DEFAR - Departamento de Farmácia
URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530
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3 resultados
Resultados da Pesquisa
Item From rational design to serendipity : discovery of novel thiosemicarbazones as potent trypanocidal compounds.(2022) Braga, Saulo Fehelberg Pinto; Santos, Viviane Corrêa; Vieira, Rafael Pinto; Silva, Elany Barbosa da; Monti, Ludovica; Krake, Susann Hannelore; Martinez, Pablo D. G.; Dias, Luiz Carlos; Caffrey, Conor R.; Siqueira Neto, Jair Lage de; Oliveira, Renata Barbosa de; Ferreira, Rafaela SalgadoChagas disease is a major public health problem caused by Trypanosoma cruzi, with an estimated 6–7 million people infected and 70 million at risk of infection. T. brucei gambiense and T. brucei rhodesiense are two subspecies of related parasites that cause human African trypanosomiasis, a neglected tropical disease with also millions of people at risk of infection. Pharmacotherapy for both diseases suffers from low efficacy, side effects, or drug resistance. Recently, we reported a noncovalent competitive inhibitor of cruzain (IC50 26 μM, Ki 3 μM) and TbrCatL (IC50 50 μM), two cysteine proteases considered promising drug targets for trypanosomiasis. Here, we describe the design and synthesis of derivatives of our lead compound. The new thiosemicarbazone derivatives showed potency in the nanomolar concentration range against the two enzymes, but they were later charac- terized as aggregators. Nevertheless, the thiosemicarbazone derivatives showed promising antiparasitic activities against T. b. brucei (EC50 13–49.7 μM) and T. cruzi (EC50 0.027–0.59 μM) under in vitro conditions. The most active thiosemicarbazone was 200-fold more potent than the current anti-chagasic drug, benznidazole, and showed a selectivity index of 370 versus myoblast cells. We have identified an excellent candidate for further optimization and in vivo studies.Item Discovery and characterization of trypanocidal cysteine protease inhibitors from the ‘malaria box’.(2019) Pereira, Glaécia Aparecida do Nascimento; Silva, Elany Barbosa da; Braga, Saulo Fehelberg Pinto; Leite, Paulo Gaio; Martins, Luan Carvalho; Vieira, Rafael Pinto; Soh, Wai Tuck; Villela, Filipe Silva; Costa, Francielly Morais Rodrigues da; Ray, Debalina; Andrade, Saulo Fernandes de; Brandstetter, Hans; Oliveira, Renata Barbosa; Caffrey, Conor R.; Machado, Fabiana Simão; Ferreira, Rafaela SalgadoChagas disease, Human African Trypanosomiasis, and schistosomiasis are neglected parasitic diseases for which new treatments are urgently needed. To identify new chemical leads, we screened the 400 compounds of the Open Access Malaria Box against the cysteine proteases, cruzain (Trypanosoma cruzi), rhodesain (Trypanosoma brucei) and SmCB1 (Schistosoma mansoni), which are therapeutic targets for these diseases. Whereas just three hits were observed for SmCB1, 70 compounds inhibited cruzain or rhodesain by at least 50% at 5 mM. Among those, 15 commercially available compounds were selected for confirmatory assays, given their potency, time-dependent inhibition profile and reported activity against parasites. Additional assays led to the confirmation of four novel classes of cruzain and rhodesain in- hibitors, with potency in the low-to mid-micromolar range against enzymes and T. cruzi. Assays against mammalian cathepsins S and B revealed inhibitor selectivity for parasitic proteases. For the two competitive inhibitors identified (compounds 7 and 12), their binding mode was predicted by docking, providing a basis for structure-based optimization efforts. Compound 12 also acted directly against the trypomastigote and the intracellular amastigote forms of T. cruzi at 3 mM. Therefore, through a combi- nation of experimental and computational approaches, we report promising hits for optimization in the development of new trypanocidal drugs.Item Antidepressant-like effect of terpineol in an inflammatory model of depression : involvement of the cannabinoid system and d2 dopamine receptor.(2020) Vieira, Graziela; Cavalli, Juliana; Gonçalves, Elaine Cristina Dalazen; Braga, Saulo Fehelberg Pinto; Ferreira, Rafaela Salgado; Santos, Adair Roberto Soares; Cola, Maíra; Raposo, Nádia Rezende Barbosa; Capasso, Raffaele; Dutra, Rafael CyprianoDepression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-likemechanism of action of terpineol while usingmolecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100–200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a β-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.