- Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis
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Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, we chemically optimized our previously reported benzhydroxamate-based inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by the highly potent inhibitor 5o. Structure-based optimization of the novel inhibitors was carried out using the available crystal structures as well as docking studies on smHDAC8. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs (hHDAC). The in vitro and docking results were used for detailed structure activity relationships. The synthesized compounds were further investigated for their lethality against the schistosome larval stage using a fluorescence-based assay. The most promising inhibitor 5o showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
- Darwish, Salma,Erdmann, Frank,Ghazy, Ehab,Heimburg, Tino,Jung, Manfred,Lancelot, Julien,Pierce, Raymond,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Shaik, Tajith B.,Simoben, Conrad V.,Sippl, Wolfgang,Truhn, Anne,Zeyen, Patrik
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- Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists
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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μΜ.
- Durner, Anna,Koufaki, Maria,Kritsi, Eftichia,Nicke, Annette,Papakostas, Alexios,T. Pournara, Dimitra,Zoumpoulakis, Panagiotis
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supporting information
p. 2530 - 2543
(2020/10/19)
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- FUSED BICYCLIC COMPOUNDS AND USES THEREOF IN MEDICINE
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Fused bicyclic compounds and uses thereof in medicine. In particular, provided are fused bicyclic compounds used as ASK1 active regulator and and use of the compounds in the manufacture of a drug for treating a disease regulated by ASK1. Further provided are a pharmaceutical composition and a method of treating a disease regulated by ASK1 comprising administering the compounds or pharmaceutical composition thereof.
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Paragraph 00196; 00213
(2019/03/05)
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- Compound JK-03M having higher protein kinase G inhibitory activity or pharmaceutically acceptable salt thereof and preparation method thereof
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The invention discloses a compound which has higher protein kinase G inhibitory activity and is shown in a formula I or pharmaceutically acceptable salt thereof and a preparation method thereof. The compound JK-03M having the higher protein kinase G inhibitory activity comprises a pharmaceutical composition of a new compound and application of the new compound in treatment of pain, in particular to chronic pain. The formula (1) is shown in the description.
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Paragraph 0093; 0157; 0159-0160
(2018/11/03)
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- Compounds with higher PKG (protein kinase G) inhibitory activity and preparation method of compounds
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The invention discloses compounds which have higher PKG (protein kinase G) inhibitory activity and are represented as a formula I, pharmaceutically acceptable salts, pharmaceutical composition containing the novel compounds, as well as an application of the novel compounds in treatment of pain, especially chronic pain. The invention further discloses a preparation method of the compounds and new intermediates. R1 and R2 are the same or different and are selected from a group comprising halogen (such as F or Cl), C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R3 is a terminal group and is selected from a group comprising H, halogen, alkyl, naphthenic base, alkenyl, alkynyl, aryl and heteroaryl; n is the number of repetitive units and is an integer in a range from 1 to 15.
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Paragraph 0184; 0185; 0186; 0187; 0188; 0189
(2016/10/08)
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- COMPOUND HAVING HIGHER INHIBITION OF PROTEIN KINASE G ACTIVITY AND PREPARATION METHOD THEREFOR
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Disclosed are a compound of Formula I having higher inhibition of protein kinase G (PKG) activity and pharmaceutically acceptable salts thereof. In Formula I, R1 and R2 are the same or different, each being independently chosen from the halogens, the C1-C6 alkoxyl group, the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group; R3 is chosen from H, the halogens, the substituted or unsubstituted C1-C6 alkyl group, C3-C6 cycloalkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group, aryl group, and heteroaryl group; and n is an integer between 0 and 15. Also disclosed is a pharmaceutical composition comprising said compound, the use of the compound in treating pains, in particular chronic pain, a preparation method for the compound, and a new intermediate.
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Paragraph 0083; 0084
(2016/12/12)
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- Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis
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Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
- Heimburg, Tino,Chakrabarti, Alokta,Lancelot, Julien,Marek, Martin,Melesina, Jelena,Hauser, Alexander-Thomas,Shaik, Tajith B.,Duclaud, Sylvie,Robaa, Dina,Erdmann, Frank,Schmidt, Matthias,Romier, Christophe,Pierce, Raymond J.,Jung, Manfred,Sippl, Wolfgang
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supporting information
p. 2423 - 2435
(2016/04/10)
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- LRRK2 GTP BINDING INHIBITORS FOR TREATMENT OF PARKINSON'S DISEASE AND NEUROINFLAMMATORY DISORDERS
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Compounds, and methods of using the same, are provided as therapies for the treatment leucine-rich repeat kinase-2 (LRRK2)-related disorders including, but not limited to, neurodegenerative and neuroinflammatory disorders, such as Parkinson's Disease.
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Paragraph 0161; 0162; 0163; 0166; 0167
(2015/12/30)
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- One-pot synthesis of novel 3,5-disubstituted-1,2,4-oxadiazoles from indazole carboxylic acid esters and amidoximes
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An efficient and high-yielding one-pot synthesis of 3,5-disubstituted-1,2, 4-oxadiazoles from indazole carboxylic acid methyl esters and amidoximes is described. In this study a series of novel 3,5-disubstituted-1,2,4-oxadiazoles (3a-d), (4a-d), (5a-d), (6a-d), (7a-d) were synthesized using amidoximes 2a-d and indazole carboxylic acid esters (3-6).
- Swamy, Udutha Kumara,Mohan, H. Rama,Prasad, U. Viplava,Suresh,Kumar, T. Laxmi
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p. 1921 - 1930
(2014/06/09)
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- GLUTAMATE DERIVATIVES OR SALTS THEREOF
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Compounds having an excellent CaSR agonist activity are in demand. The invention provides glutamate derivatives or salts thereof, pharmaceutical compositions comprising the glutamate derivatives, preventive or therapeutic agents for diarrhea, hyperparathyroidism or peptic ulcer.
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Paragraph 0150
(2013/03/26)
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- PROPHYLACTIC AGENT OR THERAPEUTIC AGENT FOR DIABETES OR OBESITY
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A medicament having an excellent CaSR agonist action which enables the prevention or treatment of diabetes or obesity is provided by a composition comprising the compound represented by general formula (I) as defined, or a salt thereof.
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Paragraph 0123
(2013/03/26)
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- Efficient indoles and anilines syntheses employing tert-butyl sulfinamide as ammonia surrogate
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tert-Butyl sulfinamide is an ammonia equivalent for the palladium-catalyzed amination of aryl bromides and aryl chlorides. Using these amine derivatives, it has been observed that indoles and anilines with sensitive functional groups can be readily prepared. This surrogate has also been used for the synthesis of indoles from 2-halophenols using palladium catalyzed cross coupling reaction as the key step.
- Prakash, Anjanappa,Dibakar, Mullick,Selvakumar, Kumaravel,Ruckmani, Kandasamy,Sivakumar, Manickam
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p. 5625 - 5628
(2011/11/06)
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- Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides
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A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC50 values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites.
- Rando, Daniela G.,Avery, Mitchell A.,Tekwani, Babu L.,Khan, Shabana I.,Ferreira, Elizabeth I.
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p. 6724 - 6731
(2008/12/22)
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- Substituted N-arylazetidinones, β-lactamases potential inhibitors
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Two classes of substituted N-aryl azetidinones have been prepared by cyclization of various β-bromopropionanilides. The 7a class possess a carboxylic function in ortho, meta or para of the nitrogen and possibly another alkyl substituent on the aromatic nucleus. In the 7a class, the aromatic nucleus is substituted by a bromomethyl group instead of the alkyl one. Few of these azetidinones show a good affinity for various cell-free β-lactamases preparations, and thus are pretty good competitive inhibitors. Nevertheless, they do not act synergistically with ampicillin on β-lactamase producing bacterial strains. A poor antibacterial activity has been detected for few compounds. The azetidinones 7b which possess a latent electrophilic quinonimine methide function, do not give any progressive (suicide type) inhibition, or inactivation, of the enzymatic activity.
- Zrihen,Labia,Wakselman
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p. 307 - 314
(2007/10/02)
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