Selective defluorinative functionalization of trifluoromethylarenes(ArCF3)to obtain the pharmaceutically commonα,α-difluorobenzylic motif is an attractive and elegant synthetic route.Over the past decade,although C(...Selective defluorinative functionalization of trifluoromethylarenes(ArCF3)to obtain the pharmaceutically commonα,α-difluorobenzylic motif is an attractive and elegant synthetic route.Over the past decade,although C(sp^(3))-F bonds functionalization have been greatly developed,catalytic cross-coupling of trifluoromethylarenes with C-H of terminal alkynes remains a challenge.Here,we report an approach to achieve Sonogashira-type cross-coupling of trifluoromethylarenes with terminal alkynes C(sp)-H bonds via photoredox and Cu/L dual catalysis.Tridentate anionic ligand is pivotal to realize this C-H sp-sp^(3) cross-coupling.Moreover,this unique catalytic system is also suitable for cross-coupling of C(sp^(3))-F bonds with azoles C(sp^(2))-H bonds.A series of trifluoromethylarenes,terminal alkynes and azoles with various functional groups are compatible with this protocol affording a variety of defluoroalkynylation or defluoroazolation products.Preliminary mechanistic studies indicated that deprotonated BINOL involved as a photocatalyst to activate ArCF3 rather than a ligand to the metal.展开更多
Azole fungicides(AFs)play an important role in the prevention and treatment of fungal diseases in agricultural crops.However,limited studies are addressing the fate and ecological risk of AFs in the urban water cycle ...Azole fungicides(AFs)play an important role in the prevention and treatment of fungal diseases in agricultural crops.However,limited studies are addressing the fate and ecological risk of AFs in the urban water cycle at a large watershed scale.To address this gap,we investigated the spatiotemporal distribution and ecological risk of twenty AFs in the lower reaches of the Yangtze River across four seasons.Carbendazim(CBA),tebuconazole(TBA),tricyclazole(TCA),and propiconazole(PPA)were found to be the dominant compounds.Their highest concentrations were measured in January(188.3 ng/L),and November(2197.1 ng/L),July(162.0 ng/L),and November(1801.9 ng/L),respectively.The comparison between wastewater treatment plants(WWTPs)effluents and surface water suggested that industrial WWTPs are major sources of AFs in the Yangtze River.In particular,TBA and PPA were found to be the most recalcitrant AFs in industrial WWTPs,while difenoconazole(DFA)was found to be the most potent pollutant in municipal WWTPs,with an average removal rate of less than60%.The average risk quotient(RQ)for the entire AFs was 6.45 in the fall,which was higher than in January(0.98),April(0.61),and July(0.40).This indicates that AFs in surface water posed higher environmental risks during the dry season.Additionally,the exposure risk of AFs via drinking water for sensitive populations deserves more attention.This study provides benchmark data on the occurrence of AFs in the lower reaches of the Yangtze River,and offers suggestions for better reduction of AFs.展开更多
Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias....Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.展开更多
Objective: To appraise the activity of voriconazole against Leishmania major(L. major) in vitro and its effectiveness on wound regeneration in cutaneous leishmaniasis in BALB/c mice Methods: The IC_(50) of voriconazol...Objective: To appraise the activity of voriconazole against Leishmania major(L. major) in vitro and its effectiveness on wound regeneration in cutaneous leishmaniasis in BALB/c mice Methods: The IC_(50) of voriconazole against promastigotes and intra-macrophage amastigotes of L. major was investigated in vitro. The in vivo study was performed by treating the L. major infected BALB/c mice. When the wounds appeared in the base of tail, treatment was started by administration of 30 mg/kg voriconazole for 28 consecutive days orally. Results: The IC_(50) of voriconazole against promastigotes and intra-macrophage amastigotes were 0.74 and 0.89μM, respectively. Voriconazole decreased lipid peroxidation and IL-6 level. Histopathologica findings indicated accelerated healing in the voriconazole treated group compared to other groups. Conclusions: Our results demonstrate that voriconazole can be an option in treating the cutaneous leishmaniasis by L. major.展开更多
Azole derivatives such as 2-mercaptobenzothiazole(MBT) and 2-mercaptobenzimidazole(MBI) were introduced as corrosion inhibitors into the interlayer space of sodium montmorillonite clay(Na+-MMT). The corrosion protecti...Azole derivatives such as 2-mercaptobenzothiazole(MBT) and 2-mercaptobenzimidazole(MBI) were introduced as corrosion inhibitors into the interlayer space of sodium montmorillonite clay(Na+-MMT). The corrosion protection behavior of mild steel in solutions containing MBT, MBI, MMT + MBT, MMT + MBI, Na^+-MMT, and NaCl(3.5 wt%) was evaluated using polarization and electrochemical impedance spectroscopy(EIS). Also, the release of penetrated species into the medium from the clay nanocarriers was evaluated using ultraviolet-visible(UV-Vis) spectroscopy. Small-angle X-ray scattering(SAXS) confirmed the insertion of MBT and MBI into the inner space of the clay layers and the interaction between two organic and inorganic phases. Scanning electron microscopy(SEM) was used to assess the morphology of the surface of the steel samples after the samples had been immersed for 24 h in the extraction solution. The corrosion protection in the solutions with clay nanocarriers containing MBT and MBI was better than that in solutions without MMT. The UV-Vis results showed that the release of MBI species from Na+-MMT nanocarriers in neutral pH was far lower than that of MBT species.展开更多
Rechargeable lithium-sulfur(Li-S)batteries are considered one of the most promising energy storage techniques owing to the high theoretical energy density.However,challenges still remain such as the shuttle effect of ...Rechargeable lithium-sulfur(Li-S)batteries are considered one of the most promising energy storage techniques owing to the high theoretical energy density.However,challenges still remain such as the shuttle effect of lithium polysulfides(LPSs)and the instability of lithium metal anode.Herein,we propose to use nitrogen-rich azoles,i.e.,triazole(Ta)and tetrazole(Tta),as trifunctional electrolyte additives for Li-S batteries.The azoles afford strong lithiophilicity for the chemisorption of LPSs.The density functional theory and experimental analysis verify the presence of Li bonds between the azoles and LPSs.The azoles can also interact with lithium salt in the electrolyte,leading to increase ionic conductivity and lithiumion transference number.Moreover,the azoles render particle-like lithium deposition on the lithium metal anode,leading to superlong cycling of a Li symmetric cell.The Li-S batteries with Ta and Tta exhibit the initial discharge capacity of 1425.5 and 1322.2 m Ah g^(-1),respectively,at 0.2 C rate,and promising cycling stability.They also enable enhanced cycling performance of a Li-organosulfide battery.展开更多
Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a su...Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B(RAB) and riccardin D(RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.展开更多
Widespread use of azole fungicides and low removal efficiency in wastewater treatment plants(WWTPs) have led to the elevated concentration of azole fungicides in receiving environment. However, there was limited resea...Widespread use of azole fungicides and low removal efficiency in wastewater treatment plants(WWTPs) have led to the elevated concentration of azole fungicides in receiving environment. However, there was limited research about the removal mechanism of azole fungicides in the biological treatment of WWTPs. Imidazole fungicide climbazole and triazole fungicide fluconazole were selected to investigate the biodegradation mechanism of azole fungicides in activated sludge under aerobic conditions. Climbazole was found to be adsorbed to solid sludge and resulted in quick biodegradation. The degradation of climbazole in the aerobic activated sludge system was fitted well by the first-order kinetic model with a half-life of 5.3 days, while fluconazole tended to stay in liquid and had only about 30% of loss within 77 days incubation. Ten biotransformation products of climbazole were identified by high resolution mass spectrometry using suspect and non-target screening method. But no biodegradation products of fluconazole were identified due to its limited removal. The possible biodegradation pathways for climbazole were proposed based on the products identification and pathway prediction system, and involves oxidative dehalogenation, side chain oxidation and azole ring loss. The findings from this study suggest that it should be a concern for the persistence of fluconazole in the environment.展开更多
Objective: To investigate the azole susceptibility of Candida albicans(C.albicans)from vulvovaginal candidosis patients and to analyze the relationship between ERG11 gene mutations in these isolates and azole resistan...Objective: To investigate the azole susceptibility of Candida albicans(C.albicans)from vulvovaginal candidosis patients and to analyze the relationship between ERG11 gene mutations in these isolates and azole resistance.Methods: Three hundred and two clinical isolates of Candida species were collected.Azole susceptibility was tested in vitro in microdilution studies. The ERG11 genes of 17 isolates of C. albicans(2 susceptibles, 5 dose-dependent resistants and 10 resistants) were amplified and sequenced.Results: Of the 302 isolates collected, 70.2% were C. albicans, of which 8.5%, 3.8% and4.2% were resistant to fluconazole, itraconazole and voriconazole, respectively. In total,27 missense mutations were detected in ERG11 genes from resistant/susceptible dosedependent isolates. Among them, Y132 H, A114 S, and Y257 H substitutions were most prevalent and were known to cause fluconazole resistance. G464 S and F72 S also have been proved to cause fluconazole resistance. Two novel substitutions(T285A, S457P) in hotspot regions were identified.Conclusions: Twenty seven mutations in the ERG11 gene were identified in azoleresistant C. albicans isolates, which indicated a possible relation with the increase in resistance to azole drugs and the recurrence of vulvovaginal candidosis. The relationship of two novel substitutions(T285A, S457P) with fluconazole resistance needs to be further verified by site-directed mutagenesis.展开更多
Triadimefon(TDM)and cyproconazole(CPZ)are two triazoles widely used as fungicides.Several azoles were synthe-sised starting from commercial TDM and CPZ.The compounds were evaluated against phytopathogenic filamentous ...Triadimefon(TDM)and cyproconazole(CPZ)are two triazoles widely used as fungicides.Several azoles were synthe-sised starting from commercial TDM and CPZ.The compounds were evaluated against phytopathogenic filamentous fungi,including Aspergillus fumigatus(AF),A.niger(AN),A.ustus(AU),A.japonicus(AJ),A.terreus(AT),Fusarium oxyspo-rum and Botrytis cinerea isolated from grapevine in the province of San Juan,Argentina.Three of the synthesised compounds(1-(Biphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one,1;2-(Biphenyl-4-yl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,3;3-Cyclopropyl-2-(4’-fluorobiphenyl-4-yl)-1-(1H-1,2,4-triazol1-yl)butan-2-ol,4)presented remarkable in vitro fungicidal properties,with better effects than TDM and CPZ on some of the target fungi.Cytotoxicity was assessed using human lung fibroblasts MRC5.Derivative 1,with IC50 values of 389.4μM,was less toxic towards MRC-5 human lung fibroblasts than commercial TDM(248.5μM)and CPZ(267.4μM).Docking analysis and molecular dynamics simulations suggest that the compounds present the same interaction in the binding pocket of the CYP51B enzyme and with the same amino acids as CPZ.The derivatives investigated could be considered broad-spectrum but with some selectivity towards imperfect fungi.展开更多
Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) ...Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) along with increase in resistance over the time. Therefore, it is highly emergent to consider alternative treatments for candidal infections, having fewer adverse effects and is cost-effective. The current in-vitro study is undertaken to assess and compare the antifungal effects of the herbs, Berberis aristata (B. aristata, Darehald/Darhald) and Punica granatum (P. granatum, Pomegranate) with fluconazole and voriconazole, based on culture and sensitivity of candidal isolates. Materials and Methods: Ethanolic extracts of herbs (Berberis aristata and Punica granatum) and concentrations were formulated as per standard procedure. 130 samples were obtained for the study from in and out patients reported in clinical subsets of Ziauddin Hospital, Karachi from March to May, 2018. Samples were collected and grown according to the standard procedures like, wet mount test and gram’s staining. Species were identified by CHROM agar candida and API 20 C AUX methods. Sensitivity tests were performed by Kirby Bauer’s disc diffusion method according to CLSI guide lines M-44 A2, 2009. Data analysis was done by one-way ANOVA to compare the antifungal activities of drugs and herbs. Results: Mean inhibitory zones of herbs, B. aristata and P. granatum were highly significant against clinical candidal isolates with respective p-values of 0.00 and 0.02. Both of the herbs, B. aristata and P. granatum were found to be more sensitive, 98.5% and 97.7% respectively in comparison to fluconazole showing 42.3% and voriconazole showing 29.2% sensitivity against candidal isolates. The most resistant candidal specie was C. tropicalis that showed resistance against both fluconazole and voriconazole, contrary to that, this specie was highly sensitive to both of the herbs, showing sensitivity of 100% respective for Darehald and Pomegranate. Conclusion: In comparison to azoles: Culture sensitivity of both herbs (B. aristata and P. granatum) displayed more sensitivity against candidal isolates of patients having non-invasive and invasive candidiasis. These herbs can be considered as substitute or alternative antifungal agents to the conventional antifungal therapy, particularly in cases of treating candidemia patients, which is a life threating condition.展开更多
Some azoles were tested such as 3-amino-1,2,4-triazole (ATA), 3-4’-bitriazole -1,2,4 (BiTA)and 2-Mercaptobenzimidazole (MBI) against Cu-30Ni alloy corrosion in 3%NaCl polluted by ammonia using potentiodynamic measure...Some azoles were tested such as 3-amino-1,2,4-triazole (ATA), 3-4’-bitriazole -1,2,4 (BiTA)and 2-Mercaptobenzimidazole (MBI) against Cu-30Ni alloy corrosion in 3%NaCl polluted by ammonia using potentiodynamic measurements and electrochemical impedance spectroscopy and non-electrochemical techniques (scanning Electron Microscopy (SEM)) studied surface morphology has been used to characterize electrode surface. This study permitted to follow the evolution of the inhibitory effect of some azoles, on Cu-30Ni alloy corrosion in 3%NaCl polluted by ammonia and indicate that the tested inhibitors act as a good mixed-type inhibitor retarding the anodic and cathodic reactions. An increase of the inhibitors concentration leads to a decrease of corrosion rate and inhibition efficiency increase.展开更多
Heterocyclic compounds represent a pivotal class of organic molecules with a profound impact on daily life.In particular,thiazole and isothiazole stand out as fundamental scaffolds that are widely used in medicinal ch...Heterocyclic compounds represent a pivotal class of organic molecules with a profound impact on daily life.In particular,thiazole and isothiazole stand out as fundamental scaffolds that are widely used in medicinal chemistry,agrochemicals,and materials science(Figure 1a)[1].Despite their importance,the functionalization of these heterocycles,including alkylation,and amination,predominantly relies on cross-coupling reactions,which are often constrained by limited regioselectivity and harsh reaction conditions[2,3].展开更多
A selenium-catalyzed electrosynthesis involving regio-and stereo-selective N-olefination of azoles was developed.The room-temperature reaction was efficient(up to 97%yield)and compatible with various styrenes and azol...A selenium-catalyzed electrosynthesis involving regio-and stereo-selective N-olefination of azoles was developed.The room-temperature reaction was efficient(up to 97%yield)and compatible with various styrenes and azoles.Mechanistic study showed that the cascade reaction was triggered by the selenium-cation-mediated electrophilictrans-aminoselenation,and followed by an oxidative cis-elimination of selane.The electrosynthesis was also wellcompatible with the more challenging internal alkene substrates,giving the desired N-vinyl azoles in up to 88%yield and>20:1 Z/E ratio.展开更多
Chemical insecticides targeting the digestive system of diamondback moth(DBM),Plutella xylostella,have not been developed.The discovery of an insecticide with novel mode of action is a challenge for the control of DBM...Chemical insecticides targeting the digestive system of diamondback moth(DBM),Plutella xylostella,have not been developed.The discovery of an insecticide with novel mode of action is a challenge for the control of DBM.In this study,a class of selenium-and difluoromethyl-modified azoles(fluoroazole selenoureas,FASU)were designed and synthesized for the control of DBM.Of these azoles,compound B4 showed the highest insecticidal activity against DBM.The LC50of third-and second-instar larvae reached 32.3 and 4.6μg mL^(–1),respectively.The midgut tissue of larvae was severely disrupted,and the larval intestinal tissue was dotted with unique red spots after treatment with compound B4.Compound B4 led to disintegration of the peritrophic matrix,swelling of the midgut epithelium,fracture of the microvilli,and extensive leakage of cellular debris in the midgut lumen.Surviving larvae grew very slowly,and the larval duration was significantly prolonged after exposure to compound B4 at sublethal doses(LC10,LC25and LC50).Furthermore,the pupation rate,emergence rate and pupae weight were significantly decreased.Compound B4 also induced abnormal pupae,causing adults to be trapped in the cocoon or failure to fly due to twisted wings.These results demonstrated that FASU could reduce the population of DBM in sublethal doses.FASU is the first synthetic insecticidal lead compound that has been shown to disrupt the midgut tissue of the larvae of DBM,and its mode of action totally differs from that of commercial chemical insecticides.展开更多
Background: Vulvovaginal candidiasis (VVC) is a common cause of significant morbidity, affecting millions of women worldwide. It is estimated that approximately 75%of women of childbearing age will have at least one e...Background: Vulvovaginal candidiasis (VVC) is a common cause of significant morbidity, affecting millions of women worldwide. It is estimated that approximately 75%of women of childbearing age will have at least one episode of candidiasis in their lifetime. In the last decades, resistance to azoles has become a public health problem. Although studies on vulvovaginitis have been done, there is lack of VVC studies in our area. The aim of this study was to describe the etiological and resistance profiles of vulvovaginal candidiasis to standard antifungus at the Saint Camille Hospital of Ouagadougou (HOSCO), Burkina Faso. Methods: We conducted a prospective study from January 2018 to December 2022. From vulvovaginal swabs, Candida species were identified using the ChromID® Candida Agar medium and the API® Candida gallery. Antifungal susceptibility testing was performed using Kirby-Bauer agar disk diffusion. Results: A total of 4789 women were sampled. The average age of sexually active women was 27.80+/−6.77 years, with extremes ranging from 15 to 64 years. Vaginal Candida infections accounted for 74.16% of the cases. The 20 - 29 age group was the most affected by vulvovaginal candidiasis. Pregnant women accounted for 28.76% of our study population. Women in the second (2nd) trimester of pregnancy had more Candida infections. Candida albicans was the most isolated species (55.12%), followed by Candida glabrata (27.64%), Candida tropicalis (6.91%), Candida famata (6.67%), Candida krusei (2.56%). All the Candida species isolated showed very high of resistance to Fluconazole (45.2%), Miconazole (23.7%) and Clotrimazole (45.7%). Conclusion: Species-specific antifungal results should always be considered to avoid antifungal resistance associated with vulvovaginal candidiasis. Identifying the causative species using vaginal fungal cultures can help guide therapy and improve outcomes for these patients.展开更多
A new Cu(Ⅱ) complex,[Cu_(4)Cl_(6)O(1-TrTz)_(4)]where 1-TrTz is 1-trityl-1H-[1,2,4]triazole,was synthesized by the reaction of 1-trityl-1H-[1,2,4]triazole with two hydrated cupric chlorides,and its structure was chara...A new Cu(Ⅱ) complex,[Cu_(4)Cl_(6)O(1-TrTz)_(4)]where 1-TrTz is 1-trityl-1H-[1,2,4]triazole,was synthesized by the reaction of 1-trityl-1H-[1,2,4]triazole with two hydrated cupric chlorides,and its structure was characterized by X-ray single-crystal diffraction.[Cu4Cl6O(1-TrTz)4]is of monoclinic system,space group P21/c,a=12.5024(13),b=26.400(3),c=28.588(3)A,β=112.807(4)°,V=8698.1(16)A^(3),Z=4,ρcalc=1.411 g/cm^(3),μ=1.265 mm^(–1),F(000)=3772,the final R=0.1293 and w R=0.3644 for 55774 observed reflections (I>2s(I)),R(all data)=0.1972,w R(all data)=0.3989,completeness to theta of 25.242 is 99.9%and GOF=1.103.In the structure of[Cu_(4)Cl_(6)O(1-TrTz)_(4)],the central O atom is tetrahedral and is coordinated with four Cu atoms.The distance between copper and oxygen bond is 1.909(6)A.In addition,the catalytic property of this complex was investigated and it could effectively catalyze the Ullmann coupling reaction of various (hetero)aryl chlorides with azoles.展开更多
An efficient catalytic system of CuI/8-hydroxyquinalidine was developed for the coupling of aryl iodides and indole as well as some azoles. The reaction could be carried out at 90 ~C under the condition of relatively ...An efficient catalytic system of CuI/8-hydroxyquinalidine was developed for the coupling of aryl iodides and indole as well as some azoles. The reaction could be carried out at 90 ~C under the condition of relatively low cata- lyst loading, affording various N-arylindoles and N-aryl azoles in good yields. The functionalized and hindered aryl iodides were suitable substrates for this transformation.展开更多
Objectives:By assessing and comparing the phenotypic changes on the stepwise acquisition of fluconazole resistant Candida albicans isolates,we could find and describe the relationship between drug resistance and biofi...Objectives:By assessing and comparing the phenotypic changes on the stepwise acquisition of fluconazole resistant Candida albicans isolates,we could find and describe the relationship between drug resistance and biofilm formation ability in a series of clonal strains.Methods:We performed antifungal susceptibility of five drugs(fluconazole,itraconazole,voriconazole,caspofungin and amphotericin B)to further verify the antifungal activity of the six isolates in vitro.Then we combined hyphal formation assay,cell surface hydrophobicity test positively related to adherence ability,and biofilm assays in vitro to observe and compare the phenotypic characteristics of our six clonal strains.Results:Biofilm capability is enhanced for four drug-intermediate strains,whereas the initial susceptible strain and the final resistant strain are both poor in adherence,hyphal growth and biofilm formation.Conclusions:It was suggested that the biofilm formation ability were not absolutely related to the degree of fluconazole resistance.展开更多
基金support of this work by the National Natural Science Foundation of China(Nos.22371307,21971267)the program for Guangdong Introducing Innovative and Entrepreneurial Teams(No.2017ZT07C069).
文摘Selective defluorinative functionalization of trifluoromethylarenes(ArCF3)to obtain the pharmaceutically commonα,α-difluorobenzylic motif is an attractive and elegant synthetic route.Over the past decade,although C(sp^(3))-F bonds functionalization have been greatly developed,catalytic cross-coupling of trifluoromethylarenes with C-H of terminal alkynes remains a challenge.Here,we report an approach to achieve Sonogashira-type cross-coupling of trifluoromethylarenes with terminal alkynes C(sp)-H bonds via photoredox and Cu/L dual catalysis.Tridentate anionic ligand is pivotal to realize this C-H sp-sp^(3) cross-coupling.Moreover,this unique catalytic system is also suitable for cross-coupling of C(sp^(3))-F bonds with azoles C(sp^(2))-H bonds.A series of trifluoromethylarenes,terminal alkynes and azoles with various functional groups are compatible with this protocol affording a variety of defluoroalkynylation or defluoroazolation products.Preliminary mechanistic studies indicated that deprotonated BINOL involved as a photocatalyst to activate ArCF3 rather than a ligand to the metal.
基金supported by the National Natural Science Foundation of China(Nos.52270072,4222780043)。
文摘Azole fungicides(AFs)play an important role in the prevention and treatment of fungal diseases in agricultural crops.However,limited studies are addressing the fate and ecological risk of AFs in the urban water cycle at a large watershed scale.To address this gap,we investigated the spatiotemporal distribution and ecological risk of twenty AFs in the lower reaches of the Yangtze River across four seasons.Carbendazim(CBA),tebuconazole(TBA),tricyclazole(TCA),and propiconazole(PPA)were found to be the dominant compounds.Their highest concentrations were measured in January(188.3 ng/L),and November(2197.1 ng/L),July(162.0 ng/L),and November(1801.9 ng/L),respectively.The comparison between wastewater treatment plants(WWTPs)effluents and surface water suggested that industrial WWTPs are major sources of AFs in the Yangtze River.In particular,TBA and PPA were found to be the most recalcitrant AFs in industrial WWTPs,while difenoconazole(DFA)was found to be the most potent pollutant in municipal WWTPs,with an average removal rate of less than60%.The average risk quotient(RQ)for the entire AFs was 6.45 in the fall,which was higher than in January(0.98),April(0.61),and July(0.40).This indicates that AFs in surface water posed higher environmental risks during the dry season.Additionally,the exposure risk of AFs via drinking water for sensitive populations deserves more attention.This study provides benchmark data on the occurrence of AFs in the lower reaches of the Yangtze River,and offers suggestions for better reduction of AFs.
文摘Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.
文摘Objective: To appraise the activity of voriconazole against Leishmania major(L. major) in vitro and its effectiveness on wound regeneration in cutaneous leishmaniasis in BALB/c mice Methods: The IC_(50) of voriconazole against promastigotes and intra-macrophage amastigotes of L. major was investigated in vitro. The in vivo study was performed by treating the L. major infected BALB/c mice. When the wounds appeared in the base of tail, treatment was started by administration of 30 mg/kg voriconazole for 28 consecutive days orally. Results: The IC_(50) of voriconazole against promastigotes and intra-macrophage amastigotes were 0.74 and 0.89μM, respectively. Voriconazole decreased lipid peroxidation and IL-6 level. Histopathologica findings indicated accelerated healing in the voriconazole treated group compared to other groups. Conclusions: Our results demonstrate that voriconazole can be an option in treating the cutaneous leishmaniasis by L. major.
文摘Azole derivatives such as 2-mercaptobenzothiazole(MBT) and 2-mercaptobenzimidazole(MBI) were introduced as corrosion inhibitors into the interlayer space of sodium montmorillonite clay(Na+-MMT). The corrosion protection behavior of mild steel in solutions containing MBT, MBI, MMT + MBT, MMT + MBI, Na^+-MMT, and NaCl(3.5 wt%) was evaluated using polarization and electrochemical impedance spectroscopy(EIS). Also, the release of penetrated species into the medium from the clay nanocarriers was evaluated using ultraviolet-visible(UV-Vis) spectroscopy. Small-angle X-ray scattering(SAXS) confirmed the insertion of MBT and MBI into the inner space of the clay layers and the interaction between two organic and inorganic phases. Scanning electron microscopy(SEM) was used to assess the morphology of the surface of the steel samples after the samples had been immersed for 24 h in the extraction solution. The corrosion protection in the solutions with clay nanocarriers containing MBT and MBI was better than that in solutions without MMT. The UV-Vis results showed that the release of MBI species from Na+-MMT nanocarriers in neutral pH was far lower than that of MBT species.
基金supported by the National Natural Science Foundation of China(Grant Nos.U2004214,21975225,and 51902293)。
文摘Rechargeable lithium-sulfur(Li-S)batteries are considered one of the most promising energy storage techniques owing to the high theoretical energy density.However,challenges still remain such as the shuttle effect of lithium polysulfides(LPSs)and the instability of lithium metal anode.Herein,we propose to use nitrogen-rich azoles,i.e.,triazole(Ta)and tetrazole(Tta),as trifunctional electrolyte additives for Li-S batteries.The azoles afford strong lithiophilicity for the chemisorption of LPSs.The density functional theory and experimental analysis verify the presence of Li bonds between the azoles and LPSs.The azoles can also interact with lithium salt in the electrolyte,leading to increase ionic conductivity and lithiumion transference number.Moreover,the azoles render particle-like lithium deposition on the lithium metal anode,leading to superlong cycling of a Li symmetric cell.The Li-S batteries with Ta and Tta exhibit the initial discharge capacity of 1425.5 and 1322.2 m Ah g^(-1),respectively,at 0.2 C rate,and promising cycling stability.They also enable enhanced cycling performance of a Li-organosulfide battery.
基金funded by the National Natural Science Foundation(Nos.81630093,81773786,81402804)the Young Scholars Program of Shandong University
文摘Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B(RAB) and riccardin D(RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.
基金supported by the National Natural Science Foundation of China(Nos.41473105,41877358 and 21806043)Scientific Research and Technology Development Program of Guangxi(No.2018AB36018)+1 种基金Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety(No.2019B030301008)the Pearl River Talent Plan of Guangdong Province(No.2017GC010244)。
文摘Widespread use of azole fungicides and low removal efficiency in wastewater treatment plants(WWTPs) have led to the elevated concentration of azole fungicides in receiving environment. However, there was limited research about the removal mechanism of azole fungicides in the biological treatment of WWTPs. Imidazole fungicide climbazole and triazole fungicide fluconazole were selected to investigate the biodegradation mechanism of azole fungicides in activated sludge under aerobic conditions. Climbazole was found to be adsorbed to solid sludge and resulted in quick biodegradation. The degradation of climbazole in the aerobic activated sludge system was fitted well by the first-order kinetic model with a half-life of 5.3 days, while fluconazole tended to stay in liquid and had only about 30% of loss within 77 days incubation. Ten biotransformation products of climbazole were identified by high resolution mass spectrometry using suspect and non-target screening method. But no biodegradation products of fluconazole were identified due to its limited removal. The possible biodegradation pathways for climbazole were proposed based on the products identification and pathway prediction system, and involves oxidative dehalogenation, side chain oxidation and azole ring loss. The findings from this study suggest that it should be a concern for the persistence of fluconazole in the environment.
基金Supported by the National Natural Science Foundation of China(No.31072125 and 31272549)by a National Science and Technology Project (China) grant (2008ZX-10004-011)
文摘Objective: To investigate the azole susceptibility of Candida albicans(C.albicans)from vulvovaginal candidosis patients and to analyze the relationship between ERG11 gene mutations in these isolates and azole resistance.Methods: Three hundred and two clinical isolates of Candida species were collected.Azole susceptibility was tested in vitro in microdilution studies. The ERG11 genes of 17 isolates of C. albicans(2 susceptibles, 5 dose-dependent resistants and 10 resistants) were amplified and sequenced.Results: Of the 302 isolates collected, 70.2% were C. albicans, of which 8.5%, 3.8% and4.2% were resistant to fluconazole, itraconazole and voriconazole, respectively. In total,27 missense mutations were detected in ERG11 genes from resistant/susceptible dosedependent isolates. Among them, Y132 H, A114 S, and Y257 H substitutions were most prevalent and were known to cause fluconazole resistance. G464 S and F72 S also have been proved to cause fluconazole resistance. Two novel substitutions(T285A, S457P) in hotspot regions were identified.Conclusions: Twenty seven mutations in the ERG11 gene were identified in azoleresistant C. albicans isolates, which indicated a possible relation with the increase in resistance to azole drugs and the recurrence of vulvovaginal candidosis. The relationship of two novel substitutions(T285A, S457P) with fluconazole resistance needs to be further verified by site-directed mutagenesis.
文摘Triadimefon(TDM)and cyproconazole(CPZ)are two triazoles widely used as fungicides.Several azoles were synthe-sised starting from commercial TDM and CPZ.The compounds were evaluated against phytopathogenic filamentous fungi,including Aspergillus fumigatus(AF),A.niger(AN),A.ustus(AU),A.japonicus(AJ),A.terreus(AT),Fusarium oxyspo-rum and Botrytis cinerea isolated from grapevine in the province of San Juan,Argentina.Three of the synthesised compounds(1-(Biphenyl-4-yloxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one,1;2-(Biphenyl-4-yl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,3;3-Cyclopropyl-2-(4’-fluorobiphenyl-4-yl)-1-(1H-1,2,4-triazol1-yl)butan-2-ol,4)presented remarkable in vitro fungicidal properties,with better effects than TDM and CPZ on some of the target fungi.Cytotoxicity was assessed using human lung fibroblasts MRC5.Derivative 1,with IC50 values of 389.4μM,was less toxic towards MRC-5 human lung fibroblasts than commercial TDM(248.5μM)and CPZ(267.4μM).Docking analysis and molecular dynamics simulations suggest that the compounds present the same interaction in the binding pocket of the CYP51B enzyme and with the same amino acids as CPZ.The derivatives investigated could be considered broad-spectrum but with some selectivity towards imperfect fungi.
文摘Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) along with increase in resistance over the time. Therefore, it is highly emergent to consider alternative treatments for candidal infections, having fewer adverse effects and is cost-effective. The current in-vitro study is undertaken to assess and compare the antifungal effects of the herbs, Berberis aristata (B. aristata, Darehald/Darhald) and Punica granatum (P. granatum, Pomegranate) with fluconazole and voriconazole, based on culture and sensitivity of candidal isolates. Materials and Methods: Ethanolic extracts of herbs (Berberis aristata and Punica granatum) and concentrations were formulated as per standard procedure. 130 samples were obtained for the study from in and out patients reported in clinical subsets of Ziauddin Hospital, Karachi from March to May, 2018. Samples were collected and grown according to the standard procedures like, wet mount test and gram’s staining. Species were identified by CHROM agar candida and API 20 C AUX methods. Sensitivity tests were performed by Kirby Bauer’s disc diffusion method according to CLSI guide lines M-44 A2, 2009. Data analysis was done by one-way ANOVA to compare the antifungal activities of drugs and herbs. Results: Mean inhibitory zones of herbs, B. aristata and P. granatum were highly significant against clinical candidal isolates with respective p-values of 0.00 and 0.02. Both of the herbs, B. aristata and P. granatum were found to be more sensitive, 98.5% and 97.7% respectively in comparison to fluconazole showing 42.3% and voriconazole showing 29.2% sensitivity against candidal isolates. The most resistant candidal specie was C. tropicalis that showed resistance against both fluconazole and voriconazole, contrary to that, this specie was highly sensitive to both of the herbs, showing sensitivity of 100% respective for Darehald and Pomegranate. Conclusion: In comparison to azoles: Culture sensitivity of both herbs (B. aristata and P. granatum) displayed more sensitivity against candidal isolates of patients having non-invasive and invasive candidiasis. These herbs can be considered as substitute or alternative antifungal agents to the conventional antifungal therapy, particularly in cases of treating candidemia patients, which is a life threating condition.
文摘Some azoles were tested such as 3-amino-1,2,4-triazole (ATA), 3-4’-bitriazole -1,2,4 (BiTA)and 2-Mercaptobenzimidazole (MBI) against Cu-30Ni alloy corrosion in 3%NaCl polluted by ammonia using potentiodynamic measurements and electrochemical impedance spectroscopy and non-electrochemical techniques (scanning Electron Microscopy (SEM)) studied surface morphology has been used to characterize electrode surface. This study permitted to follow the evolution of the inhibitory effect of some azoles, on Cu-30Ni alloy corrosion in 3%NaCl polluted by ammonia and indicate that the tested inhibitors act as a good mixed-type inhibitor retarding the anodic and cathodic reactions. An increase of the inhibitors concentration leads to a decrease of corrosion rate and inhibition efficiency increase.
文摘Heterocyclic compounds represent a pivotal class of organic molecules with a profound impact on daily life.In particular,thiazole and isothiazole stand out as fundamental scaffolds that are widely used in medicinal chemistry,agrochemicals,and materials science(Figure 1a)[1].Despite their importance,the functionalization of these heterocycles,including alkylation,and amination,predominantly relies on cross-coupling reactions,which are often constrained by limited regioselectivity and harsh reaction conditions[2,3].
基金support from the National Natural Science Foundation of China(No.22071269)Pearl River Recruitment Program of Talent(No.2019QN01L149)Guangdong Provincial Key Laboratory of Construction Foundation(No.2023B1212060022).
文摘A selenium-catalyzed electrosynthesis involving regio-and stereo-selective N-olefination of azoles was developed.The room-temperature reaction was efficient(up to 97%yield)and compatible with various styrenes and azoles.Mechanistic study showed that the cascade reaction was triggered by the selenium-cation-mediated electrophilictrans-aminoselenation,and followed by an oxidative cis-elimination of selane.The electrosynthesis was also wellcompatible with the more challenging internal alkene substrates,giving the desired N-vinyl azoles in up to 88%yield and>20:1 Z/E ratio.
基金financially supported by funding from the Guangdong Basic and Applied Basic Research Foundation,China(2019B151502052)the Program of Science and Technology of Guangzhou,China(202002030295)。
文摘Chemical insecticides targeting the digestive system of diamondback moth(DBM),Plutella xylostella,have not been developed.The discovery of an insecticide with novel mode of action is a challenge for the control of DBM.In this study,a class of selenium-and difluoromethyl-modified azoles(fluoroazole selenoureas,FASU)were designed and synthesized for the control of DBM.Of these azoles,compound B4 showed the highest insecticidal activity against DBM.The LC50of third-and second-instar larvae reached 32.3 and 4.6μg mL^(–1),respectively.The midgut tissue of larvae was severely disrupted,and the larval intestinal tissue was dotted with unique red spots after treatment with compound B4.Compound B4 led to disintegration of the peritrophic matrix,swelling of the midgut epithelium,fracture of the microvilli,and extensive leakage of cellular debris in the midgut lumen.Surviving larvae grew very slowly,and the larval duration was significantly prolonged after exposure to compound B4 at sublethal doses(LC10,LC25and LC50).Furthermore,the pupation rate,emergence rate and pupae weight were significantly decreased.Compound B4 also induced abnormal pupae,causing adults to be trapped in the cocoon or failure to fly due to twisted wings.These results demonstrated that FASU could reduce the population of DBM in sublethal doses.FASU is the first synthetic insecticidal lead compound that has been shown to disrupt the midgut tissue of the larvae of DBM,and its mode of action totally differs from that of commercial chemical insecticides.
文摘Background: Vulvovaginal candidiasis (VVC) is a common cause of significant morbidity, affecting millions of women worldwide. It is estimated that approximately 75%of women of childbearing age will have at least one episode of candidiasis in their lifetime. In the last decades, resistance to azoles has become a public health problem. Although studies on vulvovaginitis have been done, there is lack of VVC studies in our area. The aim of this study was to describe the etiological and resistance profiles of vulvovaginal candidiasis to standard antifungus at the Saint Camille Hospital of Ouagadougou (HOSCO), Burkina Faso. Methods: We conducted a prospective study from January 2018 to December 2022. From vulvovaginal swabs, Candida species were identified using the ChromID® Candida Agar medium and the API® Candida gallery. Antifungal susceptibility testing was performed using Kirby-Bauer agar disk diffusion. Results: A total of 4789 women were sampled. The average age of sexually active women was 27.80+/−6.77 years, with extremes ranging from 15 to 64 years. Vaginal Candida infections accounted for 74.16% of the cases. The 20 - 29 age group was the most affected by vulvovaginal candidiasis. Pregnant women accounted for 28.76% of our study population. Women in the second (2nd) trimester of pregnancy had more Candida infections. Candida albicans was the most isolated species (55.12%), followed by Candida glabrata (27.64%), Candida tropicalis (6.91%), Candida famata (6.67%), Candida krusei (2.56%). All the Candida species isolated showed very high of resistance to Fluconazole (45.2%), Miconazole (23.7%) and Clotrimazole (45.7%). Conclusion: Species-specific antifungal results should always be considered to avoid antifungal resistance associated with vulvovaginal candidiasis. Identifying the causative species using vaginal fungal cultures can help guide therapy and improve outcomes for these patients.
基金Supported by the Natural Science Foundation of Tianjin (No.16JCYBJC19700)the National Natural Science Foundation of China (No.21771138)。
文摘A new Cu(Ⅱ) complex,[Cu_(4)Cl_(6)O(1-TrTz)_(4)]where 1-TrTz is 1-trityl-1H-[1,2,4]triazole,was synthesized by the reaction of 1-trityl-1H-[1,2,4]triazole with two hydrated cupric chlorides,and its structure was characterized by X-ray single-crystal diffraction.[Cu4Cl6O(1-TrTz)4]is of monoclinic system,space group P21/c,a=12.5024(13),b=26.400(3),c=28.588(3)A,β=112.807(4)°,V=8698.1(16)A^(3),Z=4,ρcalc=1.411 g/cm^(3),μ=1.265 mm^(–1),F(000)=3772,the final R=0.1293 and w R=0.3644 for 55774 observed reflections (I>2s(I)),R(all data)=0.1972,w R(all data)=0.3989,completeness to theta of 25.242 is 99.9%and GOF=1.103.In the structure of[Cu_(4)Cl_(6)O(1-TrTz)_(4)],the central O atom is tetrahedral and is coordinated with four Cu atoms.The distance between copper and oxygen bond is 1.909(6)A.In addition,the catalytic property of this complex was investigated and it could effectively catalyze the Ullmann coupling reaction of various (hetero)aryl chlorides with azoles.
文摘An efficient catalytic system of CuI/8-hydroxyquinalidine was developed for the coupling of aryl iodides and indole as well as some azoles. The reaction could be carried out at 90 ~C under the condition of relatively low cata- lyst loading, affording various N-arylindoles and N-aryl azoles in good yields. The functionalized and hindered aryl iodides were suitable substrates for this transformation.
基金National Science and Technology Major Project(No.2018ZX10734404-007 to Liu WD)the CAMS Initiative for Innovative Medicine[Grant No.2016-I2M-3-021 to(Liu WD&Li XF)]+2 种基金National Natural Science Foundation of China(No.81573059 to Li XF,No.81903229 to Zhou XW)the PUMC Youth Fund&Fundamental Research Funds for the Central Universities(Grant No.2017310033 to Zhou XW)the Basical Scientific Research Fund Projects of Chinese Academy of Medical Sciences(No.2018PT31013 to Liu WD).
文摘Objectives:By assessing and comparing the phenotypic changes on the stepwise acquisition of fluconazole resistant Candida albicans isolates,we could find and describe the relationship between drug resistance and biofilm formation ability in a series of clonal strains.Methods:We performed antifungal susceptibility of five drugs(fluconazole,itraconazole,voriconazole,caspofungin and amphotericin B)to further verify the antifungal activity of the six isolates in vitro.Then we combined hyphal formation assay,cell surface hydrophobicity test positively related to adherence ability,and biofilm assays in vitro to observe and compare the phenotypic characteristics of our six clonal strains.Results:Biofilm capability is enhanced for four drug-intermediate strains,whereas the initial susceptible strain and the final resistant strain are both poor in adherence,hyphal growth and biofilm formation.Conclusions:It was suggested that the biofilm formation ability were not absolutely related to the degree of fluconazole resistance.
