Review Article Cytochromes P450 in fungi

Summary. The article gives an overview on the history of the discovery of P450 cytochromes and on their occurrence in nature, especially on their interactions with metabolic pathways in fungi. The significance of the P450 cytochromes in the ergosterol synthesis as well as in the inhibitory mechanisms caused by imidazole and triazole antimycotics is described is detail. Zusammenfassung. Der Artikel gibt eine Übersicht über die Entdeckungsgeschichte der P450-Cytochrome und ihr Vorkommen in der Natur. Insbesondere wird eingegangen auf das Vorkommen der P450-Cytochrome in Pilzen und ihre Interaktionen mit Stoffwechselprozessen der Pilzzellen. Die Bedeutung der P450-Cytochrome für die Ergosterol-Synthese der Pilze und für deren Hemmechanismen durch Imidazol- und Triazol-Antimykotika wird im Detail dargestellt.     

Epidemiology of invasive fungal infections in lung transplant recipients on long‐term azole antifungal prophylaxis

Lung transplant recipients (LTR) at our institution receive prolonged and mostly lifelong azole antifungal (AF) prophylaxis. The impact of this prophylactic strategy on the epidemiology and outcome of invasive fungal infections (IFI) is unknown. This was a single‐center, retrospective cohort study. We reviewed the medical records of all adult LTR from January 2002 to December 2011. Overall, 16.5% (15 of 91) of patients who underwent lung transplantation during this time period developed IFI. Nineteen IFI episodes were identified (eight proven, 11 probable), 89% (17 of 19) of which developed during AF prophylaxis. LTR with idiopathic pulmonary fibrosis were more likely to develop IFI (HR: 4.29; 95% CI: 1.15–15.91; p = 0.03). A higher hazard of mortality was observed among those who developed IFI, although this was not statistically significant (hazard ratio [HR]: 1.71; 95% confidence interval [CI] [0.58–4.05]; p = 0.27). Aspergillus fumigatus was the most common cause of IFI (45%), with pulmonary parenchyma being the most common site of infection. None of our patients developed disseminated invasive aspergillosis, cryptococcal or endemic fungal infections. IFI continue to occur in LTR, and the eradication of IFI appears to be challenging even with prolonged prophylaxis. Azole resistance is uncommon despite prolonged AF exposure.     

Isatin–azole hybrids and their anticancer activities

Isatin and azole moieties, which have the ability to form various noncovalent interactions with different therapeutic targets, are common pharmacophores in drug development. Isatin and azole derivatives possess promising in vitro and in vivo anticancer activity, and many of them, such as semaxanib, sunitinib, and carboxyamidotriazole, could be used to treat various cancers. Thus, it is conceivable that hybridization of the isatin moiety with azole may provide a valuable therapeutic intervention for the treatment of cancer. Substantial efforts have been made to develop isatin–azole hybrids as novel anticancer agents, and some of the isatin–azole hybrids exhibited considerable activity. This review emphasizes isatin–azole hybrids with potential anticancer activity, covering articles published between 2010 and 2019. The structure–activity relationships as well as the mechanisms of action are also discussed to provide insights for the rational design of more effective candidates.     

New systemic antifungal drugs: mechanisms of action,drug interactions and side effects

New antifungal agents are needed to match the currently increasing rate of systemic fungal infections and the development of resistant fungal strains. This appears possible by the introduction of second generation azole antifungals which potently inhibit ergosterol synthesis, but also by a partial synthetic echinocandin analogue which acts by the suppression of the enzyme glucan synthase. Voriconazole and caspofungin have been approved for the treatment of invasive aspergillosis. Both drugs are well tolerated if contraindications and--with voriconazole--also possible drug interactions are respected. Possibly these drugs are also suitable for other severe fungal infections including systemic and oropharyngeal candidosis in the immunocompromised host.     

Synthesis of some 3,4-disubstituted-6,7-dihydro-imidazo[2,1-b][1,3]thiazole and 3,4-disubstituted-7,8-dihydro-6H-imidazo[2,1-b][1,3]thiazine derivatives and evaluation of their cytotoxicities against F2408 and 5RP7 cells

This article describes the synthesis of 3,4-disubstituted-6,7-dihydro-imidazo[2,1-b][1,3]thiazoles and 3,4-disubstituted-7,8-dihydro-6H-imidazo[2,1-b][1,3]thiazines, having substituted or nonsubstituted phenyl rings at the 5,6 and 2,3 positions, respectively, their cytotoxic effects through noncancer (F2408) and cancer (5RP7) cells, and their detailed ¹H- and ¹³C-nuclear magnetic resonance (NMR) spectral characterization. The title compounds were obtained by the cyclization of 4,5-diaryl-imidazole-2-thione and dihaloalkane (i.e., 1,2-dihaloethane or 1,3-dihalopropane), in the presence of potassium carbonate (K₂CO₃) in N,N-dimethyl formamide (DMF). 4,5-Diaryl-imidazole-2-thione was prepared by condensation of α-hydroxyketones (acyloins), which were obtained by treating aldehydes with cyanide, with thioureas in AcOH. The structure of imidazo[2,1-b][1,3]thiazole and imidazo[2,1-b][1,3]thiazine derivatives was confirmed by infrared (IR), ¹H-NMR, and ¹³C-NMR. The cytotoxicities of the synthesized compounds on both of noncancer (F2408) and cancer (5RP7) cells were measured by 3-(4,5-dimethyl-thiazollyl-2)-2,5-diphenyltetrazolium (MTT) assay. In the presence of only lower doses of compounds 9 and 11, bearing methyl or methoxy substituents on the phenyl ring of imidazo[2,1-b][1,3]thiazole scaffold, the cytotoxic effect was higher on 5RP7 cells than control cells after 24 h.     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代氨基-2-丙醇的合成及其抗真菌活性

根据氮唑类抗真菌药物的构效关系,设计合成了８个１－（１Ｈ－１,２,４－三唑－１－基）－２－（２,４－二氟苯基）－３－取代氨基－２－丙醇类化合物。体外抗真菌活性试验表明,该类化合物对几种常见的浅部致病真菌有一定活性,对深部真菌的活性较弱,其中化合物１ａ、１ｂ对卡氏枝孢霉菌的活性比氟康唑强。     

氮唑类抗真菌药物药效构象及其与酶活性位点对接

目的：研究氮唑类抗真菌药物与其受体蛋白活性位点相互作用机理。方法：用随机构象搜寻和分子动力学模拟退火法确定１５个４种不同类型的氮唑类抗真菌药物最低能量构象;用活性类似物法限定药物分子药效基团之间的距离,搜寻到各化合物药效构象;将各化合物药效构象对接到白色念珠菌羊毛甾醇１４α去甲基化酶活性位点中。结果：４种结构类型的氮唑类药物在酶活性位点中有相似的对接位置;真菌和哺乳动物的活性位点结构特异性的残基分布在Ｆ螺旋Ｃ端、β６１和β６２区中;氮唑类抗真菌药物共同的卤代芳环结构落入相同的疏水空穴中,其中Ｙ１３２的侧链羟苯基结构可与抑制剂卤代芳环形成电子迁移复合物。结论：对接结果与已知ＳＡＲ分析结论相符,阐明了氮唑类药物与活性位点的氨基酸残基作用方式,探讨结构选择性药物的结构需求。     

New developments in chemotherapy for non-invasive fungal infections

Dermatomycosis and subcutaneous mycosis comprise the non-invasive fungal infections commonly encountered in clinical practice around the world. The limited activity of early topical antifungal agents prompted the development of more effective systemic agents. While griseofulvin has been used for more than four decades, the use of early azoles, such as ketoconazole have resulted in better patient compliance and thus greater success. However, poor response and recurrence in dermatomycosis, as well as toxicity associated with ketoconazole therapy, has led to the search for newer antifungal agents and more effective treatment strategies. Terbinafine, itraconazole and fluconazole have the advantage of non-toxicity and a broad spectrum of activity. An overview of non-invasive fungal infections, antifungal agents in clinical use and recent developments in antifungal therapy is reviewed in this article.     

Azole antifungals: 35 years of invasive fungal infection management

Prior to 1981, treatment options for invasive fungal infections were limited and associated with significant toxicities. The introduction of ketoconazole marked the beginning of an era of dramatic improvements over previous therapies for non–life-threatening mycosis. After nearly a decade of use, ketoconazole was quickly replaced by the triazoles fluconazole and itraconazole due to significant improvements in pharmacokinetic profile, spectrum of activity and safety. The triazoles posaconazole and voriconazole followed, and were better known for their further extended spectrum, specifically against emerging mold infections. With the exception of fluconazole, the triazoles have been plagued with significant inter- and intrapatient pharmacokinetic variability and all possess significant drug interactions. Azoles currently in development appear to combine an in vitro spectrum of activity comparable to voriconazole and posaconazole with more predictable pharmacokinetics and fewer adverse effects.