| Autor: |
Barbosa da Silva E; Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brazil.; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0657, United States., Rocha DA; Pharmaceutical Synthesis Group (PHARSG), Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil.; Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil., Fortes IS; Pharmaceutical Synthesis Group (PHARSG), Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil.; Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil., Yang W; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0657, United States., Monti L; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0657, United States., Siqueira-Neto JL; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0657, United States., Caffrey CR; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0657, United States., McKerrow J; Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093-0657, United States., Andrade SF; Pharmaceutical Synthesis Group (PHARSG), Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil.; Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil.; Graduate Program in Agricultural and Environmental Microbiology, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90040-060, Brazil., Ferreira RS; Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brazil. |
| Abstrakt: |
The cysteine proteases, cruzain and Tbr CATL (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 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. |
