcomes.

The cultivation of oil palms is of great importance in the global agricultural industry due to its role as a primary source of vegetable oil with a wide range of applications. However, the sustainability of this industry is threatened by the presence of pathogenic fungi, particularly Ganoderma spp., which cause detrimental oil palm disease known as basal stem rot (BSR). This unfavorable condition eventually leads to significant productivity losses in the harvest, with reported yield reductions of 50–80 % in severely affected plantations. Azole-based fungicides offer potential solutions to control BSR, but their efficacy is hampered by limited solubility, penetration, distribution, and bioavailability. Recent advances in nanotechnology have paved the way for the development of nanosized delivery systems. These systems enable effective fungicide delivery to target pathogens and enhance the bioavailability of azole fungicides while minimising environmental and human health risks. In field trials, the application of azole-based nanofungicides resulted in up to 75 % reduction in disease incidence compared to conventional fungicide treatments. These innovations offer opportunities for the development of sustainable agricultural practices. This review highlights the importance of oil palm cultivation concerning the ongoing challenges posed by pathogenic fungi and examines the potential of azole-based fungicides for disease control. It also reviews recent advances in nanotechnology for fungicide delivery, explores the mechanisms behind these nanodelivery systems, and emphasises the opportunities and challenges associated with azole-based nanofungicides. Hence, this review provides valuable insights for future nanofungicide development in effective oil palm disease control.

[Display omitted] New 7-amino-6-nitro-substituted [1,2,4]triazolo- and pyrazolo[1,5- a ]pyrimidines were synthesized by an alternative strategy based on amino azoles and 2-nitro-3-(p -tolylamino)acrylonitrile. Unexpectedly, 3,5-dinitro- N -(p -tolyl)pyridine-2,6-diamine was formed when the starting 5-amino-1,2,4-triazoles contained NO 2 or CF 3 substituents. [ABSTRACT FROM AUTHOR]

Introduction. Vulvovaginal candidiasis is an extremely common pathology of the female genital organs, leading to a long-term recurrent course and multiple complications. Although currently it is widely known about developing antibiotic resistance of bacterial pathogens, it is necessary to remember about similar phenomenon observed in other groups of infectious agents. In this regard, fungal infection also requires development of new therapeutic techniques and medicinal antifungal drugs, such as ibrexafungerp. Aim: to analyze available publications revealing the mechanism of action, efficacy, antifungal spectrum and results of clinical trials for a new oral antifungal drug ibrexafungerp. Materials and Methods. A search for publications in the electronic databases PubMed, eLibrary and ClinicalTrials.gov, published over the last 25 years was conducted using the following keywords in Russian and English: “candidiasis”, “vulvovaginal candidiasis”, “antifungal drugs”, “ibrexafungerp”, “clinical trials”, “mechanism of action”. Articles were assessed according to PRISMA guidelines. The titles and abstracts of identified publications were independently reviewed to retrieve relevant full text studies. After the selection procedure, 46 articles were included in the review. Results. This review provides information on the creation of the drug ibrexafungerp, its mechanism of action, the activity against a relatively wide range of pathogens, as well as the results from 13 ongoing and completed clinical trials in patients with fungal infection. Conclusion. The analysis of ibrexafungerp-related clinical studies showed its good oral bioavailability, high antifungal efficacy, so that its one-day dosage may further eliminate a need for unnecessarily long hospitalization and complex dosing schedules, thereby increasing adherence to therapy and odds for treatment success.

From the standpoint of chemical structures, the organic backbones of energetic materials can be classified into aromatic rings, nonaromatic rings, and open chains. Although the category of aromatic energetic compounds exhibits several advantages in the regulation of energetic properties, the nonaromatic heterocycles, assembling nitramino explosophores with simple alkyl bridges, still have prevailed in benchmark materials. The methylene bridge plays a pivotal role in the constructions of the classic nonaromatic heterocycle-based energetic compounds, e.g., hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), whereas ethylene bridge is the core moiety of state-of-the-art explosive 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20). In this context, it is of great interest to employ simple and practical bridges to assemble aromatic and nonaromatic nitrogen-rich heterocycles, thereby expanding the structural diversity of energetic materials, e.g., bridged and fused nitrogen-rich poly-heterocycles. Furthermore, alkyl-bridged poly-heterocycles highlight the potential for the open chain type of energetic materials. In this review, the development of alkyl bridges in linking nitrogen-rich heterocycles is presented, and the perspective of the newly constructed energetic backbones is summarized for the future design of advanced energetic materials.

A stereoselective N-alkenylation of azoles with alkynes and iodine(III) electrophile is reported. The reaction between various azoles and internal alkynes is mediated by benziodoxole triflate as the electrophile in a trans-fashion, affording azole-bearing vinylbenziodoxoles in moderate to good yields. The tolerable azole nuclei include pyrazole, indazole, 1,2,3-triazole, benzotriazole, and tetrazole. The iodanyl group in the product can be leveraged as a versatile synthetic handle, allowing for the preparation of hitherto inaccessible types of densely functionalized N-vinylazoles.

Triazoles are widely used to control pathogenic fungi. They inhibit the ergosterol biosynthetic pathway, but the precise mechanisms leading to fungicidal activities in many fungal pathogens are poorly understood. Here, we elucidate the mode of action of epoxiconazole and metconazole in the wheat pathogen Zymoseptoria tritici and the rice blast fungus Magnaporthe oryzae. We show that both azoles have fungicidal activity and reduce fluidity, but not integrity, of the plasma membrane. This impairs localisation of Cdc15-like F-BAR proteins, resulting in defective actin ring assembly and incomplete septation. However, mutant studies and pharmacological experiments in vitro and in planta show that azole lethality is due to a combination of reactive oxygen species-induced apoptosis and macroautophagy. Simultaneous inhibition of both programmed cell death pathways abolishes azole-induced cell death. Other classes of ergosterol biosynthesis inhibitors also induce apoptosis and macroautophagy, suggesting that activation of these two cell death pathways is a hallmark of ergosterol synthesis-targeting fungicides. This knowledge will inform future crop protection strategies. Antifungal azoles inhibit ergosterol biosynthesis, but how that leads to fungistatic or fungicidal activities in many pathogenic fungi is poorly understood. Here, Schuster, Kilaru & Steinberg show that azole lethality in the plant pathogens Zymoseptoria tritici and Magnaporthe oryzae is due to a combination of reactive oxygen species-induced apoptosis and macroautophagy. [ABSTRACT FROM AUTHOR]

This report describes the one‐pot direct N‐acylation of indazole with carboxylic acids using our previously developed 4‐(N,N‐dimethylamino)pyridine N‐oxide (DMAPO)/di‐tert‐butyl dicarbonate (Boc2O) system. This simple system provides N1‐acyl indazoles in high yield with high N1 selectivities and does not require the use of activated derivatives of carboxylic acids or high temperatures. This new method exhibits a wide substrate scope (>40 examples). In addition, a new synthesis of N1‐functionalized alkyl indazoles utilizing N1‐acyl indazoles as starting materials was achieved. This stepwise protocol is useful for the selective synthesis of structurally diverse N1‐functionalized alkyl indazoles, which are difficult to synthesize by other methods such as the Mitsunobu reaction and classical SN2 alkylation of indazole. [ABSTRACT FROM AUTHOR]

A novel electrochemical method is described for the direct oxidative C--N coupling of tetrahydroquinolines and azoles, enabling the synthesis of dihydroquinoline derivatives under mild reaction conditions. In this approach, 2,2,6,6-tetramethylpiperidinooxy (TEMPO) serves as a redox mediator, and NaI not only acts as an electrolyte but also functions as an iodine mediator. The reaction exhibits good functional group tolerance and high atomic economy, resulting in moderate to excellent yields of the desired dihydroquinoline derivatives. Furthermore, by adjusting the reaction conditions, the corresponding quinoline derivatives can also be selectively obtained. [ABSTRACT FROM AUTHOR]

General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp3)−C(sp3) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process. Catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein the authors describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. [ABSTRACT FROM AUTHOR]

Breast cancer, an epithelial malignant tumor that occurs in the terminal ducts of the breast, represents the most prevalent malignancy in women, with over 2 million new diagnoses annually throughout the world. Chemotherapy remains a mainstay in breast cancer therapy, but drug resistance and severe side effects are the major causes for treatment failure. Sulfonamides could act on diverse proteins, enzymes, and receptors and demonstrated promising anti-breast cancer potential. In particular, sulfonamide hybrids have the potential to overcome drug resistance and reduce the side effects since hybrid molecules could act on dual/multiple targets simultaneously. This review focuses on the anti-breast cancer activity, structure-activity relationships, and mechanisms of action of sulfonamide-five-membered heterocycle hybrids, including sulfonamide-azole hybrids, sulfonamide-7-azaindole/indole/oxindole/indoline hybrids, sulfonamide-furan hybrids, and sulfonamide-thiophene hybrids, covering articles published from 2020 to present, to open new avenues for the exploration of novel more effective and multitargeted candidates. [ABSTRACT FROM AUTHOR]

Candida albicans and C. glabrata express exporters of the ATP-binding cassette (ABC) superfamily and address them to their plasma membrane to expel azole antifungals, which cancels out their action and allows the yeast to become multidrug resistant (MDR). In a way to understand this mechanism of defense, we describe the purification and characterization of Cdr1, the membrane ABC exporter mainly responsible for such phenotype in both species. Cdr1 proteins were functionally expressed in the baker yeast, tagged at their C-terminal end with either a His-tag for the glabrata version, cg Cdr1-His, or a green fluorescent protein (GFP) preceded by a proteolytic cleavage site for the albicans version, ca Cdr1-P-GFP. A membrane Cdr1-enriched fraction was then prepared to assay several detergents and stabilizers, probing their level of extraction and the ATPase activity of the proteins as a functional marker. Immobilized metal-affinity and size-exclusion chromatographies (IMAC, SEC) were then carried out to isolate homogenous samples. Overall, our data show that although topologically and phylogenetically close, both proteins display quite distinct behaviors during the extraction and purification steps, and qualify cg Cdr1 as a good candidate to characterize this type of proteins for developing future inhibitors of their azole antifungal efflux activity. • This paper describes the purification of a clinically relevant drug transporter of pathogenic fungi • It includes a detailed methodology on working with membrane proteins, including detergent screening, purification and characterization • The use of fluorescence quenching allows to measure the affinity of the protein for its ligands • NanoDifferential Scanning Fluorimetry showed a differential stabilization of the protein, thus making it an interesting tool to screen for future inhibitors • The purification of an ATPase active protein paves the way for structural studies of these transporters. [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]

We report an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldiazonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline intermediates which undergo an iodine-mediated oxidative transformation coupled with C–H functionalization to yield the indole derivatives. [ABSTRACT FROM AUTHOR]