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Bioisosterism in the design of new antichagasic agents: integration of computational and experimental strategies

Grant number: 11/11499-0
Support type:Regular Research Grants
Duration: February 01, 2012 - March 31, 2014
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Gustavo Henrique Goulart Trossini
Grantee:Gustavo Henrique Goulart Trossini
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Adriano Defini Andricopulo ; Elizabeth Igne Ferreira ; Mauro Aquiles La Scalea


Tropical neglected diseases strongly reflect the underdevelopment of important geographic regions of the planet, being harmful for three vital features, such as physical, mental and social health. Most of the drugs that have been used to treat infected people are limited and this scenario is getting worse due to the resistant strains of the microorganisms. The lack of effective treatments has stimulating the selection of molecular targets and the design of new chemotherapeutic agents as drug candidates. Chagas´ disease is a tropical endemic, considered among the extremely neglected diseases. It is one of the most important medical problems in Latin America that infects from 18 to 20 million people, and provokes about 21 million deaths a year. In 2009, the century of discovery of Chaga´s disease by the Brazilian sanitary physician, Dr. Carlos J. R. Chagas, was celebrated. Despite the historical landmark this discovery represents for Brazilian Science, the disease completed its first century without any effective treatment, especially against its chronic form. This scenario shows the urgency for integrated actions towards the discovery of new antichagasic candidates. Cruzain, a Trypanosoma cruzi cysteino-protease involved in the development and differentiation of the parasite, was selected as molecular target in our studies. Due to its important functions in many stages of the parasite biological cycle, cruzain is an excellent macromolecular target for the development of enzyme inhibitors with high potential clinical use. Many chemical classes have been studied as chemotherapeutic alternatives for Chagas´disease and, also, as cruzain inhibitors. Among those classes we can highlight semicarbazones and chalcones. Two nitro-heterocyclic derivatives of semicarbazone, nitrofurazone and hydroxymethylnitrofurazone showed to be active against T. cruzi through trypanothione reductase and cruzain inhibition as well. Compounds containing chalcones in their structure also presented potent cruzain inhibition. Both classes, chalcones and semicarbazones, are interesting to Pharmaceutical and Medicinal Chemistry considering their chemical versatility. Based on bioisosterism, one of the most profitable processes in the introduction of drugs in therapeutics, this project aims at computational design, synthesis, electrochemical and biochemical kinetics evaluation in cruzain inhibition and in vitro biological assays of semicarbazone and chalcones bioisosters. In this project, it is planned the development of a new generation of T. cruzi cruzain inhibitors based on a Medicinal Chemistry paradigm that involves the integration between computational and experimental methods, comprehending design, biological evaluation and molecular modeling studies with the objective of achieve scientific and technological development of the work group, besides the rational search for a new antichagasic candidate. (AU)

Scientific publications (9)
(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)
SILVA, FREDSON T.; FRANCO, CAIO H.; FAVARO, DENIZE C.; FREITAS-JUNIOR, LUCIO H.; MORAES, CAROLINA B.; FERREIRA, ELIZABETH I. Design, synthesis and antitrypanosomal activity of some nitrofurazone 1,2,4-triazolic bioisosteric analogues. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 121, p. 553-560, OCT 4 2016. Web of Science Citations: 10.
SOUZA, FREDERICO B.; SHAMIM, ANWAR; ARGOMEDO, LUIZ M. Z.; PIMENTA, DANIEL C.; STEFANI, HELIO A. Synthesis of enyne and aryl vinyl sulfoxides: functionalization via Pummerer rearrangement. MOLECULAR DIVERSITY, v. 19, n. 4, p. 773-785, NOV 2015. Web of Science Citations: 3.
ALI, BAKHAT; ZUKERMAN-SCHPECTOR, JULIO; FERREIRA, FERNANDO P.; SHAMIM, ANWAR; PIMENTA, DANIEL C.; STEFANI, HELICI A. Lewis-acid catalyzed N-acyliminium ion cyclodimerization: synthesis of symmetrical 1,4-dioxanes. Tetrahedron Letters, v. 56, n. 9, p. 1153-1158, FEB 25 2015. Web of Science Citations: 4.
TROSSINI, GUSTAVO H. G.; MALTAROLLO, VINICIUS G.; SCHMIDT, THOMAS J. Hologram QSAR Studies of Antiprotozoal Activities of Sesquiterpene Lactones. Molecules, v. 19, n. 7, p. 10546-10562, JUL 2014. Web of Science Citations: 9.
VITAL, DRIELLI GOMES; ARRIBAS, MARCO; GOULART TROSSINI, GUSTAVO HENRIQUE. Molecular Modeling and Docking Application to Evaluate Cruzain Inhibitory Activity by Chalcones and Hydrazides. LETTERS IN DRUG DESIGN & DISCOVERY, v. 11, n. 3, p. 249-255, MAR 2014. Web of Science Citations: 8.
BUENO, RENATA V.; BRAGA, RODOLPHO C.; SEGRETTI, NATANAEL D.; FERREIRA, ELIZABETH I.; TROSSINI, GUSTAVO H. G.; ANDRADE, CAROLINA H. New Tuberculostatic Agents Targeting Nucleic Acid Biosynthesis: Drug Design using QSAR Approaches. CURRENT PHARMACEUTICAL DESIGN, v. 20, n. 27, p. 4474-4485, 2014. Web of Science Citations: 14.
SILVA, FREDSON TORRES; TROSSINI, GUSTAVO H. G. The Survey of the Use of QSAR Methods to Determine Intestinal Absorption and Oral Bioavailability During Drug Design. Medicinal Chemistry, v. 10, n. 5, p. 441-448, 2014. Web of Science Citations: 7.
BRITO, CHARLES DE LIMA; GOULART TROSSINI, GUSTAVO HENRIQUE; FERREIRA, ELIZABETH IGNE; LA-SCALEA, MAURO AQUILES. Nitrofurazone and its Nitroheterocyclic Analogues: a Study of the Electrochemical Behavior in Aqueous Medium. Journal of the Brazilian Chemical Society, v. 24, n. 12, p. 1964+, DEC 2013. Web of Science Citations: 5.
BLAU, LORENA; MENEGON, RENATO FARINA; TROSSINI, GUSTAVO H. G.; DUTRA MOLINO, JOAO VITOR; VITAL, DRIELLI GOMES; BARRETTO CICARELLI, REGINA MARIA; PASSERINI, GABRIELA DUO; BOSQUESI, PRISCILA LONGHIN; CHIN, CHUNG MAN. Design, synthesis and biological evaluation of new aryl thiosemicarbazone as antichagasic candidates. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 67, p. 142-151, SEP 2013. Web of Science Citations: 20.

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