Pesquisa

Structure-Based and Molecular Modeling Studies

qui, 13 fev 2020

Publicado por

Authors:

Ferreira, Rafael A. A. 1 ; Pauli, Ivani 2 ; Sampaio, Thiago S. 1 ; de Souza, Mariana L. 2 ; Ferreira, Leonardo L. G. 2 ; Magalhaes, Luma G. 2 ; Rezende Jr, Celso de O. 1 ; Ferreira, Rafaela S. 3 ; Krogh, Renata 2 ; Dias, Luiz C. 4 ; Andricopulo, Adriano D. 2


Abstract:

Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 μM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 μM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 μM). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.


1   Instituto de Química, Universidade Estadual de Campinas, Campinas, Brazil

2   Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, Brazil

3   Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil


 

Link to article:    https://www.frontiersin.org/articles/10.3389/fchem.2019.00798/full

 

 

Iron-Catalyzed Meerwein Carbooxygenation of Electron-Rich Olefins 09de19

seg, 09 dez 2019

Publicado por

Authors:

Scarpa de Souza, Edson Leonardo 1 ; Wiethan, Carson 1 ; Duarte Correia, Carlos Roque 1


Abstract:

The arylative oxygenation of the electron-rich olefins styrene, α-methylstyrene, vinyl pyrrolidinone, and vinyl oxazolidinone was accomplished using arenediazonium salts and catalytic amounts of FeSO4 in an effective single electron transfer radical process. A broad range of aryldiazonium salts was tolerated using water, methanol, or their combination with acetonitrile to furnish the corresponding carbohydroxylated and carbomethoxylated products (42 examples), including functionalized dihydroisocoumarin and dihydrobenzofuran systems in good to excellent yields (up to 88%). The protocols developed for the Fe(II)-catalyzed carbohydroxylation were also compared to Ru(II) and Ir(III) photoredox carbooxygenations of these electron-rich olefins. The Fe(II)-catalyzed process proved to be highly competitive compared to the photoredox and the uncatalyzed processes. The proposed mechanism for the Fe(II)-catalyzed reactions involves the synergic combination with an effective Fe+2/Fe+3 redox system and a radical polar crossover mechanism featuring an unprecedented capture of the reactive N-acyliminium in the case of vinyl pyrrolidinone and vinyl oxazolidinone.


1   Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Rua Josué de Castro, 13083-970, Campinas, São Paulo, Brazil


Link to article:      https://pubs.acs.org/doi/10.1021/acsomega.9b03046