25628-84-6Relevant articles and documents
Design, synthesis, molecular docking, and some metabolic enzyme?inhibition properties of novel quinazolinone derivatives
Tokal?, Feyzi S.,Taslimi, Parham,Demircio?lu, ?brahim H.,Karaman, Muhammet,Gültekin, Mehmet S.,?endil, K?v?lc?m,Gül?in, ?lhami
, (2021)
3-Amino-2-ethylquinazolin-4(3H)-one (3) was synthesized in two steps from the reaction of amide (2), which was obtained from the treatment of methyl anthranilate (1) with propionyl chloride, with hydrazine. From the reaction of 3-amino-2-ethylquinazolin-4(3H)-one (3) with various aromatic aldehydes, novel benzylidenaminoquinazolin-4(3H)-one (3a–n) derivatives were synthesized. The structures of the novel molecules were characterized using infrared spectroscopy, nuclear magnetic resonance spectroscopy (1H-NMR and 13C-NMR), and high-resolution mass spectroscopy. The novel compounds were tested against some metabolic enzymes, including α-glucosidase (α-Glu), acetylcholinesterase (AChE), and human carbonic anhydrases I and II (hCA I and II). The novel compounds showed Ki values in the range of 244–988 nM for hCA I, 194–900 nM for hCA II, 30–156 nM for AChE, and 215–625 nM for α-Glu. The binding affinities of the most active compounds were calculated as ?7.636, ?6.972, ?10.080, and ?8.486 kcal/mol for hCA I, hCA II, AChE, and α-Glu enzymes, respectively. The aromatic ring of the quinazoline moiety plays a critical role in the inhibition of the enzymes.
Fragment-based lead discovery: Screening and optimizing fragments for thermolysin inhibition
Englert, Lisa,Silber, Katrin,Steuber, Holger,Brass, Sascha,Over, Bjoern,Gerber, Hans-Dieter,Heine, Andreas,Diederich, Wibke E.,Klebe, Gerhard
experimental part, p. 930 - 940 (2011/02/24)
Fragment-based drug discovery has gained a foothold in today's lead identification processes. We present the application of in silico fragment-based screening for the discovery of novel lead compounds for the metalloendoproteinase thermolysin. We have chosen thermolysin to validate our screening approach as it is a well-studied enzyme and serves as a model system for other proteases. A protein-targeted virtual library was designed and screening was carried out using the program AutoDock. Two fragment hits could be identified. For one of them, the crystal structure in complex with thermolysin is presented. This compound was selected for structure-based optimization of binding affinity and improvement of ligand efficiency, while concomitantly keeping the fragment-like properties of the initial hit. Redesigning the zinc coordination group revealed a novel class of fragments possessing Ki values as low as 128 μm, thus they provide a good starting point for further hit evolution in a tailored lead design.
