Abstract: Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an inhouse library of 755 compounds and subsequently validated in multiple orthogonal biophys. assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC NMR. Extensive structure-activity relationships combined with mol. docking followed by chem. optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chem. probes targeting the Spire2-FMN2 interaction.
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EXAMPLE 6 p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride A mixture of 0.1 mole of <strong>[6274-22-2]N-methyl-p-aminobenzamide</strong>, 0.1 mole of 4-chloro-7-trifluoromethylquinoline, 10 ml. of concentrated hydrochloric acid and 500 ml. of absolute ethanol is stirred at about 25 C. for 30 minutes. A precipitate begins to form, and the mixture is then heated at reflux for 4 hours. The mixture is cooled and filtered to obtain p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride.
A mixture of 7.2 g of 4-chloro-7-trifluoromethylquinoline, 5.4 g of methyl 2- aminophenylacetate and 250 mL of acetonitrile is heated under reflux for 18 hours. The solvent is evaporated under reduced pressure and the residue extracted 3 times with 200 mL portions of hot water. The aqueous extract is rendered basic with 10% ammonium hydroxide whereupon the desired compound precipitated; it was recrystallized from aqueous ethanol yielding colorless needles with a melting point of 140-1410C.
General procedure: A mixture of 1 (2.31 g, 0.01 mol) and the corresponding sulfadrugs (0.012 mol) in dry DMF (20 mL) was refluxed for 12 h. The solid obtained after concentration was filtered and crystallized from dioxane to give 2-14, respectively.
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