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Chagas disease (CD) is a parasitic infection caused by Trypanosoma cruzi, endemic in Latin America and recently found in non-endemic countries of North America, Europe and Asia. The main form of transmission depends on the presence of a vector, being Triatoma infestans the most common 1. It is estimated that over eight million people are infected by the parasite and 70 million are at risk, living on endemic areas or in places where the control of other forms of transmission (oral, blood transfusion or organ transplant) is not rigid 2. CD is a two-stage disease: the acute phase, characterized by the high parasitaemia, and invasion by trypomastigote forms of different organs and the chronic phase, which may be latent for decades before appearance of clinical signs and usually associated with the development of cardiomyopathy 3,4. The available therapy for the treatment of CD is actually restricted to two approved drugs: benznidazole and nifurtimox, remains a controversial issue, with contradictory results in the chronic phase of the disease 5-8. Furthermore, these nitrocompounds showed several side effects associated to prolonged treatment regimens. Several clinical trials involving drug-repositioning (such as antifungal azoles) were carried out as well as studies involving new molecules, but none have reached the market yet 4. Therefore, new effective drugs for the treatment of CD are still needed. The Drugs for Neglected Diseases initiative (DNDi) defines that a desirable hit compound should present considerable efficacy (IC 50 < 10 µM), selectivity (>10-fold over mammalian cells) and adequate oral bioavailability 9. Natural products have always been a source of a great variety of bioactive molecules, mostly substances from the organism secondary metabolism. Many drugs available in the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products (semi-synthetic or completely synthetic) 10. The biodiversity of plants makes them a commonly explored source of novel bioactive compounds, providing molecules with distinct structures, complex or simple, with huge chemical variety 11. Several research groups are focused on the isolation and identification of novel compounds with antimicrobial activity from plant extracts, aiming to use them as prototypes for drug discovery against Chagas disease 12. In this context, licarin A is a neolignan isolated from different plant species with reported activity against Mycobacterium tuberculosis 13,14 , Schistosoma mansoni 15 , Trypanosoma cruzi 15-17 , and Leishmania major 18. Considering the promising activity against T. cruzi and the considerable amounts of licarin A isolated from the leaves of Nectandra oppositifolia (Lauraceae), this compound was selected for preparation of semi-synthetic analogues to further pharmacophore exploitation. Thereafter, licarin A was obtained in pure form and five semi-synthetic and twenty-one analogues were designed by the molecular simplification approach. The main objective wa...

The histamine receptors (HRs) are members of G-protein-coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H R and H R have been explored as targets for drug discovery, including in the search for dual-acting H R/H R ligands. The H R, the most recent histamine receptor, is a promising target for novel anti-inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H R/H R ligands herein. The results showed the compounds presented affinity (K ) for H R/H R in micromolar range, and they are more selective to H R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl-substituted compound LINS01005 has shown the higher affinity of the set for H R, but no considerable selectivity toward this receptor over H R. LINS01005 showed interesting anti-inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX-2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti-inflammatory agents.

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