Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

1区 · 医学

Article

作者: Zhao, Liyu ; Cheng, Maosheng ; Zhang, Yuxin ; Zhao, Dongmei ; Yin, Wenbo ; Cui, Hengxian ; Liu, Lei ; Sun, Yixiang ; Sun, Yin ; Qin, Qiaohua ; Jiang, Hong ; Gao, Zixuan ; Su, Xin ; Wu, Tianxiao

Invasive fungal infections are emerging as serious infectious diseases worldwide. Because of the development of antifungal drug resistance, the limited efficacy of the existing drugs has led to high mortality in patients. The use of the essential eukaryotic chaperone Hsp90, which plays a multifaceted role in drug resistance across diverse pathogenic fungal species, is considered to be a new strategy to mitigate the resistance and counter the threat posed by drug-resistant fungi. Thus, a series of 4,5-diarylisoxazole analogues as fungal Hsp90 inhibitors were designed and synthesized that had potent synergistic effects with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential mammalian toxicity of Hsp90 inhibitors based on key reside differences between humans and fungi. These data support the feasibility of targeting fungal Hsp90 as a promising antifungal strategy and further development of compound A17 as a valuable research probe for the investigation of fungal Hsp90.

2020-03-01·Pest management science

Synthesis and herbicidal activity of novel pyrazole aromatic ketone analogs as HPPD inhibitor

Article

作者: Cai, Peng‐Peng ; Zhong, Liang‐Kun ; Shen, Zhong‐Hua ; Cheng, Long ; Liu, Xing‐Hai ; Han, Liang ; Tan, Cheng‐Xia ; Fu, Qing ; Xu, Tian‐Ming

Abstract:

BACKGROUND:

4‐Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been a good target for herbicide discovery. In order to discover novel HPPD herbicides, a series of pyrazole aromatic ketone analogs were designed and synthesized.

RESULTS:

The 25 pyrazole aromatic ketone analogs synthesized were tested for herbicidal activity and compounds A1, A3, A4, A17, A20 and A25 displayed excellent herbicidal activity against Chenopodium serotinum, Stellaria media and Brassica juncea at 37.5 g ha−1. In addition, compounds A1, A5, A9, A10, A16, A17, A20 and A25 exhibited good crop selectivity for wheat, maize and rice at 150 g ha−1. Inhibition activities against AtHPPD proved the compounds were HPPD inhibitors. The structure–activity relationship of these pyrazole aromatic ketone analogs was studied using molecular docking.

CONCLUSION:

These pyrazole aromatic ketone derivatives could be used as lead structures for development of HPPD herbicides against dicotyledonous weeds with further structure modification. © 2019 Society of Chemical Industry

2020-03-01·Heart failure reviews2区 · 医学

Angiotensin II and angiotensin 1–7: which is their role in atrial fibrillation?

2区 · 医学

Review

作者: Urbanek, Konrad ; Scavone, Cristina ; De Angelis, Antonella ; Mascolo, Annamaria ; Sessa, Maurizio ; Capuano, Annalisa ; Rosano, Giuseppe Massimo Claudio ; Rossi, Francesco ; Berrino, Liberato

Atrial fibrillation (AF) is a significant cause of morbidity and mortality as well as a public health burden considering the high costs of AF-related hospitalizations. Pre-clinical and clinical evidence showed a potential role of the renin angiotensin system (RAS) in the etiopathogenesis of AF. Among RAS mediators, angiotensin II (AII) and angiotensin 1-7 (A1-7) have been mostly investigated in AF. Specifically, the stimulation of the pathway mediated by AII or the inhibition of the pathway mediated by A1-7 may participate in inducing and sustaining AF. In this review, we summarize the evidence showing that both RAS pathways may balance the onset of AF through different biological mechanisms involving inflammation, epicardial adipose tissue (EAT) accumulation, and electrical cardiac remodeling. EAT is a predictor for AF as it may induce its onset through direct (infiltration of epicardial adipocytes into the underlying atrial myocardium) and indirect (release of inflammatory adipokines, the stimulation of oxidative stress, macrophage phenotype switching, and AF triggers) mechanisms. Classic RAS blockers such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may prevent AF by affecting the accumulation of the EAT, representing a useful therapeutic strategy for preventing AF especially in patients with heart failure and known left ventricular dysfunction. Further studies are necessary to prove this benefit in patients with other cardiovascular diseases. Finally, the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.

100 项与 A-17 相关的药物交易

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