Pesquisa

Discovery of 1,2,4-oxadiazole derivatives

qui, 13 fev 2020

Publicado por

Authors:        

Maciel, Larissa G. 1 ; Oliveira, Andrew A. 2 ; Romao, Tatiany P. 3 ; Leal, Laylla L. L. 1 ; Guido, Rafael V. C. 2 ; Silva-Filha, Maria Helena N. L. 3 ; dos Anjos, Janaina V. 1 ; Soares, Thereza A. 1


Abstract:

The mosquito Aedes aegypti is the vector of arboviruses such as Zika, Chikungunya, dengue and yellow fever. These infectious diseases have a major impact on public health. The unavailability of effective vaccines or drugs to prevent or treat most of these diseases makes vector control the main form of prevention. One strategy to promote mosquito population control is the use of synthetic insecticides to inhibit key enzymes in the metabolic pathway of these insects, particularly during larval stages. One of the main targets of the kynurenine detoxification pathway in mosquitoes is the enzyme 3-hydroxykynurenine transaminase (HKT), which catalyzes the conversion of 3-hydroxykynurenine (3-HK) into xanthurenic acid (XA). In this work, we report eleven newly synthesized oxadiazole derivatives and demonstrate that these compounds are potent noncompetitive inhibitors of HKT from Ae. aegypti. The present data provide direct evidence that HKT can be explored as a molecular target for the discovery of novel larvicides against Ae. aegypti. More importantly, it ensures that structural information derived from the HKT 3D-structure can be used to guide the development of more potent inhibitors.


1   Department of Fundamental Chemistry – Federal University of Pernambuco, Av. Jornalista Aníbal Fernandes, s/n°Cidade Universitária – Recife, PE 50740-560, Brazil

2   Sao Carlos Institute of Physics – University of São Paulo, Av. Joao Dagnone, 1100 Jardim Santa Angelina, São Carlos, SP 13563-120, Brazil

3   Institute Aggeu Magalhães (IAM) – FIOCRUZ, Av. Professor Moraes Rego s/n°, Recife, PE 50740-560 Brazil


 

Link to article:   https://www.sciencedirect.com/science/article/pii/S0968089619312271?via%3Dihub

 

Structure-activity relationship

qui, 13 fev 2020

Publicado por

Authors:

Koovits, Paul J. 1 ; Dessoy, Marco A. 1 ; Matheeussen, An 2 ; Maes, Louis 2 ; Caljon, Guy 2 ; Mowbray, Charles E. 3 ; Kratz, Jadel M. 3 ; Dias, Luiz C. 1 


Abstract:

The structure-activity relationship of a 4-Azaindole-2-piperidine compound selected from GlaxoSmithKline’s recently disclosed open-resource “Chagas box” and possessing moderate activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, is presented. Despite considerable medicinal chemistry efforts, a suitably potent and metabolically stable compound could not be identified to advance the series into in vivo studies. This research should be of interest to those in the area of neglected diseases and in particular anti-kinetoplastid drug discovery.


1   Institute of Chemistry, University of Campinas (UNICAMP), Rua Josué de Castro, S/N, Cidade Universitária, Campinas, SP 13083-861, Brazil

2   Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Universiteitsplein 1, 2610 Antwerpen, Belgium

3   Drugs for Neglected Diseases Initiative (DNDi), 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland


 

Link to article:    https://www.sciencedirect.com/science/article/pii/S0960894X19307449?via%3Dihub