Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase
| Autor: | Marcelo Santos Castilho, Flavio da Silva Emery, Felipe A. Calil, Juliana S. David, Rodrigo Brito de Mello, Franco Henrique Andrade Leite, Estela R. C. Chiappetta, M. Cristina Nonato, Fernando Fumagalli |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Oxidoreductases Acting on CH-CH Group Donors
Dihydroorotate Dehydrogenase Schistosomiasis Pharmacology Ligands 01 natural sciences Structure-Activity Relationship 03 medical and health sciences parasitic diseases Drug Discovery medicine Animals Humans Potency Structure–activity relationship INIBIDORES DE ENZIMAS Anthelmintic 030304 developmental biology Anthelmintics 0303 health sciences biology 010405 organic chemistry Chemistry Organic Chemistry Quinones Schistosoma mansoni General Medicine medicine.disease biology.organism_classification Schistosomiasis mansoni 0104 chemical sciences Praziquantel Drug Design Dihydroorotate dehydrogenase Atovaquone medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 0223-5234 |
| Popis: | Schistosomiasis ranks second only to malaria as the most common parasitic disease worldwide. 700 million people are at risk and 240 million are already infected. Praziquantel is the anthelmintic of choice but decreasing efficacy has already been documented. In this work, we exploited the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. A series of quinones (atovaquone derivatives and precursors) was evaluated regarding potency and selectivity against both SmDHODH and human DHODH. The best compound identified is 17 (2-hydroxy-3-isopentylnaphthalene-1,4-dione) with IC50 = 23 ± 4 nM and selectivity index of 30.83. Some of the new compounds are useful pharmacological tools and represent new lead structures for further optimization. |
| Databáze: | OpenAIRE |
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