Search

In order to explore novel antifungal agents, twenty-seven triazole derivatives featuring an alkyne linker in the side chain were designed and synthesized by the Sonogashira reaction. Most of the target compounds exhibited good antifungal activity against eight human pathogenic fungi, especially excellent activity against Candida and Cryptococcus species, comparing with the reference drugs fluconazole, voriconazole and ravuconazole. Compounds A2 and A3 exhibited in vitro activity against all the tested fungi with MIC 80 values ranging from 0.0156 μg/mL to 0.5 μg/mL, which are superior to ravuconazole and fluconazole. SAR and molecular docking study give a clear conclusion that para -fluoro, para -chloro, and para -cyano substituted phenylalkynyl or pyridinylalkynyl side chains may promote triazole antifungal activity. [ABSTRACT FROM AUTHOR]

The incidence of life-threatening fungal infections has dramatically increased for decades. In order to develop novel antifungal agents, two series of (2 R ,3 R )-1-(1 H -1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-( N -substitutied)-2-butanols ( 3a-o , 5a-f , 8a-u ), which were analogues of voriconazole, were designed, synthesized and characterized by 1 H NMR, 13 C NMR and HRMS. The MIC 80 values showed that the target compounds 3a-o indicated better activities than fluconazole on three important fungal pathogens except for 3i . Significant activity of compounds 3d , 3k , 3n , 3m and 3o was observed on the Aspergillus fumigatus strain (MIC 80 range: 1–0.125 μg/ml). Especially, compound 3k had strong activity to inhibit the growth of ten fungal pathogens. But it didn't exhibit good activity in in vivo value. Molecular docking experiments demonstrated that 3k possessed superior affinity with target enzyme by strong hydrogen bond from morpholine ring. [ABSTRACT FROM AUTHOR]

Abstract: A series of 11,12-cyclic carbonate azithromycin-4″-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated as antibacterial agents to search for target compounds with excellent activity. The results of preliminary antibacterial tests against eight strains in vitro revealed that all of the title compounds exhibited improved activities with broad spectrum compared with the parent compound. The glycosylated side chains may be the pharmacophores responsible for the improved activity. [Copyright &y& Elsevier]

Abstract: In order to search for drugs with excellent anti-inflammatory activities, a series of novel sinomenine derivatives were designed, synthesized, and evaluated for their inhibition activities against NF-κB activation induced by lipopolysaccharide (LPS). Compared with the natural parent sinomenine, compounds 2a–w showed higher activity, while compounds 1a–o showed similar activity against NF-κB. Moreover, a molecular model for the binding between compound 2v and the active site of p50 was provided on the basis of the computational docking results. [Copyright &y& Elsevier]

A series of triazole antifungal agents with piperidine side chains were designed and synthesized. 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 compound 12 and the active site of CACYP51 was provided based on the computational docking results. The side chain of the compound 12 is oriented into substrate access channel 2 (FG loop) and forms hydrophobic and van der waals interactions with surrounding hydrophobic residues. The phenyl group of the side chain can interact with the phenyl group of Phe380 through the formation of π-π face-to-edge interaction. [ABSTRACT FROM AUTHOR]

Abstract: 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 MIC80 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. [Copyright &y& Elsevier]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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 H NMR, C 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Based on the results of computational docking to the active site of the cytochrome P450 14α-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 MIC80 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 MIC80 value of 0.0039μg/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. [Copyright &y& Elsevier]

Abstract: Based on the results of computational docking to the active site of the cytochrome P450 14α-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. [Copyright &y& Elsevier]

Acute lung injury (ALI) is a serious public health problem associated with high morbidity and mortality. However, few efficacious drugs are clinically available. Inhibition of proinflammatory cytokines is considered to be a promising method for the treatment of inflammatory diseases. Herein, the total synthesis of a dibenzylbutane lignan, 9′- O -di-(E)-feruloyl- meso -5,5′-dimethoxysecoisolariciresinol (LCA), was completed. A series of LCA derivatives were designed and synthesized, and their anti-inflammatory activities were evaluated. Derivative 14r significantly inhibited LPS-induced expression of NO and the proinflammatory cytokines TNF-α, IL-6, and IL-1β in RAW 264.7 cells and inhibited activation of the NF-κB pathway. Compound 14r reduced LPS-induced pulmonary inflammation and ALI in mice. It showed significant protective effects against LPS-induced ALI in mice and significantly reduced levels of proinflammatory cytokines in serum and bronchoalveolar lavage fluid. The ratio of wet weight to dry weight of lung tissue was normalized by compound 14r , which was consistent with suppression of neutrophil infiltration and production of proinflammatory cytokines. Compound 14r reduced the mRNA expression of some proinflammatory cytokines, improved histopathologic changes, and reduced macrophage infiltration in lung tissues. Collectively, these results suggest a new series of LCA derivatives that could be promising anti-inflammatory agents for ALI treatment. [Display omitted] • Designed and synthesized a series of LCA derivatives. • Most of the compounds effectively suppressed LPS-induced NO and the proinflammatory cytokines. • Compound 14r can exert anti-inflammatory effects through the NF-κB pathway. • Compound 14r could be a potent anti-inflammatory candidate for ALI therapy. [ABSTRACT FROM AUTHOR]

Based on our previous discovery and SAR study on the lead compounds 7d, 5 and berberine which can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans , a series of 3-(benzo[ d ][1,3]dioxol-5-yl)- N -(substituted benzyl)propanamides were designed, synthesized, and evaluated for their in vitro synergistic activity in combination with fluconazole. The series 2a – f were designed by replacing the amide moiety of the lead compound 7d with retro-amide moiety, and compounds 2a and 2b showed more activity than the lead 7d. Furthermore, introducing biphenyl moiety into series 2d – f afforded series 3a – r , most of which exhibited significantly superior activity to the series 2d – f . Especially, compound 3e , at a concentration of 1.0 µg/ml, can enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans from 128.0 µg/ml to 0.125–0.25 µg/ml. A clear SAR of the compounds is discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] Herein, the di- and trisaccharide mimics of the hexasaccharide antigen related to Bacillus anthracis were synthesized and covalently coupled with carrier proteins, such as keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA), to form the corresponding glycoconjugates 1 – 6. 2,3,4,6-Tetra- O -benzyl thioglycoside and 2-deoxyl-2-phthalylamino-3,4,6-tri- O -benzyl thioglycoside were applied as glycosyl donors to guarantee α or β -configuration of the newly formed glycosidic bonds. Glutaraldehyde was used as a homobifunctional cross-linker for high-efficiency coupling. The synthetic KLH-glycoconjugates 2 , 4 and 6 were also used to vaccinate female Balb/c mice and the preliminary results of ELISA uncovered that all three KLH-conjugates could induce immune responses and generate oligosaccharide-specific total IgG antibodies. The trisaccharide 8 , the glycosyl part of glycoconjugate 4 , is of great immunogenicity. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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 MIC80 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 MIC80 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. [Copyright &y& Elsevier]

Abstract: Based on the structure of the active site of cytochrome P450 14α-demethylase (CYP51) and the conclusions of the structure-activity relationships of azole antifungals, a series of 1-(2-(2,4-difluoro-phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-1,2,4-triazol-5(4H)-one of fluconazole analogs was synthesized. All compounds were characterized by IR, HRMS, 1HNMR and 13C NMR spectroscopic analysis. Results of preliminary antifungal in vitro test using eight human pathogenic species showed that some compounds displayed comparable or even better antifungal activities than reference drug fluconazole and that compound 3i exhibited significant activity against Candida albicans being worthy of further optimization. [Copyright &y& Elsevier]

Abstract: Using a rational approach to the design of antifungal agents, a series of azole agents with 1,3,4-oxadiazole side chains were designed and synthesized. The results of preliminary in vitro antifungal tests with eight human pathogenic compounds showed that all of the title compounds exhibited excellent activities against all of the tested fungi except Aspergillus fumigatus. Compounds 11e and 11f were found to be the most effective, with a minimum inhibitory concentration of 0.0039μg/mL, followed by voriconazole, which has a MIC of 0.0625μg/mL. The 1,3,4-oxadiazole side chain is not the major contributor but plays a role in eliciting the observed antifungal activity. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Twenty-six novel triazole analogues featuring isoxazole moieties were designed and synthesized by replacing 4-cyanophenylthioazole moiety in ravuconazole with substituted phenylisoxazole methoxyl. The in vitro antifungal activities demonstrate the introduction of isoxazole methoxyl moiety bearing medium side chains is beneficial for retaining the novel compounds antifungal activities. • Novel triazole analogues featuring isoxazole moieties were designed and synthesized. • All compounds showed potent activity against Candida spp. (MICs ≤ 0.5 μg/mL). • The single-crystal data of compound 2 was obtained. • Compound a6 showed excellent inhibitory activity against some Candida spp. (MICs = 0.0313 μg/mL). In order to develop novel antifungal agents, based on our previous work, a series of (2 R ,3 R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1 H -1,2,4-triazol-1-yl) butan-2-ol (a1 - a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC 80 values of 0.0313 μg/mL. In addition, compounds a6 , a9 , a12 , a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC 80 values ranging from 8 μg/mL to 16 μg/mL. Furthermore, compounds a6 , a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51. [ABSTRACT FROM AUTHOR]

The incidence of invasive fungal infections has dramatically increased for several decades. In order to discover novel antifungal agents with broad spectrum and anti- Aspergillus efficacy, a series of novel triazole derivatives containing 1,2,3-benzotriazin-4-one was designed and synthesized. Most of the compounds exhibited stronger in vitro antifungal activities against tested fungi than fluconazole. Moreover, 6m showed comparable antifungal activity against seven pathogenic strains as voriconazole and albaconazole, especially against Aspergillus fumigatus (MIC = 0.25 μg/ml), and displayed moderate antifungal activity against fluconazole-resistant strains of Candida albicans. A clear SAR study indicated that compounds with groups at the 7-position resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum. [ABSTRACT FROM AUTHOR]