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Optimization of natural scaffolds as new therapeutic candidates for Visceral Leishmaniasis

Grant number: 18/25128-3
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2019
Effective date (End): November 30, 2022
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:André Gustavo Tempone Cardoso
Grantee:Maiara Amaral de Oliveira
Host Institution: Instituto Adolfo Lutz (IAL). Coordenadoria de Controle de Doenças (CCD). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Visceral Leishmaniasis is a neglected protozoan disease with high mortality, and the treatment is a serious challenge to public health. Considering that natural products represent a promising source of new pharmaceutical prototypes, this proposal aims to continue the SPRINT:Oxford project (2015/50075-2), attending the research demand in the area of new drugs for VL. It will count on international collaborations of the University of Oxford, University of Dundee e Oregon State University. The anti-Leishmania (L.) infantum potential of a new series of synthetic and semi-synthetic compounds derived from neoligans from the plant Nectandra leucantha will be studied. In silico studies (physicochemical properties, ADMET and similarity with PAINS) will be carried out. From the obtained results, the derivatives will be prepared and the anti-Leishmania activity evaluated in intracellular amastigotes. Cytotoxicity studies will be performed to determine the selectivity index. The mechanism of action of the most promising compound will be analyzed by different parameters, such as: i) alterations of plasma and mitochondrial membranes (permeability and electric potential); ii) levels of Ca2+, ATP, ROS; iii) cell cycle; iv) ultrastructural changes and v) immunomodulatory potential (cytokines and NO). Finally, pharmacokinetic parameters (ADME in vitro/in vivo) will be determined, aiming the selection of a lead compound for future preclinical studies. (AU)

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Scientific publications (5)
(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)
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)
AMARAL, MAIARA; VARELA, MARINA T.; KANT, RAVI; CHRISTODOULIDES, MYRON; FERNANDES, JOAO PAULO S.; TEMPONE, ANDRE G.. Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi. LIFE-BASEL, v. 13, n. 3, p. 17-pg., . (21/04464-8, 18/26655-7, 17/50333-7, 18/03918-2, 19/24028-8, 18/25128-3)
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)
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, p. 8-pg., . (18/25128-3, 18/10279-6)
AMARAL, MAIARA; ASIKI, HANNAH; SEAR, CLAIRE E.; SINGH, SNIGDHA; PIEPER, PAULINE; HAUGLAND, MARIUS M.; ANDERSON, EDWARD A.; TEMPONE, ANDRE G.. Biological activity and structure-activity relationship of dehydrodieugenol B analogues against visceral leishmaniasis. RSC MEDICINAL CHEMISTRY, v. 14, n. 7, p. 7-pg., . (18/25128-3, 21/04464-8, 17/50333-7)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
OLIVEIRA, Maiara Amaral de. Optimization of neolignans as pharmaceutical prototypes for visceral leishmaniasis: mechanism of action and pharmacokinetic studies. 2023. Doctoral Thesis - Faculdade de Medicina (FM/SBD) São Paulo.

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