Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase

Author(s)

Calil, Felipe A. ^[1] ; David, Juliana S. ^[1] ; Chiappetta, Estela R. C. ^[2] ; Fumagalli, Fernando ^[2] ; Mello, Rodrigo B. ^[2] ; Leite, Franco H. A. ^[3] ; Castilho, Marcelo S. ^[4] ; Emery, Flavio S. ^[2] ; Cristina Nonato, M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Lab Cristalog Prot, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Lab Quim Heterocicl & Med, BR-14040903 Ribeirao Preto, SP - Brazil

^[3] Univ Estadual Feira de Santana, Lab Modelagem Mol, BR-44036900 Feira De Santana, BA - Brazil

^[4] Univ Fed Bahia, Fac Farm, Lab Bioinformat & Modelagem Mol, BR-40170115 Salvador, BA - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 167, p. 357-366, APR 1 2019.
• Web of Science Citations: 0

Abstract

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. (C) 2019 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 15/25099-5 - Antimalarial drug repositioning in the schistosomiasis treatment based on the selective inhibition of the enzyme dihydroorotate dehydrogenase
• Grantee: Felipe Antunes Calil
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/21146-4 - Heterocyclic chemistry and epigenetic for the development of library of compounds for medicinal chemistry purposes.
• Grantee: Flavio da Silva Emery
• Support type: Regular Research Grants
• FAPESP's process: 15/06588-5 - Development of library of heterocyclic fragments based on new heteroaromatic cores
• Grantee: Fernando Fumagalli
• Support type: Scholarships in Brazil - Doctorate