Novel galbonolide derivatives as IPC synthase inhibitors: design, synthesis and in vitro antifungal activities

A series of novel galbonolide derivatives having a modified methyl enol ether moiety were prepared in total synthetic procedures and evaluated for their in vitro antifungal activities. The antifungal activity was labile to modification of the enol ether functionality and almost all of the modified compounds lacked the activity except for the analogue with an introduction of a methylthio group at the C-6 position, which retained a modest antifungal potency against Cryptococcus neoformans.     

Synthesis and antifungal activities in vitro of novel pyrazino [2,1-a] isoquinolin derivatives

A series of novel pyrazino[2,1-a]isoquinolin compounds were designed and synthesized, and their antifungal activities in vitro were evaluated. The results showed that all of the compounds exhibited antifungal activities. Some of them exhibited stronger antifungal activities than that of lead compounds and among them compound 11b was the most potent one, which showed more potent than that of the active control fluconazole to the four of the five tested fungi. The studies presented here provide a new structural type for the development of novel antifungal agents.     

Synthesis and in vitro antifungal activities of new 3-substituted benzopyrone derivatives

A series of new benzopyrone compounds were designed and synthesized and their antifungal activities in vitro were evaluated. The results showed that the benzopyrone derivatives with short terminal alkyl chain exhibited potent antifungal activity, which represent a novel class of promising leads for the development of novel non-azole antifungal agents. Compound 5j is the most potent one with MIC(80) value 1.5 μg/mL against Trichophyton rubrum. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CA-CYP51 through hydrophobic and van der Waals interactions.     

Novel and efficient synthesis and antifungal evaluation of 2,3-functionalized cholestane and androstane derivatives

Synthetic modifications of cholesterol and other traditional steroid molecules have become a promising area for the exploration and development of novel antifungal agents, especially with respect to the development of fatty-acid esters of steroids. In addition, 2,3-functionalized steroids are also compounds with potentially interesting biological properties and proper functionalization of 2,3-steroids can lead to the development of efficient syntheses of building blocks for novel fatty-acid esters of steroids. In this Letter, we outline a novel and efficient approach to the synthesis of 2,3-functionalized cholestane and androstane derivatives and present their promising preliminary antifungal activities against a number of fungal species.     

Investigations on fungicides. XX. The fungitoxicity of analogues of the phy toalexin 2-(2' -methoxy-4' -hydroxyphenyl)-6-methoxybenzofuran(vignafuran)

A series of hydroxy-and methoxy-2-phenyl benzofurans, structurally related to the phytoalexin vignafuran, have been synthesised and their antifungal activity assessed both as inhibitors of spore germination in vitro and as protective foliar sprays against three pathogens. All fungitoxic compounds have a hydroxy group in the molecule although most di- and tri-hydroxy compounds were inactive. Methoxy compounds were inactive but substituting methoxy groups into the molecule of monohydroxy compounds sometimes enhanced their fungitoxicity. No close correlation was established between antifungal activity and either Hansen n values or the n.m.r. chemical shift of the phenolic protons.     

An efficient synthesis of bis(indolyl)methanes and evaluation of their antimicrobial activities

A versatile and efficient method has been developed for the synthesis of bis(indolyl)methanes by using aluminium triflate (0.5 mol%) as a novel catalyst. Further, some of the synthesized compounds were evaluated for their efficacy as antibacterial and antifungal activities. Most of the compounds have shown moderate to good inhibitory activity.     

An efficient synthesis of bis(indolyl)methanes and evaluation of their antimicrobial activities

A versatile and efficient method has been developed for the synthesis of bis(indolyl)methanes by using aluminium triflate (0.5 mol%) as a novel catalyst. Further, some of the synthesized compounds were evaluated for their efficacy as antibacterial and antifungal activities. Most of the compounds have shown moderate to good inhibitory activity.     

Glutamine analogues containing a keto function--novel inhibitors of fungal glucosamine-6-phosphate synthase

A series of novel inhibitors of glucosamine-6-phosphate synthase, analogues of AADP and BADP, have been synthesized and their inhibitory, lipophilic and antifungal properties have been tested. The improvement in lipophilicity has not much affected the antifungal activity of the new compounds. Dipeptides containing norvaline and selected inhibitors have shown substantial activity against S. cerevisiae and C. glabrata and only poor activity against C. albicans strain. These peptides do not seem to be toxic towards human cells.     

Organometallic-based antibacterial and antifungal compounds: transition metal complexes of 1,1'-diacetylferrocene-derived thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone

Organometallic-based, 1,1'-diacetylferrocene-derived antibacterial and antifungal thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone have been prepared by condensing equimolar amount of 1,1'-diacetylferrocene with thiocarbohydrazide, carbohydrazide thiosemicarbazide and semicarbazide, respectively. These were used as ligands for the preparation of their cobalt (II), copper (II), nickel (II) and zinc (II) metal complexes. All the synthesized ligands and their complexes were characterized by IR, NMR, elemental analyses, molar conductances, magnetic moments and electronic spectral data. These synthesized compounds were screened for their antibacterial activity against Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi, and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata using the agar-well diffusion method. All the compounds showed good antibacterial and antifungal activity which increased on coordination with the metal ions thus, introducing a novel class of organometallic-based antibacterial and antifungal agents.     

Synthesis and biological evaluation of novel N-acyl substituted quinolin-2(1H)-one derivatives as potential antimicrobial agents

A series of novel N-acyl substituted quinolin-2(1H)-one derivatives were synthesized and screened in vitro for their antibacterial and antifungal activities by disc diffusion method. All the compounds exhibited moderate to good antimicrobial activities, some of these compounds displayed comparable or better antibacterial or antifungal activities against some tested strains compared to the reference drugs Streptomycin and Fluconazole.     

Synthesis and antimicrobial activity of beta-lactam-bile acid conjugates linked via triazole

Synthesis of novel 1,2,3-triazole-linked beta-lactam-bile acid conjugates 17-24 using 1,3-dipolar cycloaddition reaction of azido beta-lactam and terminal alkyne of bile acids in the presence of Cu(I) catalyst (click chemistry) have been realized. These molecules were evaluated in vitro for their antifungal and antibacterial activities. Most of the compounds exhibited significant antifungal and moderate antibacterial activity against all the tested strains.     

Targeting procaspase‐3 with WF‐208, a novel PAC‐1 derivative,causes selective cancer cell apoptosis

Caspase‐3 is a critical effector caspase in apoptosis cascade, and is often over‐expressed in many cancer tissues. The first synthesized procaspase‐3 activator, PAC‐1, induces cancer cell apoptosis and exhibits antitumour activity in murine xenograft models. To identify more potent procaspase‐3 activators, a series of compounds were designed, synthesized and evaluated for their ability of inducing cancer cell death in culture. Among these compounds, WF‐208 stood out by its high cytotoxicity against procaspase‐3 overexpressed HL‐60 cells. Compared with PAC‐1, WF‐208 showed higher cytotoxicity in cancer cells and lower toxicity in normal cells. The further investigation described herein showed that WF‐208 activated procaspase‐3, degraded IAPs (The Inhibitors of apoptosis proteins) and leaded to caspase‐3‐dependent cell death in tumour cells, which possibly because of the zinc‐chelating properties. WF‐208 also showed greater antitumour activity than PAC‐1 in murine xenograft model. In conclusion, we have discovered WF‐208 as a promising procaspase‐3 activating compound, with higher activity and higher cell selectivity than PAC‐1.     

Design,synthesis, biological activities and DFT calculation of novel 1,2,4-triazole Schiff base derivatives

Series of 1,2,4-triazole Schiff bases (2a-2d, 2f-2h and 3a-3h) have been designed and synthesized. The structure of title compounds was confirmed on the basis of their spectral data and elemental analysis. All the target compounds were screened for their in vitro antifungal activity and antibacterial activity. Two of the tested compounds (2a and 2b) exhibited significant antifungal activity against most fungi, especially compound 2a showed better antifungal activity than triadimefon. Meanwhile, the antibacterial activity assay also indicated compound 2a exhibited excellent antibacterial activities comparable to chloramphenicol. The SAR manifested no substitution at position 5 of the triazole ring caused an increase in activity, and 3-phenoxy phenyl group introduced in 1,2,4-triazole scaffold can enhance the antibacterial activity. The DFT calculation indicated triazole ring, S atom and benzene ring in both of the 2a and 3a make a major contribution to the activity.     

Antifungals,arthropods and antifungal resistance prevention: lessons from ecological interactions

Arthropods can produce a wide range of antifungal compounds, including specialist proteins, cuticular products, venoms and haemolymphs. In spite of this, many arthropod taxa, particularly eusocial insects, make use of additional antifungal compounds derived from their mutualistic association with microbes. Because multiple taxa have evolved such mutualisms, it must be assumed that, under certain ecological circumstances, natural selection has favoured them over those relying upon endogenous antifungal compound production. Further, such associations have been shown to persist versus specific pathogenic fungal antagonists for more than 50 million years, suggesting that compounds employed have retained efficacy in spite of the pathogens'' capacity to develop resistance. We provide a brief overview of antifungal compounds in the arthropods’ armoury, proposing a conceptual model to suggest why their use remains so successful. Fundamental concepts embedded within such a model may suggest strategies by which to reduce the rise of antifungal resistance within the clinical milieu.     

Plant-derived antifungal proteins and peptides

Plants produce potent constitutive and induced antifungal compounds to complement the structural barriers to microbial infection. Approximately 250,000-500,000 plant species exist, but only a few of these have been investigated for antimicrobial activity. Nevertheless, a wide spectrum of compound classes have been purified and found to have antifungal properties. The commercial potential of effective plant-produced antifungal compounds remains largely unexplored. This review article presents examples of these compounds and discusses their properties.     

Novel synthetic methods for N-cyano-1H-imidazole-4-carboxamides and their fungicidal activity

A novel synthetic method of N-cyanocarboxamides has been developed with advantages of mild reaction condition, simpler procedure and easy reactant-product isolation compared with the existing methods. Using this novel method, 16 new N-cyano-1H-imidazole-4-carboxamide derivatives were synthesized and their structures were characterized by spectrum analysis. Further antifungal activity study showed that most of the newly synthesized compounds have good antifungal activity selectively against Rhizoctonia solani among the six fungi tested. Particularly, compound 12h was identified as the most promising candidate with an EC(50) of 2.63 μg/mL against R. solani.     

Novel fluconazole derivatives with promising antifungal activity

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.     

Inhibitors of the fungal cell wall. Synthesis of 4-aryl-4-N-arylamine-1-butenes and related compounds with inhibitory activities on beta(1-3) glucan and chitin synthases

As part of our project devoted to the search for antifungal agents, which act via a selective mode of action, we synthesized a series of new 4-aryl- or 4-alkyl-N-arylamine-1-butenes and transformed some of them into 2-substituted 4-methyl-tetrahydroquinolines and quinolines by using a novel three-step synthesis. Results obtained in agar dilution assays have shown that 4-aryl homoallylamines not possessing halogen in their structures, tetrahydroquinolines and quinolines, display a range of antifungal properties in particular against Epidermophyton floccosum and Microsporum canis. Regarding the mode of action, all active compounds showed in vitro inhibitory activities against beta(1-3) glucan-synthase and mainly against chitin-synthase. These enzymes catalyze the synthesis of beta(1-3) glucan and chitin, respectively, major polymers of the fungal cell wall. Since fungal but not mammalian cells are encased in a cell wall, its inhibition may represent a useful mode of action for these antifungal compounds.