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Selection and Optimization of New Drug Candidates for Leishmaniasis and Chagas Disease


Considering the morbidity and mortality of visceral leishmaniasis and Chagas' disease, and the therapeutic limitations, these neglected protozoan diseases have been prioritized by WHO. The present proposal aims the search for a new pharmaceutical prototype for each disease, through coordinated activities in Drug Discovery. Based in a multidisciplinary proposal, we propose the continuation of previous project Sprint Fapesp: University of Oxford (2015/50075-2), aligning Synthetic Organic Chemistry, Chemistry of Natural Products, Medicinal Chemistry, Pharmacology and Parasitology, for the selection and optimization of lead compounds against Leishmania (L.) infantum and Trypanosoma cruzi. Acting in two steps of Drug Discovery pipeline, the project has as main focus, the a hit-to-lead stage, through the organic synthesis of synthetic derivatives of natural metabolites, originally isolated from the plant from the genus Nectandra. Additionally, a continuous screening will be performed for the search for new natural secondary metabolites of plants, aiming in vitro potency and selectivity (hit identification). During the optimization stage, one or more hit compounds will be chemically modified based on: i) in vitro studies on intracellular amastigotes (EC50); ii) mammalian cytotoxicity (CC50); iii) mechanism of action (MoA); iv) in silico and in vitro data of absorption, distribution, metabolism, excretion, (ADME); v) in silico physicochemical parameters of solubility, log P, log D and Lipinski's Rule-of-Five; and vi) in silico studies for the elimination of interfering compounds (PAINS). At the end of the project, the synthesis of a lead compound will be scaled-up aiming the efficacy evaluation in a murine model for visceral leishmaniasis and Chagas' disease. Counting on national (UFABC) and international collaborations (University of Oxford, University of Dundee e Oregon State University), the project aims a multidisciplinary approach, taking advantage of different areas for a structure-activity relationship study towards new treatments for neglected protozoan diseases. (AU)

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Scientific publications (28)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
AMARAL, MAIARA; DE SOUSA, FERNANDA S.; SILVA, THAIS A. COSTA; JUNIOR, ANDRES JIMENEZ G.; TANIWAKI, NOEMI N.; JOHNS, DEID RE M.; LAGO, JOAO HENRIQUE G.; ANDERSON, EDWARD A.; TEMPONE, ANDRE G.. A semi-synthetic neolignan derivative from dihydrodieugenol B selectively affects the bioenergetic system of Leishmania infantum and inhibits cell division. SCIENTIFIC REPORTS, v. 9, . (18/10279-6, 15/50075-2, 18/07885-1)
SILVA, ARMENIO A. DE CARVALHO A. DA; SOUSA, ELCILENE A. DE; VERAS, MARCIA D. ALVES; ARAUJO, BRUNO Q.; THEVENARD, FERNANDA; LAGO, JOAO HENRIQUE G.; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; CHAVES, MARIANA H.. In vitro anti-Trypanosoma cruzi evaluation of sesquiterpenes from the branches of Oxandra sessiliflora. PHYTOCHEMISTRY LETTERS, v. 37, p. 59-62, . (18/10279-6, 18/07885-1)
FERREIRA, DAIANE D.; SOUSA, FERNANDA S.; COSTA-SILVA, THAIS A.; REIMAO, JULIANA Q.; TORRECILHAS, ANA C.; JOHNS, DEIDRE M.; SEAR, CLAIRE E.; HONORIO, KATHIA M.; LAGO, JOAO HENRIQUE G.; ANDERSON, EDWARD A.; et al. Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 176, p. 162-174, . (18/10279-6, 16/24524-7, 15/50075-2, 18/07885-1)
DA COSTA-SILVA, THAIS A.; ALVES CONSERVA, GEANNE A.; GALISTEO, JR., ANDRES J.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Antileishmanial activity and immunomodulatory effect of secosubamolide, a butanolide isolated from Nectandra oppositifolia (Lauraceae). Journal of Venomous Animals and Toxins including Tropical Diseases, v. 25, . (16/20633-6, 18/10279-6, 18/07885-1)
BRITO, JULIANA R.; DA COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; FERREIRA, EDGARD A.; LAGO, JOAO HENRIQUE G.. Dibenzylbutane neolignans from Saururus cernuus L. (Saururaceae) displayed anti-Trypanosoma cruzi activity via alterations in the mitochondrial membrane potential. Fitoterapia, v. 137, . (18/10279-6, 18/07885-1)
CORREA, ISABELA TERESA SANTOS; DA COSTA-SILVA, THAIS ALVES; TEMPONE, ANDRE GUSTAVO. Bioenergetics impairment of Trypanosoma cruzi by the antihypertensive manidipine: A drug repurposing strategy. Acta Tropica, v. 214, . (18/10279-6)
BARBOSA, HENRIQUE; DA SILVA, RAFAEL LEONARDO C. G.; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; ANTAR, GUILHERME M.; LAGO, JOAO HENRIQUE G.; CASELI, LUCIANO. Interaction of dicentrinone, an antitrypanosomal aporphine alkaloid isolated from Ocotea puberula (Lauraceae), in cell membrane models at the air-water interface. BIOORGANIC CHEMISTRY, v. 101, . (18/00291-9, 18/10279-6, 19/03239-0, 18/07885-1)
MORAIS, THIAGO R.; ALVES CONSERVA, GEANNE A.; VARELA, MARINA T.; COSTA-SILVA, THAIS A.; THEVENARD, FERNANDA; PONCI, VITOR; FORTUNA, ANA; FALCAO, AMILCAR C.; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.; et al. Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A. SCIENTIFIC REPORTS, v. 10, n. 1, . (18/10279-6, 16/25028-3, 18/07885-1, 16/20633-6)
OLIVEIRA, LIDIANE; FERRARINI, MARCIO; DOS SANTOS, ALEXANDRE PAES; VARELA, MARINA THEMOTEO; SANTOS CORREA, ISABELA TERESA; TEMPONE, ANDRE GUSTAVO; MELHEM, MARCIA S. C.; VALLIM, MARCELO A.; FERNANDES, JOAO PAULO S.; PASCON, RENATA C.. Coumaric acid analogues inhibit growth and melanin biosynthesis in Cryptococcus neoformans and potentialize amphotericin B antifungal activity. European Journal of Pharmaceutical Sciences, v. 153, . (18/10279-6, 18/03918-2, 15/04400-9, 16/25028-3, 16/14542-8)
IVANILDO A. BRITO; EMERSON A. OLIVEIRA; MARIANA H. CHAVES; FERNANDA THEVENARD; ANDRÉ F. RODRIGUES-OLIVEIRA; GUSTAVO BARBOSA-REIS; PATRICIA SARTORELLI; DIOGO OLIVEIRA-SILVA; ANDRE G. TEMPONE; THAIS A. COSTA-SILVA; et al. Antileishmanial Acetylene Fatty Acid and Acetogenins from Seeds of Porcelia macrocarpa. Journal of the Brazilian Chemical Society, v. 32, n. 2, p. 447-453, . (18/10279-6, 18/07885-1)
PINTO, ERIKA GRACIELLE; BARBOSA, LEANDRO R. S.; MORTARA, RENATO A.; TEMPONE, ANDRE GUSTAVO. Targeting intracellular Leishmania (L.) infantum with nitazoxanide entrapped into phosphatidylserine-nanoliposomes: An experimental study. Chemico-Biological Interactions, v. 332, . (18/10279-6)
PIEPER, PAULINE; MCHUGH, ELIZA; AMARAL, MAIARA; TEMPONE, ANDRE G.; ANDERSON, EDWARD A.. Enantioselective synthesis and anti-parasitic properties of aporphine natural products. Tetrahedron, v. 76, n. 2, SI, . (18/10279-6, 18/25128-3)
ALVES CONSERVA, GEANNE A.; QUIROS-GUERRERO, LUIS M.; COSTA-SILVA, THAIS A.; MARCOURT, LAURENCE; PINTO, ERIKA G.; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.; WOLFENDER, JEAN-LUC; QUEIROZ, EMERSON F.; LAGO, JOAO HENRIQUE G.. Metabolite profile of Nectandra oppositifolia Nees & Mart. and assessment of antitrypanosomal activity of bioactive compounds through efficiency analyses. PLoS One, v. 16, n. 2, . (16/20633-6, 18/18975-1, 18/10279-6, 15/23403-9, 18/07885-1)
LONDERO, VINICIUS S.; COSTA-SILVA, THAIS A.; ANTAR, GUILHERME M.; BAITELLO, JOAO B.; DE OLIVEIRA, LARISSA V. F.; CAMILO, FERNANDA F.; BATISTA, ANDREA N. L.; BATISTA, JR., JOAO M.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Antitrypanosomal Lactones from Nectandra barbellata. Journal of Natural Products, v. 84, n. 5, p. 1489-1497, . (14/25222-9, 17/17044-1, 18/10279-6, 21/02789-7, 18/07885-1)
LONDERO, VINICIUS S.; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; NAMIYAMA, GISLENE M.; THEVENARD, FERNANDA; ANTAR, GUILHERME M.; BAITELLO, JOAO B.; LAGO, JOAO HENRIQUE G.. Anti-Trypanosoma cruzi activity of costic acid isolated from Nectandra barbellata (Lauraceae) is associated with alterations in plasma membrane electric and mitochondrial membrane potentials. BIOORGANIC CHEMISTRY, v. 95, . (18/10279-6, 17/17044-1, 18/07885-1)
SEAR, CLAIRE E.; PIEPER, PAULINE; AMARAL, MAIARA; ROMANELLI, MAIARA M.; COSTA-SILVA, THAIS A.; HAUGLAND, MARIUS M.; TATE, JOSEPH A.; LAGO, JOAO H. G.; TEMPONE, ANDRE G.; ANDERSON, EDWARD A.. Synthesis and Structure-Activity Relationship of Dehydrodieugenol B Neolignans against Trypanosoma cruzi. ACS INFECTIOUS DISEASES, v. 6, n. 11, p. 2872-2878, . (18/25128-3, 18/10279-6)
PAROLIN, GIOVANA A.; GONCALVES, GIULIA E. G.; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; CASELI, LUCIANO; LAGO, JOAO HENRIQUE G.; PERES, LAURA O.. Evaluation of the effects in cellular membrane models of antitrypanosomal poly-thymolformaldehyde (PTF) using Langmuir monolayers. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, v. 1863, n. 2, . (18/22214-6, 14/50869-6, 18/07885-1, 18/18180-9, 18/10279-6, 19/03239-0)
GOMES, KAIO S.; DA COSTA-SILVA, THAIS A.; OLIVEIRA, IGOR H.; AGUILAR, ANDREA M.; OLIVEIRA-SILVA, DIOGO; UEMI, MIRIAM; SILVA, WENDER A.; MELO, LENNINE R.; ANDRADE, CARLOS KLEBER Z.; TEMPONE, ANDRE G.; et al. Structure-activity relationship study of antitrypanosomal chalcone derivatives using multivariate analysis. Bioorganic & Medicinal Chemistry Letters, v. 29, n. 12, p. 1459-1462, . (18/10279-6, 18/07885-1)
UMEHARA, ERIC; SILVA, THAIS A. COSTA; MENDES, VIVIANE M.; GUADAGNIN, RAFAEL C.; SARTORELLI, PATRICIA; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Differential lethal action of C17:2 and C17:0 anacardic acid derivatives in Trypanosoma cruzi - A mechanistic study. BIOORGANIC CHEMISTRY, v. 102, . (18/10279-6, 18/07885-1)
LIMA, MARTA L.; ROMANELLI, MAIARA M.; BORBOREMA, SAMANTA E. T.; JOHNS, DEIDRE M.; MIGOTTO, ALVARO ESTEVES; LAGO, JOAO HENRIQUE G.; TEMPONE, ANDRE G.. Antitrypanosomal activity of isololiolide isolated from the marine hydroid Macrorhynchia philippina (Cnidaria, Hydrozoa). BIOORGANIC CHEMISTRY, v. 89, . (18/10279-6)
MORAIS, THIAGO R.; COSTA-SILVA, THAIS A.; FERREIRA, DAIANE D.; NOVAIS, BIANCA J.; TORRECILHAS, ANA CLAUDIA T.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Antitrypanosomal activity and effect in plasma membrane permeability of (-)-bornyl p-coumarate isolated from Piper cernuum (Piperaceae). BIOORGANIC CHEMISTRY, v. 89, . (18/10279-6, 18/07885-1)
OLIVEIRA, EMERSON A.; BRITO, IVANILDO A.; LIMA, MARTA L.; ROMANELLI, MAIARA; MOREIRA-FILHO, JOSE T.; NEVES, BRUNO J.; ANDRADE, CAROLINA H.; SARTORELLI, PATRICIA; TEMPONE, ANDRE G.; COSTA-SILVA, THAIS A.; et al. Antitrypanosomal Activity of Acetogenins Isolated from the Seeds of Porcelia macrocarpa Is Associated with Alterations in Both Plasma Membrane Electric Potential and Mitochondrial Membrane Potential. Journal of Natural Products, v. 82, n. 5, p. 1177-1182, . (18/10279-6, 18/07885-1)
MENDES, VIVIANE DE MELO; TEMPONE, ANDRE GUSTAVO; TREIGER BORBOREMA, SAMANTA ETEL. Antileishmanial activity of Hi-antihistamine drugs and cellular alterations in Leishmania (L.) infantum. Acta Tropica, v. 195, p. 6-14, . (18/10279-6, 14/24908-4)
TEMPONE, ANDRE G.; PIEPER, PAULINE; BORBOREMA, SAMANTA E. T.; THEVENARD, FERNANDA; LAGO, JOAO HENRIQUE G.; CROFT, SIMON L.; ANDERSON, EDWARD A.. Marine alkaloids as bioactive agents against protozoal neglected tropical diseases and malaria. NATURAL PRODUCT REPORTS, v. 38, n. 12, p. 2214-2235, . (18/10279-6, 19/10434-4, 18/07885-1)
ERICK P. DANTAS; JACKSON MONTEIRO; LÍVIA S. DE MEDEIROS; MAIARA M. ROMANELLI; MAIARA AMARAL; ANDRE G. TEMPONE; JOÃO HENRIQUE G. LAGO; MARISI G. SOARES; PATRICIA SARTORELLI. Dereplication of Aporphine Alkaloids by UHPLC-HR-ESI-MS/MS and NMR from Duguetia lanceolata St. -Hil (Annonaceae) and Antiparasitic Activity Evaluation. Journal of the Brazilian Chemical Society, v. 31, n. 9, p. 1908-1916, . (16/24985-4, 18/10279-6)
MESQUITA, JULIANA TONINI; ROMANELLI, MAIARA MARIA; TRINCONI TRINCONI, CRISTIANA DE MELO C. M.; GUERRA, JULIANA MARIOTTI; TANIWAKI, NOEMI NOSOMI; BORTOLIN ULIANA, SILVIA RENI; REIMAO, JULIANA QUERO; TEMPONE, ANDRE GUSTAVO. Repurposing topical triclosan for cutaneous leishmaniasis: Preclinical efficacy in a murineLeishmania (L.) amazonensismodel. Drug Development Research, . (18/10279-6, 15/23403-9)
BARBOSA, HENRIQUE; COSTA-SILVA, THAIS A.; ALVES CONSERVA, GEANNE A.; ARAUJO, ADELSON J.; LORDELLO, ANA LUISA L.; ANTAR, GUILHERME M.; AMARAL, MAIARA; SOARES, MARISI G.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Aporphine Alkaloids from Ocotea puberula with Anti-Trypanosoma Cruzi Potential - Activity of Dicentrine-beta-N-Oxide in the Plasma Membrane Electric Potentials. CHEMISTRY & BIODIVERSITY, v. 18, n. 4, . (18/10279-6, 18/07885-1)

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