EF24, a schistosomicidal curcumin analog: Insights from its synthesis and phenotypic, biochemical and cytotoxic activities

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Badoco, Fernanda R. ; Paula, Lucas A. L. ; Orenha, Renato P. ; Mendes, Tiago M. F. ; Squarisi, Iara S. ; El-Sakkary, Nelly ; Loiola, Messias C. ; Katz, Naftale ; Tavares, Denise C. ; Sairre, Mirela I. ; Parreira, Renato Luis T. ; Cabral, Fernanda Janku ; Alegretti, Silmara M. ; Caffrey, Conor R. ; Magalha, Lizandra G.

• Tipo de documento: Artigo Científico
• Fonte: Chemico-Biological Interactions; v. 368, p. 11-pg., 2022-10-13.

Resumo

Praziquantel (PZQ) is the only drug available for community-based control programs which aim to reduce the prevalence and morbidity associated with schistosomiasis. Here, we synthesized and evaluated the schistoso-micidal, biochemical and cytotoxic activities of EF24, a synthetic curcumin analog, against different isolates of Schistosoma mansoni. EF24 elicited marked phenotypic alterations at 10 mu M against schistosomula and 42-day-old adult worms of the Naval Medical Research Institute (NMRI) isolate. EF24 had 50% effective concentration (EC50) values of <10 mu M against the Luis Evangelista (LE), Sergipe (SE), Belo Horizonte (BH) and Belo Horizonte less sensitive to PZQ (BH < PZQ) isolates of adult S. mansoni; however, the respective sensitivities of these isolates differed. Changes in the parasite included, vacuolization of the tegument and focal lysis of the interstitial tissue and muscle layers. Against 28-day-old juvenile worms (LE isolate), EF24 was about three times more potent than PZQ. After 6 h at 12.5 mu M, EF24 increased reactive oxygen species (ROS) and the activity of the antioxidant enzyme, glutathione-S-transferase (GST), by 32 and 19% in female and male adult worms, respec-tively. By contrast, after 6 h at 12.5 mu M glutathione reductase (GR) activity decreased by 43 and 30%, and glutathione peroxidase (GPx) activity decreased by 67 and 44% in females and males, respectively. EF24 was less cytotoxic to mammalian host cells than to S. mansoni, with selectivity indexes (SIs) of 1.8-3.4 and 2.7-7.5 for juvenile and adult worms, respectively. Given the current evidence for the in vitro schistosomicidal effect of EF24, the structure-activity relationship of additional analogs to identify new candidates for schistosomiasis treatment is warranted. (AU)

• Processo FAPESP: 17/24856-2 - O Mecanismo da Reação de Substituição do Ligante Nitrosil por Aqua em Compostos de Coordenação de Rutênio
• Beneficiário: Renato Pereira Orenha
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/50011-2 - Exploring turmeric curcuminoids to treat schistosomiasis: an evaluation of their pre-clinical potential
• Beneficiário: Lizandra Guidi Magalhães
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/01394-8 - Estudo do análogo de curcumina EF-24 e praziquantel nos aspectos bioquímicos e morfológicos envolvidos com a morte celular do parasito Schistosoma mansoni
• Beneficiário: Fernanda Rafacho Badoco
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 14/02018-7 - Avaliação do análogo de curcumina EF24 em vermes adultos de Schistosoma mansoni
• Beneficiário: Fernanda Rafacho Badoco
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 16/18045-9 - Estudo da reação multicomponente de Hantzsch para a síntese de novos inibidores da dipeptidil peptidase 4 (DPP-4) para o tratamento de Diabetes tipo II
• Beneficiário: Mirela Inês de Sairre
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/24456-1 - Curcuminóides monocetônicos para o tratamento da esquistossomose: uma avaliação pré-clínica da atividade esquistossomicida
• Beneficiário: Lizandra Guidi Magalhães
• Modalidade de apoio: Auxílio à Pesquisa - Regular