- Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2
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The COVID-19 pandemic has been disastrous to society and effective drugs are urgently needed. The papain-like protease domain (PLpro) of SARS-CoV-2 (SCoV2) is indispensable for viral replication and represents a putative target for pharmacological intervention. In this work, we describe the development of a potent and selective SCoV2 PLpro inhibitor, 19. The inhibitor not only effectively blocks substrate cleavage and immunosuppressive function imparted by PLpro, but also markedly mitigates SCoV2 replication in human cells, with a submicromolar IC50. We further present a convenient and sensitive activity probe, 7, and complementary assays to readily evaluate SCoV2 PLpro inhibitors in vitro or in cells. In addition, we disclose the co-crystal structure of SCoV2 PLpro in complex with a prototype inhibitor, which illuminates their detailed binding mode. Overall, these findings provide promising leads and important tools for drug discovery aiming to target SCoV2 PLpro.
- Shan, Hengyue,Liu, Jianping,Shen, Jiali,Dai, Jialin,Xu, Gang,Lu, Kuankuan,Han, Chao,Wang, Yaru,Xu, Xiaolong,Tong, Yilun,Xiang, Huaijiang,Ai, Zhiyuan,Zhuang, Guanglei,Hu, Junhao,Zhang, Zheng,Li, Ying,Pan, Lifeng,Tan, Li
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p. 855 - 9,865
(2021/05/18)
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- Synthesis and structure-activity relationship study of pyrrolidine-oxadiazoles as anthelmintics against Haemonchus contortus
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Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78–22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
- Ruan, Banfeng,Zhang, Yuezhou,Tadesse, Solomon,Preston, Sarah,Taki, Aya C.,Jabbar, Abdul,Hofmann, Andreas,Jiao, Yaqing,Garcia-Bustos, Jose,Harjani, Jitendra,Le, Thuy Giang,Varghese, Swapna,Teguh, Silvia,Xie, Yiyue,Odiba, Jephthah,Hu, Min,Gasser, Robin B.,Baell, Jonathan
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supporting information
(2020/02/04)
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- 3-(ureido-methyl)-4-aryl-pyridine compound, preparation method thereof and application thereof as anti-hepatoma medicament
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The invention discloses a 3-(ureido-methyl)-4-aryl-pyridine compound, a preparation method thereof and application thereof as an anti-hepatoma medicament. The invention discloses a compound shown as aformula I or a pharmacologically-acceptable salt, crystal form and solvate thereof, wherein X is O or S; n is an integer of 0 to 3; R1, R2, R3, R4 and R5 are independently selected from H, cyan, COOR11, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, trifluoromethyl, amino, nitro, hydroxyl, mercapto or halogen; R11 is selected from H or alkyl having 1 to 4 carbon atoms. Meanwhile, the invention also discloses a preparation method of the compound shown as the formula I. The compound disclosed by the invention has lower median inhibitory concentration (IC50), and a very good inhibition function on hepatoma carcinoma cells; moreover, the preparation method of the compound disclosed by the invention is simple and convenient, and has the advantages of mild reaction condition, convenience in operation and control, low energy consumption, high yield and low cost, and can be suitable for industrial production. The formula I is shown in the description.
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Paragraph 0135; 0136; 0137
(2018/03/26)
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- Phenotypic Optimization of Urea-Thiophene Carboxamides to Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss
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Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a urea-thiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 μM with protection against 200 μM neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structure-activity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.
- Chowdhury, Sarwat,Owens, Kelly N.,Herr, R. Jason,Jiang, Qin,Chen, Xinchao,Johnson, Graham,Groppi, Vincent E.,Raible, David W.,Rubel, Edwin W,Simon, Julian A.
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supporting information
p. 84 - 97
(2018/02/10)
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- Biological activity of analogues of YM022. Novel (3-amino substituted phenyl)urea derivatives of 1,4-benzodiazepin-2-one as gastrin/cholecystokinin-B receptor antagonists
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A series of (3-substituted phenyl)urea analogues of the potent gastrin/cholecystokinin (CCK)-B receptor antagonist YM022 has been prepared. Structure activity relationship studies of this series suggested that a number of analogues retained good in vitro potency for gastrin/CCK-B receptor. In particular, the (3-amino substituted phenyl)urea derivatives (10-12) were more potent inhibitors of pentagastrin-induced gastric acid secretion in rats than YM022 on intraduodenal (i.d.) administration.
- Satoh, Masato,Okamoto, Yoshinori,Koshio, Hiroyuki,Ohta, Mitsuaki,Nishida, Akito,Akuzawa, Shinobu,Miyata, Keiji,Mase, Toshiyasu,Semple, Graeme
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p. 1412 - 1414
(2007/10/03)
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- Catalytic oxidation of formamides to form isocyanates
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This invention relates to a process for preparing isocyanates from formamides wherein a formamide corresponding to the formula R--NHCHO)n, where R is an organic group and n is 1 or 2, is oxidized with an oxygen containing gas at a temperature in the range of 300° C. to 600° C. in the presence of a catalytic amount of copper and/or one or more metals of the Groups IB and VIII of the 5th and 6th period of the Periodic System of Elements to yield the corresponding isocyanate R (NCO)n where R and n have the same meaning as above, and the resultant gaseous isocyanate containing reaction mixture is subjected to a separation process to separate the product isocyanate from water of reaction.
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