期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 17, 页码 13054-13071出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01151
关键词
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资金
- CAPES
- CNPq
- FAPEMIG
- FAPERGS through CNPq [141841/2018-4]
- FAPERGS through CNPq.Universal 01/2016 [402318/2016-1]
- FAPERGS through CAPES [Edital 51/2013]
- FAPEMIG (Rede Mineira de Imunobiologicos grant) [REDE-00140-16, PPM-0034216]
- CNPq (Bolsa de Produtividade em Pequisa) [306606/2017-8]
- NIH-NIAID [R21AI141210, R21AI133394]
The study describes a competitive cruzain inhibitor and its analogs, which exhibit low micromolar inhibition of the target proteases, cidal activity against Trypanosoma cruzi, and potential therapeutic effects.
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 N-4-benzyl-N-2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (K-i = 1.4 mu M). 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.
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