Monoketo enone curcuminoids the treatment of schistosomiasis: an pre-clinical evaluation of schistosomicidal activity

Abstract

According to the World Health Organization, more than 200 million people are infected with schistosomiasis, most of them in African countries. Schistosomiasis control programs are based mainly on chemotherapy, which is almost limited to praziquantel (PZQ). However, due to the widespread and intensive use of praziquantel, there is an increasing concern about the development of drug-resistant strains. In order to provide new hit/lead structures, which can be used in drug development to control schistosomiasis, the search for antiparasitic compounds from natural sources, mainly from plants, has been intensified in the last years. Studies have been shown that curcumin, a biologically active compound extracted from rhizomes of Curcuma longa, shows schistosomicidal activity in vitro and in vivo. However, curcumin has poor absorption, biodistribution, metabolism, and bioavailability. Thus, studies have been shown that monoketo enone curcuminoids analogs have effects leishmanicidal and trypanocida. Thus, this research project aim is pre-clinical and toxicological evaluation for the development of prototypes drugs for treating of schistosomiasis mansonica. Thus the compounds will be tested at the Center for Discovery and Innovation in Parasitic Diseases (University of California, San Diego) against schistosomula in vitro using a high-content imaging. After, the compounds that have shown a Lethal Concentration (LC50) 10µM will be re-evaluated on juvenile and adult S. mansoni Puerto Rican isolated. In parallel the compounds will be evaluated in vitro on juvenile and adult worms S. mansoni LE (Luiz Evangelista strain) at the University of Franca. The compounds that have shown a LC50 10µM against S. mansoni will be evaluated in vitro on juvenile and adult worms S. mansoni Belo Horizonte (BH), Sergipe (SE), São José dos Campos (SJ) and Belo Horizonte-PZQ resistant (BH-resistant). Additionally, the mechanism of actions and cytotoxicity on mammalian cells also will be evaluated in in vitro for the active compounds. Beside, a possible class effects and structure-activity relationships will be discussed. Based on in vitro performance active compounds will be assayed regarding toxicity for mammalian experimental animals, as well as their therapeutic potential in experimental models of schistosomiasis. (AU)