Structure-Based de Novo Design, Synthesis, and Biological Evaluation of Non-Azole Inhibitors Specific for Lanosterol 14α-Demethylase of Fungi

Ji, Haitao; Zhang, Wannian; Zhang, Min; Kudo, Makiko; Aoyama, Yumi; Yoshida, Yasuhiko; Sheng, Chunquan; Song, Yuelin; Song, Yang; Zhou, Youjun; Lü, Jing; Zhu, Jin

doi:10.1021/jm020362c

Cited by 106 publications

(62 citation statements)

References 35 publications

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“…Then the solvent was removed in vacuo giving 0.28 g (80%) of a dark brown oil: GC/MS (70 eV) m/z (%) 213 (M þ , 100). Other spectroscopic data were in agreement with the literature [24].…”

Section: General Procedures For the Synthesis Of 4-substituted Anilinesupporting

confidence: 91%

2-Aminobenzothiazole derivatives: Search for new antifungal agents

Catalano

Carocci

Defrenza

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tA new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4e8 mg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells.

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“…Then the solvent was removed in vacuo giving 0.28 g (80%) of a dark brown oil: GC/MS (70 eV) m/z (%) 213 (M þ , 100). Other spectroscopic data were in agreement with the literature [24].…”

Section: General Procedures For the Synthesis Of 4-substituted Anilinesupporting

confidence: 91%

2-Aminobenzothiazole derivatives: Search for new antifungal agents

Catalano

Carocci

Defrenza

et al. 2013

European Journal of Medicinal Chemistry

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“…In fact the importance of charge transfer between azole derivatives and the iron atom of lanosterol 14α-desmethylase active site heme portion has already been reported. [24][25][26][27] Taken together, this analysis suggests that the dipole moment (JGI4) and the presence of the C-O fragment at topological distance of 06 and 07, that relates to OH in the most active compounds, are important for the largest activity of these compounds.…”

Section: B06[co] and B07mentioning

confidence: 78%

In vitro screening and chemometrics analysis on a series of azole derivatives with fungicide activity against moniliophthora perniciosa

Mota¹,

Barros²,

Castilho³

2010

J. Braz. Chem. Soc.

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Moniliophthora perniciosa, o agente causal da vassoura-de-bruxa do cacaueiro, diminuiu significativamente a produção de cacau, especialmente no estado da Bahia, a maior região produtora de cacau do continente americano. As formas de controle desenvolvidas até o momento têm baixa eficiência. Derivados de azol são ativos tanto in vitro quanto in loco contra M. perniciosa, porém não há um estudo sistemático sobre a atividade dos azóis contra este fitopatogeno. Dados biológicos, obtidos em um ensaio padronizado, foram utilizados para criação de modelos quimiométricos, que destacam características físico e estruturais importantes para a atividade fungicida de derivados de azol frente a M. perniciosa. De acordo com os modelos de PCA e SIMCA, características eletrônicas, representadas pelos descritores BEHe3 e JGI4, paralelamente à possibilidadde de realizar ligações de H e ausência de átomos de cloro, distantes de 6-8 ligações dos nitrogênios do anel azólico, parecem contribuir para atividade fungicida dos compostos estudados Moniliophthora perniciosa, the causal agent of witches' broom disease in Theobroma cacao, significantly decreased cacao production, especially in Bahia State, the largest cocoa producing of the American continent. Control programs developed so far have low efficiency. Azole derivatives are active both in vitro and in loco against M. perniciosa, however there is no comprehensive study on the activity of azoles against this phytopatogen. Standardized in vitro biological data were employed to develop supervised and unsupervised chemometric models that highlight physicochemical and structural features that are crucial for azole's fungicidal activity against M. perniciosa. Thus, PCA and SIMCA models suggest that electronegativity (BEHe3) and dipolar moment (JGI4), as well as H-bonding to M. pernciosa's lanosterol 14α-desmethylase active site and lack of Cl atoms 6 to 8 bonds from the azole's nitrogen atoms play a major role to azoles' fungicide activity.

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“…On the basis of the three-dimensional model of lanosterol 14α-demethylase (CYP51) from C albicans constructed in previous studies [15][16][17][18] , a series of 2-aminotetralin compounds was designed and synthesized as antifungal agents. We hope that these compounds are able to interact with amino acid residues in the active site of CYP51 and avoid connection with the iron atom of heme, and therefore they can not only generate potent antifungal activity but attenuate severe toxicities of azoles.…”

Section: Discussionmentioning

confidence: 99%

2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway

et al. 2009

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Aim: To investigate the action mechanism of a novel chemical structural aminotetralin derivate, 2-Amino-Nonyl-6-Methoxyl-Tetralin Muriate (10b), against Candida albicans (C albicans) in the ergosterol biosynthetic pathway. Methods: Antifungal susceptibility test of 10b was carried out using broth microdilution method, the action mechanism of 10b against C albicans was investigated by GC-MS spectrometry and real-time RT-PCR assay, and cytotoxicity of 10b in vitro was assessed by MTS/ PMS reduction assay. Results: 10b reduced the ergosterol content markedly, and the 50% ergosterol content inhibitory concentration (ECIC 50 value) was 0.08 μg/mL. Although the sterol composition of 10b-grown cells was completely identical with that of erg24 strain, the content of ergosta-8,14,22-trienol in 10b-grown cells was much higher than that in erg24 strain. Real-time RT-PCR assay revealed a global upregulation of sterol metabolism genes. In addition, the 50% inhibitory concentration (IC 50 value) of 10b was 11.30 μg/mL for murine embryonic fibroblasts and 35.70 μg/mL for human normal liver cells. Conclusion: 10b possessed a mode of action different from that of azoles and morpholines, whose targets were sterol C-14 reductase (encoded by ERG24 gene) and sterol C-5 desaturase (encoded by ERG3) related enzyme. Although 10b seemed to reduce MTS/PMS reduction in a dose dependent manner, IC 50 value for mammalian cells was much higher than 50% minimum inhibitory concentration (MIC 50 ) value for C albicans. This indicates that the formulation is preliminarily safe and warrants further study for possible human applications.

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Structure-Based de Novo Design, Synthesis, and Biological Evaluation of Non-Azole Inhibitors Specific for Lanosterol 14α-Demethylase of Fungi

Cited by 106 publications

References 35 publications

2-Aminobenzothiazole derivatives: Search for new antifungal agents

2-Aminobenzothiazole derivatives: Search for new antifungal agents

In vitro screening and chemometrics analysis on a series of azole derivatives with fungicide activity against moniliophthora perniciosa

2-Amino-nonyl-6-methoxyl-tetralin muriate inhibits sterol C-14 reductase in the ergosterol biosynthetic pathway

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