色酮及硫色酮类抗真菌化合物的研究进展

本文综述了近年来色酮及硫色酮类抗真菌化合物的研究进展,分别对色酮和硫色酮两种化合物进行详细介绍。文章重点阐述了色酮及硫色酮类化合物在抗真菌方面的研究进展及开发现状,介绍了色酮及硫色酮类化合物不同位置的化学修饰及其生物活性,并对其机理和构效关系的进行了分析研究。通过对色酮及硫色酮化合物的抗真菌活性的研究,以期得到更多的有效作用靶点,合成和开发出更多高效、低毒、广谱的抗真菌类药物。     

大蒜有机硫化合物药理活性的研究进展

大蒜的主要药理活性成分是有机硫化合物.大蒜有机硫化合物能通过多种途径抑制肿瘤生长,诱导肿瘤细胞凋亡,并具有抗菌消炎、提高机体免疫力、预防和治疗心血管疾病等药理作用.本文对大蒜有机硫化合物药理活性的研究进展做一综述.     

二硫戊环类化合物的合成

目的 二硫戊环类天然产物是强效的抗氧化剂,但来源有限,通过开发其高效的化学合成方法并合成多种二硫戊环类化合物以研究其生物活性。方法 基于海洋天然产物kottamide E中的二硫戊环氨基酸结构,以廉价易得的三(羟甲基)硝基甲烷为起始原料,通过简洁高效、条件温和的路线合成二硫戊环类化合物。结果 合成了七种二硫戊环类化合物,包括三种双巯基化合物、一种二硫戊环类化合物及两种二硫戊环亚砜类化合物,本工作为该类化合物的合成和进一步研究其生物活性提供了新的思路和方法。     

新型抗真菌药物的研究进展

近年来抗真菌药物研究取得了很多进展,主要是发现了一些新的作用靶点和新的行导化合物。本文综述了作用于真菌细胞壁、抑制真菌蛋白质合成、抑制鞘脂生物合成和电子转移抑制剂四类新型抗真菌药物的作用机制和研究进展。     

有机硼化合物的药理活性及构效关系研究进展

综述具有药理活性的有机硼化合物及其构效关系的研究进展,包括硼酸类抗肿瘤化合物、含硼杂环类及硼烷类抗感染化合物、硼酸类凝血酶抑制剂以及硼酸类二肽基肽酶抑制剂等。并重点介绍了已上市抗肿瘤药物硼替佐米的药理作用机制、合成方法、药效及临床研究。     

小檗红碱药理作用及其结构修饰研究进展

天然来源的小檗红碱具有多种药理活性,对于其药物活性及结构修饰多有报道。本文围绕小檗红碱抗癌、抗炎、抗神经系统疾病、抗心血管疾病、抗真菌、抗糖尿病方面进行综述。同时对其结构修饰也作概述,为小檗红碱合理开发利用提供参考。     

抗真菌微生物天然产物的研究进展

真菌感染疾病近年在增加．能有效治疗这种疾病的药物不多．因此．开发新的抗真菌药物成为当务之急。天然产物在新药及新药先导化合物的发现中起着重要作用。本文主要综述微生物来源的天然抗真菌药物的发展，并根据化合物作用机制将其分为细胞壁成分合成抑制剂、鞘脂类合成抑制剂、蛋白质合成抑制剂和作用于新靶点的抑制剂四类。     

硫色满酮3位Mannich碱衍生物的合成及其抗真菌活性

目的 设计、合成硫色满酮3位Mannich碱类化合物，并对其抗真菌活性进行初步评价。方法 以对氟苯硫酚为原料，经多步反应合成目标化合物，并测定目标化合物的抗真菌活性。结果共合成了10个未见文献报道的新化合物，经红外光谱、核磁共振氟谱及元素分析确证了其结构。其中化合物3对大部分供试真菌活性强于或相当于对照品克霉唑。结论 硫色满目3位取代Mannich碱具有较强的抗真菌活性。     

1－［2－（取代苯基）烯丙基］－1H－唑类抗真菌化合物的合成

根据唑类抗真菌药物的构效关系，合成了１４个１－［２－（取代苯基］烯丙基］－１Ｈ－唑类化合物。体外抗真菌活性试验结果表明，此类化合物对几种常见的深部致病真菌都有不同程度的抗真菌活性。     

水溶性五环三萜酸衍生物的制备及研究进展

综述几种常见水溶性五环三萜酸衍生物的研究进展。五环三萜酸类化合物多具有广泛的生物活性,但因水溶性差、生物利用度低使其临床应用受到限制。以五环三萜酸为先导化合物,经结构修饰合成水溶性衍生物,并从中寻找出有生物活性和临床应用价值的化合物是当前天然药物化学研究的热点之一。     

Heterocyclic Coenzyme A - independent transacylase inhibitors

The efforts of scientists to optimise the performance of existing antifungal drugs has resulted in their continued commercial success and also in renewed efforts of drug design within the pharmaceutical industry. Modification of existing compounds and the discovery and synthesis of new antifungal compounds in an attempt to produce efficacious drugs for the treatment of a range of human mycoses has led to a substantial increase in the number of patent applications in this area over the past decade. Recent filings include a range of process and application issues for both natural and semi-synthetic derivatives and a large proportion of patents describe compounds that target fungal enzymes and cell structural components. New leading compounds which appear to show good biological activity as both immunosuppressive and antifungal agents arise mainly from the macrolide class. These and other fermentation and synthetic compounds look promising; further development of many compounds is likely.     

IPC synthase as a useful target for antifungal drugs

Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.     

Natural and synthetic naphthoquinones active against Trypanosoma cruzi: an initial step towards new drugs for Chagas disease

Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.     

Polyoxins and nikkomycins: progress in synthetic and biological studies

Polyoxins and nikkomycins are naturally-occurring peptidyl nucleoside antibiotics. As inhibitors of chitin synthetase, they exhibit antifungal activity, but lack antibacterial activity. Since they also lack mammalian toxicity, they represent potentially useful models for the development of effective agents for the treatment of opportunistic fungal infections. Direct clinical application of the natural peptidyl nucleosides is compromised by their attenuated in vivo activity, apparently due to their hydrolytic lability and inefficient fungal cell wall permeability. Thus, extensive efforts have focused on syntheses of natural peptidyl nucleosides, their components and analogs in anticipation of establishing useful structure-activity-relationships (SAR) for the development of new antifungal agents. A comprehensive and critical review of the synthetic effort and subsequent biological studies reveals that while much has been accomplished, ideal antifungal agents have not yet been developed from the natural peptidyl nucleoside leads. The need for continued study of agents with novel modes of action is emphasized by the realization that other structurally varied antifungal agents currently used clinically have limitations and often severe side effects, including nephrotoxicity.     

Recent anticancer cytotoxic agents

In spite of the impressive progress in diagnosis, surgery and therapy that occurred since the Sixties, the overall cancer mortality is still high and the medical need is largely unmet. A number of innovative strategies, aimed to target malignant abnormalities of tumor cells are in development and begin to give important results. In alternative, angiogenesis inhibition has been addressed with the aim to limit the tumor ability to grow and metastasize. However, it will likely take some years to fully define the therapeutic role of different innovative drugs. Therefore, cytotoxic drugs will continue to represent a chief part of the therapy in the forthcoming years, possibly in combination with innovative agents addressing molecular targets. Most important traditional chemotherapeutic drugs or investigational anticancer agents were derived from natural sources also through synthetic structural modifications. In the Nineties, taxanes and camptothecins represented important success stories of this approach, while among DNA interacting agents anthracyclines continued to represent a structural platform for discovering new drugs and DNA minor groove binders represented a new field of investigation. Combinatorial chemistry combined with high-throughput screening programs are an important source of totally synthetic new agents, however, it should not be disregarded the fact that nature already performed combinatorial chemistry and leads selection through the ages. New natural or semisynthetic agents acting as tubulin stabilizers or DNA interactive agents of various mechanisms of action are presently investigated and will probably continue to give important contribution to cancer therapy in the near future. In this review, the medicinal chemistry and the development status of these anticancer cytotoxic agents are focused and discussed.     

Stilbene derivatives as new perspective in antifungal medicinal chemistry

The high incidence and mortality of invasive fungal infections and serious drug resistance have become a global public health issue. There is an urgent need for alternative antimicrobials to control fungal infections and targeting it by antifungal substances from the natural sources represents a promising new strategy for the development of novel antifungal agents. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a phytoalexin produced by plant species in response to environmental stress or pathogenic attacks. It has many known and potential therapeutic applications in human general homeostasis; it mediates a great number of biological responses relevant for human health such as anticancer, cardio and neuroprotective, antioxidant, and antimicrobial activities. Resveratrol is a natural antifungal agent, therefore it can be considered as a scaffold for designing structural relatives potentially capable of mediating more intense responses in a more specific way. Also, stilbenes produced by several plants may be useful lead structure for the chemical synthesis of antifungal. Their antifungal potential represents a useful solution to the drug resistance and side effect complications that occur after pharmacological treatment of infectious diseases. The purpose of this review is to present an overview on resveratrol derivatives, both natural and synthetic, with antifungal activity and summarize the chemical structure and the therapeutic versatility of stilbene-containing compounds.     

Mechanisms of fungal resistance: an overview

The increased use of antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antifungal resistance from different angles. In this article we discuss antifungal susceptibility testing, the mode of action of antifungals and mechanisms of resistance. Antifungals are grouped into five groups on the basis of their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which bind to fungal membrane sterol, resulting in the formation of aqueous pores through which essential cytoplasmic materials leak out; allylamines, which block ergosterol biosynthesis, leading to accumulation of squalene (which is toxic to the cells); candins (inhibitors of the fungal cell wall), which function by inhibiting the synthesis of beta 1,3-glucan (the major structural polymer of the cell wall); and flucytosine, which inhibits macromolecular synthesis. Different mechanisms contribute to the resistance of antifungal agents. These mechanisms include modification of ERG11 gene at the molecular level (gene mutation, conversion and overexpression), over expression of specific drug efflux pumps, alteration in sterol biosynthesis, and reduction in the intracellular concentration of target enzymes. Approaches to prevent and control the emergence of antifungal resistance include prudent use of antifungals, treatment with the appropriate antifungal and conducting surveillance studies to determine the frequency of resistance.     

The echinocandin antifungals: an overview of the pharmacology,spectrum and clinical efficacy

For over four decades, the principal target of antifungal therapy has been the fungal cell membrane sterol ergosterol. Although this has proven to be a successful and relatively selective antifungal target, collateral toxicity to mammalian cells (amphotericin B) and drug interactions (azoles) have been by-products of agents that target the fungal cell membrane. In the 1970s, the echinocandins were identified during the screening of fungal fermentation products for new antibiotic agents. These agents were subsequently shown to inhibit production of β(1,3)-glucan, a key structural component of the fungal cell wall. Subsequent chemical modification of these natural products has led to the development of safer, semi-synthetic β(1,3)-glucan synthase inhibitors with enhanced microbiological and clinical efficacy against infections caused by Candida and Aspergillus species. In this review, the pharmacology, spectrum and clinical efficacy of the three leading β(1,3)glucan synthase inhibitors (caspofungin, micafungin and anidulafungin), which have completed phase III clinical trials, will be discussed and a perspective for the role of these agents in the management of life-threatening mycoses will be offered.     

The echinocandin antifungals: an overview of the pharmacology,spectrum and clinical efficacy

For over four decades, the principal target of antifungal therapy has been the fungal cell membrane sterol ergosterol. Although this has proven to be a successful and relatively selective antifungal target, collateral toxicity to mammalian cells (amphotericin B) and drug interactions (azoles) have been by-products of agents that target the fungal cell membrane. In the 1970s, the echinocandins were identified during the screening of fungal fermentation products for new antibiotic agents. These agents were subsequently shown to inhibit production of beta(1,3)-glucan, a key structural component of the fungal cell wall. Subsequent chemical modification of these natural products has led to the development of safer, semi-synthetic beta(1,3)-glucan synthase inhibitors with enhanced microbiological and clinical efficacy against infections caused by Candida and Aspergillus species. In this review, the pharmacology, spectrum and clinical efficacy of the three leading beta(1,3)glucan synthase inhibitors (caspofungin, micafungin and anidulafungin), which have completed phase III clinical trials, will be discussed and a perspective for the role of these agents in the management of life-threatening mycoses will be offered.     

抗真菌药物研究进展

综述近年来抗真菌药物的研究进展,包括抗真菌抗生素与合成抗真菌药.还概述了开发中的新药.