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Discovery of 1,2,4-oxadiazole derivatives as a novel class of noncompetitive inhibitors of 3-hydroxykynurenine transaminase (HKT) from Aedes aegypti

Texto completo
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]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Fed Pernambuco, Dept Fundamental Chem, Ave Jornalista Anibal Fernandes S-N Cidade Univ, BR-50740560 Recife, PE - Brazil
[2] Univ Sao Paulo, Sao Carlos Inst Phys, Ave Joao Dagnone, 1100 Jardim Santa Angelina, BR-13563120 Sao Carlos, SP - Brazil
[3] Fiocruz MS, IAM, Ave Prof Moraes Rego S-N, BR-50740560 Recife, PE - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Bioorganic & Medicinal Chemistry; v. 28, n. 2 JAN 15 2020.
Citações Web of Science: 0

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. (AU)

Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
Beneficiário:Glaucius Oliva
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs