Banca de DEFESA: JÉSSICA ALVES NUNES

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : JÉSSICA ALVES NUNES
DATE: 20/06/2023
TIME: 09:00
LOCAL: SALA DA PÓS-GRADUAÇÃO DO IQB
TITLE:

Rational design of new coumarins as potential cysteine protease inhibitors from Trypanosoma cruzi and Trypanosoma brucei.

KEY WORDS:

Chagasdisease;HumanAfricantrypanosomiasis;Cruzain;Rhodesain;Rationaldrugdesign.

PAGES: 110
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUMMARY:

Neglected diseases are responsible for causing morbidity and mortality worldwide, being prevalent in tropical and subtropical countries. Among these diseases, Chagas disease, caused by Trypanosoma cruzi, and Human African Trypanosomiasis, caused by T. brucei gambiense or T. brucei rhodesiense, constitute public health problems, mainly in countries in Latin America and sub-Saharan Africa, respectively. Pharmacological therapies currently employed in the treatment of such diseases have problems of efficacy, toxicity, and/or resistance. In this context, it is necessary to invest in the discovery of more effective drugs against these diseases. Cruzain (CRZ) from T. cruzi and a cathepsin L-
like enzyme (TbrCATL) from T. brucei are cysteine proteases considered promising targets for the development of new compounds with trypanocidal activity, since they play vital roles in these parasites. Coumarin analogs have been reported as promising trypanocidal agents. Therefore, this study aims to develop rationally designed coumarins aimed at inhibiting these cysteine proteases from the T. cruzi and T. brucei protozoa. Thus, to discover potential inhibitors of such targets, the vFBDD technique was initially applied, which made it possible to obtain a coumarin- thiosemicarbazone derivative (FN-27), as the most active molecule against such proteases, CRZ (IC50: 14.4 μM ± 0.02) and TbrCATL (IC50: 2.0 μM ± 0.6), in addition to exhibiting effective activity against cells infected by T. cruzi amastigotes (EC50: 11.7 μM). At the same time, a coumarin-chalcone analog (FN-10) with promising activity against T. brucei trypomastigotes (EC50: 4.8 μM ± 0.15) was also obtained, but it did not demonstrate activity against CRZ or TbrCATL. Additionally, from molecular docking studies, in which FN-27 was considered as a positive control, a series of new coumarins was planned, structural modifications, and subsequent biological evaluation. Finally, it is expected, at the end of this work, to produce potentially active molecules against the T. cruzi and T. brucei parasites, through enzymatic inhibition, as well as to help in the development of future drug prototypes

BANKING MEMBERS:
Presidente - 3182336 - EDEILDO FERREIRA DA SILVA JUNIOR
Interno(a) - 1613338 - JOSUE CARINHANHA CALDAS SANTOS
Externo(a) ao Programa - 1461121 - SILVIA HELENA CARDOSO
Externo(a) ao Programa - 1488396 - TICIANO GOMES DO NASCIMENTO