Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs

As part of ongoing studies in developing new antimicrobials, a class of structurally novel 4-thiazolidinone derivatives incorporating three known bioactive nuclei such as thiazole, thiazolidinone and adamantane was synthesized by the multi-step reaction protocol, already reported in the literature. NMR and Molecular Modeling techniques were employed for structure elucidation and Z/E potential isomerism configuration of the analogues. Evaluation of antibacterial and antifungal activity showed that almost all compounds exhibited better results than reference drugs thus they could be promising candidates for novel drugs.     

Action of imidazole-containing antifungal drugs

During the past few years several promising new antifungal drugs (e.g. miconazole and ketoconazole) have emerged from a large and diverse group of synthetic imidazole-containing compounds. Potentially, these agents could provide the first major break-through in the management of systematic mycoses in over 20 years. Although this review briefly traces the historical development of antifungal imidazoles and summarizes pertinent information regarding chemical characteristics, biological properties, and growth inhibitory activities, it is primarily concerned with experimental findings and current ideas with respect to mode of action. Physiological, biochemical, and cytological studies have established that the primary adverse effect of imidazoles on fungal cells is disorganization of the plasma membrane. Normal structural and permeability characteristics of the membrane are altered to the extent that the fungal cell cannot adequately govern cytoplasmic levels of essential ions and low molecular weight metabolites. This much seems clear, but the biochemical mechanisms involved in membrane disorganization have not been resolved. There are currently two major hypotheses, each of which is based on substantial experimental evidence. The first suggests that imidazoles interfere with one or more enzymatic steps in the biosynthesis of ergosterol, an integral sterol component of fungal cell membranes. In the second hypothesis, membrane disorganization is explained in purely physicochemical terms. It is postulated that imidazoles and unsaturated fatty acid components of the membrane undergo hydrophobic interactions that are the direct cause of structural alterations and loss of normal permeability controls.     

Novel broad-spectrum metal-based antifungal agents

Summary Copper(II) complexes of the type [Cu(L)X], where L=tridentate anion of 2-acetylpyridineN ⁴-diethyl thiosemicarbazone and X=C1 or Br, were screened against seven fungal strains pathogenic to man viz.Aspergillus niger, Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Tricophyton rubrum, Epidermophyton foccosum andMicrosporum canis. The greater growth inhibition exhibited by the bromo complex can be explained on the basis of its lower Cu(II)/Cu(I) redox couple and greater covalent bonding. These compounds represent a novel class of metal-based antifungal agents which provide opportunities for a large number of synthetic variations for modulation of the activities.     

Novel dendrimeric lipopeptides with antifungal activity

A series of new cationic lipopeptides containing branched, amphiphilic polar head derived from (Lys)Lys(Lys) dendron and C(8) or C(12) chain at C-end were designed, synthesized and characterized. Antimicrobial in vitro activity expressed as minimal inhibitory concentration (MIC) was evaluated against Gram-positive and Gram-negative bacteria and yeasts from the Candida genus. A significant enhancement of antimicrobial potency along with increased selectivity against Candida reference strains was detected for derivatives with the C(12) residue. Several compounds were characterized by a low hemotoxicity. The antifungal activity of branched lipopeptides is multimodal and concentration dependent. Several compounds, studied in detail, induced potassium leakage from fungal cells, caused morphological alterations of fungal cells and inhibited activity of candidal β(1,3)-glucan synthase.     

Novel strategies in antifungal lead discovery

There have been significant developments in fungal genomics over the past year. The recently released genome sequences of Aspergillus fumigatus and Cryptococcus neoformans have provided unprecedented opportunities for comparative genomics studies of many clinically relevant fungal pathogens. Emerging experimental analysis tools, such as fitness profiling and protein microarrays, have greatly enhanced our ability to conduct genome-wide functional studies.     

抗真菌感染新药研究进展

随着免疫功能缺陷人群的增多,侵袭性真菌感染（invasive fungal infections,IFIs）的发病率和死亡率逐年上升,严重威胁人类健康。目前临床常用抗侵袭性真菌感染药物有三唑类（氟康唑）、多烯类（两性霉素B）、棘白菌素类（卡泊芬净）等,然而这些药物并不能满足临床需要,侵袭性真菌感染的死亡率仍居高不下。因此,本文着重于目前处于临床研究阶段的抗真菌感染新药,根据作用靶点不同依次介绍：作用于细胞壁的新型葡聚糖合成酶抑制剂CD101和SCY-078、几丁质合成酶抑制剂尼可霉素Z、GPI锚定蛋白抑制剂APX001;作用于细胞膜的CYP51抑制剂VT-1161和VT-1129、破坏细胞膜通透性药物CAmB;影响细胞代谢的嘧啶合成抑制剂F901318,以及生物制剂包括细胞表面凝集素样序列3蛋白疫苗（NDV-3）和抗真菌感染抗体Mycograb。本文主要综述了上述新药的研究进展,包括作用机制、体内外活性、临床研究结果等,为相关药物的研发与未来的临床应用提供参考。     

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.     

Resistance of human fungal pathogens to antifungal drugs

Resistance mechanisms can be engaged in clinically relevant fungal pathogens under different conditions when exposed to antifungal drugs. Over past years, active research was undertaken in the understanding of the molecular basis of antifungal drug resistance in these pathogens, and especially against the class of azole antifungals. The isolation of various alleles of the gene encoding the target of azoles has enabled correlation of the appearance of resistance with distinct mutations. Resistance mechanisms to azoles also converge to the upregulation of multidrug transporter genes, whose products have the capacity to extrude from cells several chemically unrelated antifungal agents and toxic compounds. Genome-wide studies of azole-resistant isolates are now permitting a more comprehensive analysis of the impact of resistance on gene expression, and may deliver new clues to their mechanisms. Several laboratories are also exploring, as well as possible alternative resistance pathways, the role of biofilm formation by several fungal species in the development of resistance to various antifungals, including azoles.     

Novel benzyl-substituted molybdocene anticancer drugs

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(3,4-dimethoxyphenyl) fulvene (1b) and 6-(3,4,5-trimethoxyphenyl) fulvene (1c) with LiBEt₃H, lithiated cyclopentadienide intermediates (2a-c) were synthesised. These intermediates were then transmetallated to molybdocene using MoCl₄ (synthesized in situ) to yield the benzyl-substituted molybdocenes bis-[(p-methoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3a), bis-[(3,4-dimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3b), and bis-[(3,4,5-trimethoxybenzyl)cyclopentadienyl] molybdenum (IV) dichloride (3c). The molybdocene 3a was characterised by single crystal X-ray diffraction. All three molybdocenes had their cytotoxicity investigated through MTT based preliminary in vitro testing on the human renal cell line Caki-1 in order to determine their IC50 values and compare them with the corresponding titanocene and vanadocene dichloride derivatives. Molybdocenes 3b-c were found to have the same IC50 values of 290 μM, while 3a yielded a value of 84 μM, respectively     

Pharmacodynamics of antifungal drugs: A strategy to optimize efficacy

Pharmacodynamic studies examine the relationship between drug pharmacokinetics and outcome. These investigations have been shown to be helpful for the design of dosing intervals, choice of optimal dose levels, and the development of susceptibility breakpoints. Pharmacodynamic studies with available antifungal agents have been useful in developing optimal dosing regimens to improve efficacy and reduce treatment-associated toxicities. This review summarizes accepted antifungal concepts and discusses recent advances in the field.     

Genomics, molecular targets and the discovery of antifungal drugs

Comparative analyses of fungal genomes and molecular research on genes associated with fungal viability and virulence has led to the identification of many putative targets for novel antifungal agents. So far the rational approach to antifungal discovery, in which compounds are optimized against an individual target then progressed to efficacy against intact fungi and ultimately to infected humans has delivered no new agents. However, the approach continues to hold promise for the future. This review critically assesses the molecular target-based approach to antifungal discovery, outlines problems and pitfalls inherent in the genomics and target discovery strategies and describes the status of heavily investigated examples of target-based research.     

A microautomated dilution method for susceptibility testing with antifungal drugs

The authors perfected, for standardization purposes, a microautomated system (Dynatech MIC 2000 Inoculator) to obtain the accurate quantitative results, i.e., determination of minimum inhibitory (MIC) and fungicidal (MFC) concentrations, avoiding the work and time consuming procedure of the classic broth dilution method in tubes. The spectrum of activity of seven antifungal antibiotics against 204 yeast isolates of six different species, in two different media comparatively, is described.     

Quantitative and qualitative analysis of the antifungal activity of allicin alone and in combination with antifungal drugs

The antifungal activity of allicin and its synergistic effects with the antifungal agents flucytosine and amphotericin B (AmB) were investigated in Candida albicans (C. albicans). C. albicans was treated with different conditions of compounds alone and in combination (allicin, AmB, flucytosine, allicin + AmB, allicin + flucytosine, allicin + AmB + flucytosine). After a 24-hour treatment, cells were examined by scanning electron microscopy (SEM) and atomic force microscopy (AFM) to measure morphological and biophysical properties associated with cell death. The clearing assay was conducted to confirm the effects of allicin. The viability of C. albicans treated by allicin alone or with one antifungal drug (AmB, flucytosine) in addition was more than 40% after a 24-hr treatment, but the viability of groups treated with combinations of more than two drugs was less than 32%. When the cells were treated with allicin alone or one type of drug, the morphology of the cells did not change noticeably, but when cells were treated with combinations of drugs, there were noticeable morphological changes. In particular, cells treated with allicin + AmB had significant membrane damage (burst or collapsed membranes). Classification of cells according to their cell death phase (CDP) allowed us to determine the relationship between cell viability and treatment conditions in detail. The adhesive force was decreased by the treatment in all groups compare to the control. Cells treated with AmB + allicin had a greater adhesive force than cells treated with AmB alone because of the secretion of molecules due to collapsed membranes. All cells treated with allicin or drugs were softer than the control cells. These results suggest that allicin can reduce MIC of AmB while keeping the same efficacy.     

Sensitivity of fungi of the genus Candida to antifungal drugs

Seventy two Candida strains isolated from patients with candidiosis of the oral mucosa were studied with respect to their sensitivity to nystatin, levorin, decamine, ethonium, sanguiritrin and clotrimazole. At concentrations of 0.5 to 5 micrograms/ml all the Candida species i.e. C. albicans, C. tropicalis, C. krusei and C. quilliermondii were highly sensitive to clotrimazole. Fungistatic action of levorin, nystatin and sanguiritrin was observed in 91, 67 and 38 per cent of the strains respectively. The Candida strains were resistant to decamine and ethonium used in the above concentrations.     

Novel liposomal forms of antifungal antibiotics modified by amphiphilic polymers

A novel method was developed to incorporate macrocyclic polyene antibiotics, nystatin and amphotericin B, into liposomes prepared from the mixture of phosphatidylcholine and cholesterol (7: 3) or phosphatidylcholine, cholesterol, and cardiolipin (7: 3: 1). Membranes of the liposomes were modified using the amphiphilic polymer N-vinylpyrrolidone with the molecular mass (MM) of the polymer fragment of 4000 and a single terminal n-octadecyl group. The content of the antibiotic incorporated within such nanosize liposomal carriers can reach 17–22%. The obtained modified liposomes, 150–200 nm in size, were more stable during prolonged storage and more resistant to various destructive factors, such as destabilizing agents (Triton X-100, ethanol) and ultrasound. The liposomal preparations showed higher antifungal activity than non-immobilized antifungal antibiotics.