- Discovery of benzo[d]oxazole derivatives as the potent type-I FLT3-ITD inhibitors
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Fms-like tyrosine kinase 3 (FLT3) has been considered as a potential drug target for the treatment of acute myeloid leukemia (AML), because of its high and aberrant expression in AML patients, especially the patients with FLT3-ITD mutation. Initiating from a hit compound (IC50: 500 nM against FLT3-ITD), a series of compounds were designed and synthesized based on benzo[d]oxazole-2-amine scaffold to discover new potent FLT3-ITD inhibitors. During the medicinal chemistry works, flexible molecular docking was used to provide design rationale and study the binding modes of the target compounds. Through the mixed SAR exploration based on the enzymatic and cellular activities, compound T24 was identified with potent FLT3-ITD inhibitory (IC50: 0.41 nM) and anti-proliferative (IC50: 0.037 μM against MV4-11 cells) activities. And the binding mode of T24 with “DFG-in” FLT3 was simulated by a 20-ns molecular dynamics run, providing some insights into further medicinal chemistry efforts toward novel FLT3 inhibitors in AML therapy.
- Bao, Jiyin,Liu, Haichun,Zhi, Yanle,Yang, Wenqianzi,Zhang, Jiawei,Lu, Tao,Wang, Yue,Lu, Shuai
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- Synthesis of Isothiocyanates and Unsymmetrical Thioureas with the Bench-Stable Solid Reagent (Me4N)SCF3
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A highly efficient, selective, and rapid transformation of primary amines and diamines to isothiocyanates and cyclic thioureas is disclosed. As opposed to established approaches that employ toxic or volatile electrophilic liquids and require reaction control (i.e., slow addition, cooling), this protocol utilizes the bench-stable, solid reagent (Me4N)SCF3 at room temperature. The method is characterized by operational simplicity, high speed, efficiency, high functional group tolerance, and late-stage applicability. The byproducts are solids, allowing isolation of the target compounds by filtration.
- Scattolin, Thomas,Klein, Alexander,Schoenebeck, Franziska
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supporting information
p. 1831 - 1833
(2017/04/11)
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- Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders
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A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB2R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB1and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB2R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with “balanced” affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.
- Dolles, Dominik,Nimczick, Martin,Scheiner, Matthias,Ramler, Jacqueline,Stadtmüller, Patricia,Sawatzky, Edgar,Drakopoulos, Antonios,Sotriffer, Christoph,Wittmann, Hans-Joachim,Strasser, Andrea,Decker, Michael
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supporting information
p. 1270 - 1283
(2016/07/27)
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- Synthesis and SAR of selective small molecule neuropeptide y Y2 receptor antagonists
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Highly potent and selective small molecule neuropeptide Y Y2 receptor antagonists are reported. The systematic SAR exploration of a hit molecule N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide, identified from HTS, led to the discovery of highly potent NPY Y2 antagonists 16 (CYM 9484) and 54 (CYM 9552) with IC50 values of 19 nM and 12 nM respectively.
- Mittapalli, Gopi Kumar,Vellucci, Danielle,Yang, Jun,Toussaint, Marion,Brothers, Shaun P.,Wahlestedt, Claes,Roberts, Edward
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scheme or table
p. 3916 - 3920
(2012/07/03)
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- Anthelmintic 1-(substituted phenyl)-3-alkanimidoyl ureas
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The compounds of this invention are novel imidoylureas having anthelmintic activity and imidoylthioureas having antifertility activity. They are prepared by the reaction of appropriate amidines with appropriate isocyanates or isothiocyanates.
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