Study of the immunomodulatory activity of lignans and neolignans obtained by partial synthesis and oxidative coupling as a potential in developing new antiparasitic drugs

Abstract

Chagas disease and schistosomiasis are considered neglected tropical diseases that affect millions of people in developing and underdeveloped countries. Currently, there are two medicines used for treatment of Chagas disease: nifurtimox (which is already banned in Brazil) and benznidazole. However, these medications have series of serious side effects and have low efficiency. For schistosomiasis, praziquantel is still the used drug in control of this parasitosis throughout the world. This compound is effective against all species of Schistosoma and does not display severe side effects, however, there are numerous reports demonstrating the increasing emergence of resistant strains to this medicine. Isolated lignans from Piper cubeba as (-)-cubebin and its semi-synthetic derivatives presented significant anti-inflammatory, analgesic, tripanocidal and schistosomicidal activities. Neolignans, small molecules biosynthesized by dimerization through oxidative coupling of phenylpropanoids units (C6C3)n, have also attracted great interest due to its numerous biological activities in humans.Biological tests performed recently by our research group, have been demonstrated excellent schistosomicidal activities (PI 0503951-7/process Fapesp 04/08784-1) and tripanocidal (PI 0201237-5/01/12006 Process Fapesp-6) in vitro and in vivo for tetrahydrofuran neolignans and dibenzylbutirolactones lignans. In view of these promising results obtained and the biological activities of these substances, it is necessary the continuation of the work carried out, being indispensable the evaluation of other lignans and neolignans (including furofuran and dihydrobenzofuran), as previously laid down in the patent granted (PI 0503951-7-Process Fapesp 04/08784-1). To enlarge the knowledge of the intrinsic characteristics of this class of substance in relation to the profile of biological activity with the chemical characteristics of the same, the proposal is to obtain several lignans and neolignans through isolation and oxidative coupling reactions of phenylpropanoids which will have their biological activities assessed in vivo in Chagas disease and experimental Schistosomiasis during acute and chronic phases. In addition, it will be evaluated the potential of substances to stimulate the immune response of the host as well as evaluate the cytotoxic effect in mammalian cells. In order to identify potential targets of action of active compounds in S. mansoni, proteomics analysis will be conducted with adult worms of S. mansoni incubated with active compounds. (AU)