Search

1.In this study, the pharmacokinetics of new triazole antifungal iodiconzole creams at target sites after single-dose topical application was investigated.2.30 healthy Chinese volunteers were randomly divided into three groups after being stratified by sex, each group was given a single topical dose of 1%, 2%, 4% iodiconazole cream (0.4 g). Stratum corneum (SC) samples of treated sites were collected by tape-stripping method after the chosen contact times, and were extracted and analysed by a validated LC-MS method.3.After single-dose topical application of 1%, 2%, 4% iodiconazole creams, the C

This study aimed to improve the biological effectiveness and pharmacokinetic properties of chlorin e

Chiral separation of iodiconazole, a new antifungal drug, and 12 new structurally related triadimenol analogues were studied by capillary electrophoresis with seven neutral cyclodextrins. It was found that hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was the most effective chiral selector. Furthermore, the influence of the concentration of HP-γ-CD, buffer pH, buffer concentration, temperature, and applied voltage was investigated, and the method was validated. The study of the analyte structure-enantioseparation relationships showed that substitutions in the side chains had important influences on enantiomeric separation.

Glucocorticoids (GCs) are routinely believed to take effect through genomic mechanisms, which are also largely responsible for GCs' side effects. Beneficial non-genomic effects of GCs have been reported as being independent of the genomic pathway. Here, we synthesized a new type of GCs, which took effect mainly via non-genomic mechanisms. Hydrocortisone was conjugated with glycine, lysine and phenylalanine to get a bigger molecular structure, which could hardly go through the cell membrane. Evaluation of the anti-inflammatory efficacy showed that hydrocortisone-conjugated glycine (HG) and lysine could inhibit neutrophil degranulation within 15 min. HG could inhibit IgE-mediated histamine release from mast cells via a non-genomic pathway, and rapidly alleviate allergic reaction. Luciferase reporter assay showed that HG would not activate the glucocorticoid response element within 30 min, which verified the rapid effects independent of the genomic pathway. The work proposes a novel insight into the development of novel GCs, and provides new tools for experimental study on non-genomic mechanisms.

B-Cell lymphoma-2 (Bcl-2) protein is a new promising target for anticancer drugs. A number of anticancer Bcl-2 inhibitors with diverse chemical structures have been discovered in recent years. In this paper, the flexible docking was performed to determine the binding modes of the representative inhibitors from different structural types. Subsequently, the binding modes of inhibitor were used to construct a primary three- dimensional (3D) pharmacophore model. It proved that this model can effectively disrupt the binding of the BH3 domain of proapoptotic Bcl-2 family members to Bcl-2, and match the structural requirement of a new type of Bcl-2 inhibitors. However, these distances between pharmacophoric points are not optimal due to the fact that not all of individual functional groups are located in the ideal position when inhibitors bind to its receptor. In this paper, we proposed a new idea to improve the quality of the pharmacophore model: the multiple copy simultaneous search (MCSS) method was performed to determine the energetically favorable distribution of functional groups with similar features to these pharmacophoric points in the active site of Bcl-2 first. Then their most energetically favorable minima in the positions near the pharmacophoric points were used to optimize the distances between pharmacophoric points. By examining the binding modes of several inhibitors from the same structural type, it was found that the more potent the inhibitor was, the closer it was to the optimized distances between pharmacophoric points. The optimized 3D pharmacophore model obtained in this paper may provide a good starting point for further rational design of Bcl-2 inhibitors.

Based on the active site of Candida albicans lanosterol 14α-demethylase (CACYP51), novel triazole compounds structurally different from the current triazole drugs were designed and synthesized. In vitro antifungal activities showed that compounds 10, 11, 16 and 20 exhibited strong activities. In addition, compounds 10, 11 and 16 also displayed certain activities against fluconazole-resistant fungi.

Nine racemic homocamptothecin derivatives were synthesized and in vitro antitumor activities were evaluated by standard MTT method. The results showed that some of the compound had higher antitumor activity than iritecan.

In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.

In recent years, the incidence of infections caused by invasive fungal pathogens has increased dramatically. However, most antifungal agents used in clinic have many drawbacks and cannot meet the demand of the clinical use. Therefore, for the development of new generation of antifungal agents, it is of great significance to find antifungal lead compounds with novel chemical scaffolds and new mode of action. Novel antifungal lead compounds reported in recent years are reviewed. Their chemical structures, antifungal activity and structure-activity relationship are discussed in detail, and current problems and trends in future research are also emphasized.

To clarify the important functional residues in the active site of N-myristoyltransferase (NMT), a novel antifungal drug target, and to guide the design of specific inhibitors, multiple sequence alignments were performed on the NMT family and thus evolutionary trace was constructed. The important functional residues in myristoyl CoA binding site, catalytic center and inhibitor binding site of NMT family were identified by ET analysis. The trace residues were mapped onto the active site of CaNMT. Trpl26, Asn175 and Thr211 are highly conserved trace residues and do not interact with current NMT inhibitors, which are potential novel drug binding sites for the novel inhibitor design. Pro338, Leu350, Ile352 and Ala353 are class-specific trace residues, which are important for the optimization of current NMT inhibitors. The trace residues identified by ET analysis are of great importance to study the structure-function relationship and also to guide the design of specific inhibitors.

A series of triazole antifungals were synthesized to search for novel triazole antifungals with more potent activity, less toxicity and broader spectrum.Nineteen 1-(1,2,4-triazolyl-1H-1-yl)-2-(2,4-diflurophenyl)-3-(4-substituted benzyl-1-piperazinyl)-2-propanols were designed and synthesized, on basis of the three dimensional structure of P450 cytochrome 14 alpha-sterol demethylase (CYP51) and their antifungal activities were also evaluated.All the title compounds were first reported. Results of preliminary biological tests showed that most of the title compounds exhibited high activity against the eight common pathogenic fungi and the activities against deep fungi were higher than that against shallow fungi.Most of the title compounds showed higher antifungal activities than Fluconazole and Terbinafine. Compound VIII-1, 10, 12, 17 showed best antifungal activity with broad antifungal spectrum and were chosen for further development.