27142-44-5Relevant academic research and scientific papers
Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors
Barbosa Da Silva, Elany,Rocha, Débora A.,Fortes, Isadora S.,Yang, Wenqian,Monti, Ludovica,Siqueira-Neto, Jair L.,Caffrey, Conor R.,McKerrow, James,Andrade, Saulo F.,Ferreira, Rafaela S.
, p. 13054 - 13071 (2021/09/13)
The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (Ki = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.
Antibacterial activity of a series of N2, N4- disubstituted quinazoline-2,4-diamines
Van Horn, Kurt S.,Burda, Whittney N.,Fleeman, Renee,Shaw, Lindsey N.,Manetsch, Roman
, p. 3075 - 3093 (2014/05/06)
A series of N2,N4-disubstituted quinazoline-2,4- diamines has been synthesized and tested against multidrug resistant Staphylococcus aureus. A structure-activity and structure-property relationship study was conducted to identify new hit compounds. This study led to the identification of N2,N4-disubstituted quinazoline-2,4- diamines with minimum inhibitory concentrations (MICs) in the low micromolar range in addition to favorable physicochemical properties. Testing of biological activity revealed limited potential for resistance to these agents, low toxicity, and highly effective in vivo activity, even with low dosing regimens. Collectively, these characteristics make this compound series a suitable platform for future development of antibacterial agents.
Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists
Rueeger, Heinrich,Rigollier, Pascal,Yamaguchi, Yasuchika,Schmidlin, Tibur,Schilling, Walter,Criscione, Leoluca,Whitebread, Steven,Chiesi, Michele,Walker, Mary W.,Dhanoa, Dale,Islam, Imadul,Zhang, Jack,Gluchowski, Charles
, p. 1175 - 1179 (2007/10/03)
The design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identification of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 affinity. The synthesis and SAR towards CGP71683A is described. (C) 2000 Elsevier Science Ltd. All rights reserved.
