Shichong Yu

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.

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.

Synthesis, molecular docking, and biological evaluation of novel triazole derivatives as antifungal agents.

Twenty‐eight novel triazole derivatives (compounds 1a‐v, 2a‐f) have been synthesized for structure–activity relationship studies as antifungal agents. The compounds were designed on the basis of the structure of fluconazole and molecular modeling of the active site of the cytochrome P450 14α‐demethylase (CYP51). All of them are reported for the first time. Their chemical structures are characterized by 1H NMR, 13C NMR, LC‐MS, and elemental analysis. The antifungal activities have been evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 1a‐v exhibited higher activity against nearly all fungi tested except Aspergillus fumigatus (A. fum) than fluconazole (FCZ). The computational molecular docking experiments indicated that the inhibition of CYP51 involves a coordination bond with iron of the heme group, a hydrophilic H‐bonding region, a hydrophobic region, and a narrow hydrophobic binding cleft.

First identification of xanthone sulfonamides as potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors.

Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) would be useful anti-atherogenic agents, since an absence of ACAT affects the absorption and transformation of cholesterol, indirectly resulting in the reduction of cholesteryl ester accumulation in blood vessels. This report discloses xanthone sulfonamides as novel class small molecule inhibitors of ACAT. A series of xanthone sulfonamides were synthesized and evaluated to result in the identification of several potent ACAT inhibitors, among which 2n proved to be more potent than the positive control Sandoz58-35. Moreover, a molecular model for the binding between 2n and the active site of ACAT-2 was provided based computational docking results.

Synthesis of mangiferin derivatives as protein tyrosine phosphatase 1B inhibitors

Protein tyrosine phosphatase 1B (PTP1B) has received much attention due to its pivotal role in type 2 diabetes and obesity as a negative regulator of the insulin signaling pathway. Mangiferin, a xanthone glucoside, has been reported to possess significant antidiabetic activity. In the present study, a series of mangiferin derivatives was synthesized and evaluated for their PTP1B inhibitory activity. Some of the screened compounds displayed good PTP1B inhibitory activity.

Synthesis and in vitro antitumor activities of xanthone derivatives containing 1,4-disubstituted-1,2,3-triazole moiety

To explore the more active antitumor compounds, two series of new xanthones, containing 1,4-disubstituted-1,2,3-triazole moiety were designed and synthesized. Eaton’s Reagent and “click reaction” were used in the synthesis. Most of the title compounds showed good inhibitory activity against the hepatoma carcinoma cell line (Bel-7402) and human cervical carcinoma cell line (HeLa) in vitro. Compounds 10a, 10e, 10f, 11r and 11t had potent activity with IC50 values, ranging from 2.2 ± 0.17 to 7.1 ± 0.27 ∝M, which was equivalent to Doxorubicin.

Design, synthesis, and biological evaluation of novel 1, 2, 4-triazole derivatives as antifungal agent.

A series of novel 1, 2, 4-triazole derivatives (9a–p) have been designed and synthesized as the potential antifungal agents. All compounds were characterized by 1H-NMR, 13C-NMR, and LCMS. Their antifungal activities against seven human pathogenic fungi were evaluated in vitro by measuring the minimal inhibitory concentrations. Most of the tested compounds were found to be more potent against Candida albicans than the control drug fluconazole.