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

• Published in: European journal of medicinal chemistry 2019-04, Vol.167, p.357-366
• Main Authors: Calil, Felipe A., David, Juliana S., Chiappetta, Estela R.C., Fumagalli, Fernando, Mello, Rodrigo B., Leite, Franco H.A., Castilho, Marcelo S., Emery, Flavio S., Nonato, M.Cristina
• Format: Article
• Language: English
• Subjects: Inhibitor; Naphthoquinones; Schistosomiasis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.02.018

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. [Display omitted] •A series of quinones (Atovaquone derivatives and precursors) was synthesized.•The compounds were tested as inhibitors of SmDHODH and HsDHODH.•12 compounds were identified as nanomolar inhibitors.•The best compound 17 exhibited IC50 = 23 ± 4 nM against SmDHODH and SI of 30.83.