Xiaoyun Chai

Design, synthesis and antifungal activities of novel 1,2,4-triazole derivatives.

A series of novel 1,2,4-triazole derivatives with a 4-(4-substitutedphenyl) piperazine side chain were designed and synthesized based on the structure of lanosterol 14α-demethylase (CYP51). Their antifungal activities against eight human pathogenic fungi were evaluated in vitro by measuring the minimal inhibitory concentrations. Nearly all tested compounds were found to be more potent against Candida albicans than control drug fluconazole. Noticeably, the MIC(80) value of compounds 6,7,9,14 and 29 is 16 times lower than that of voriconazole against C. albicans. The activities of compounds 7 and 21 against Cryptococcus neoformans in vitro are comparable to that of voriconazole with a MIC(80) value of 0.0156 μg/mL. Moreover, the molecular model for the binding between compound 7 and the active site of CACYP51 was provided based on the computational docking results.

Near-Infrared Phosphorus-Substituted Rhodamine with Emission Wavelength above 700 nm for Bioimaging

Phosphorus has been successfully fused into a classic rhodamine framework, in which it replaces the bridging oxygen atom to give a series of phosphorus-substituted rhodamines (PRs). Because of the electron-accepting properties of the phosphorus moiety, which is due to effective σ*-π* interactions and strengthened by the inductivity of phosphine oxide, PR exhibits extraordinary long-wavelength fluorescence emission, elongating to the region above 700 nm, with bathochromic shifts of 140 and 40 nm relative to rhodamine and silicon-substituted rhodamine, respectively. Other advantageous properties of the rhodamine family, including high molar extinction coefficient, considerable quantum efficiency, high water solubility, pH-independent emission, great tolerance to photobleaching, and low cytotoxicity, stay intact in PR. Given these excellent properties, PR is desirable for NIR-fluorescence imaging in vivo.

New triazole derivatives as antifungal agents: synthesis via click reaction, in vitro evaluation and molecular docking studies.

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (5a-5y) which are analogues of fluconazole, have been designed and synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition on the basis of computational docking experiments to the active site of the cytochrome P450 14α-demethylase (CYP51). The in vitro antifungal activities of all the target compounds were evaluated against eight human pathogenic fungi. Compound 5l showed the best antifungal activities.

Design, synthesis, and biological evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase

Based on the results of computational docking to the active site of the cytochrome P450 14alpha-demethylase (CYP51), a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. The MIC(80) values indicate that compounds 1a-n exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus than fluconazole, while compounds 2a-f, 3a-f showed no activity or only moderate activity against all fungi tested. Noticeably, the MIC value of compounds 1a, 1b and 1g is 64 times lower than that of fluconazole against Microsporum gypseum in vitro. And compounds 1a, 1b and 2b showed 128 times higher activity (with the MIC(80) value of 0.0039 microg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. Computational docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. In addition, the activity of the compounds would be enhanced when the side chains were shorter.

Design, synthesis, and biological evaluation of novel 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted benzylamino-2-propanols.

Based on the results of computational docking to the active site of the cytochrome P450 14alpha-demethylase (CYP51), a series of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted benzylamino-2-propanols as analogs of fluconazole were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent activities with broad spectrum.

Synthesis and antifungal evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14α-demethylase

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1a-v, 2a-w), which are analogues of fluconazole, have been designed and synthesized as the potential antifungal agents by the click reaction. Click reaction approach toward the synthesis of two sets of novel 1,2,3-triazolyl linked triazole antifungal derivatives 1a-v, 2a-w was achieved by Cu(I)-catalyzed 1,3-dipolar cycloaddition of propargylated intermediate 8 with substituted azidomethyl benzene. The 1,2,3-triazolyl group was inserted into the side chain of the target molecule which can increase the antifungal activity of compounds.

Design, synthesis and molecular docking studies of novel triazole as antifungal agent.

In order to meet the urgent need for novel antifungal agents with improved activity and broader spectrum, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substituted trifluoromethyl phenyl)-piperazin-1-yl]-propan-2-ols were designed, synthesized and evaluated as antifungal agents. The MIC(80) values indicate that the compounds 7a-7q, 8a-8d showed higher antifungal activities against Candida albicans than 5a-5i, 6a-6j. Moreover, the molecular model for the binding between compound 5a, 7a and the active site of CACYP51 was provided based on the computational docking results, and the structure-activity relationship was analyzed.

New azoles with antifungal activity: Design, synthesis, and molecular docking

In order to search for many target compounds with excellent activities, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluoro-phenyl)-3-[(4-substituted phenyl)-piperazin-1-yl]-propan-2-ols were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent activities with broad spectrum. Moreover, a molecular model for the binding between 5a and the active site of CACYP51 was provided based on the computational docking results.

Synthesis, in vitro evaluation and molecular docking studies of new triazole derivatives as antifungal agents.

On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of 1-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-1,2,4-triazol-5(4H)-one derivatives were synthesized as fluconazole analogs. Results of the preliminary antifungal tests against eight human pathogenic fungi in vitro showed that these compounds exhibited activities to some extent, and some displayed excellent antifungal activities against C. albicans than reference drug fluconazole. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the target compounds. The designed compounds interact with CACYP51 through hydrophobic, van der Waals and hydrogen-bonding interactions.

Discovery of novel xanthone derivatives as xanthine oxidase inhibitors

Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. In this study, a series of xanthone derivatives were synthesized as effective and a new class of xanthine oxidase inhibitor. Compounds 8a, 8c, 8i, 8g and 8r showed good inhibition against xanthine oxidase. The presence of a cyano group at the para position of benzyl moiety turned out to be the preferred substitution pattern. Molecular modeling studies were performed to gain an insight into its binding mode with xanthine oxidase, and to provide the basis for further structure-guided design of new non-purine xanthine oxidase inhibitors associated with the xanthone framework.