Banca de DEFESA: JORGE LUCAS FERREIRA LACERDA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : JORGE LUCAS FERREIRA LACERDA
DATE: 29/07/2024
TIME: 09:00
LOCAL: https://meet.google.com/pdh-qqfu-uep
TITLE:

DEVELOPMENT AND INVESTIGATION OF THE ANTI-TRYPANOSOMA CRUZI ACTIVITY OF NEW CURCUMINOIDS

KEY WORDS:

diarylheptanoids, bioisosterism, antiparasitic chemotherapy, neglected tropical diseases, Chagas disease

PAGES: 206
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:

Curcumin (1) is a natural product of the diarylheptanoid class, being the majority component of the Curcuma longa, which presents a wide variety of applications in medicinal
chemistry since antitumor activity, until anti-inflammatory, antioxidant, antiparasitic, among
others that classify it as a multitarget substance. Despite a variety of works in the literature
relating the activity of curcumin (1) against Leshimania amazonensis and Plasmodium
falciparum, there are few reports from studies about its activities against Trypanosoma
cruzi, the etiological agent by Chagas Disease (CD). CD affects approximately 8 million
people worldwide, with only two drugs, benznidazole (7) and nifurtimox (8), available to
treat the patients. Both drugs present low efficacy for long-term treatment and much
systemic toxicity, with collateral severe effects, and only benznidazole is now available in
Brazil. In previous work, the LaQuiMed group was one of the pioneers in researching the
activity of curcumin (1) against T. cruzi (Dm-28c strains), obtaining IC50 values in vitro of
10,13 μM against epimastigotes forms and investigating the interactions with tubulin, by in
silico methods, as its possible molecular target. Thereby, this work's objective is to
synthesize a series of products planned by medicinal chemistry strategies of non-classic
bioisosterism (33 - 41), like natural curcuminoids (1 - 3) analogs, and molecular
hybridization as hybrids (54 - 56) with nitroimidazoles portions, aiming to enhance the
curcuminoids biological activity against parasite amastigotes forms (intracellular replicative
form), following the in silico investigation of the interactions of the product with its potential
molecular target and pharmacokinetic profile (ADME) to reduce cytotoxic effects
to the host and justify the products selectivity. From that, it was possible to obtain a hit
(compound 33) among ten synthetic derivatives (33 - 41, 55) obtained at this work. The set
of derivatives was tested against mammalian cells (LLC-MK2), which was the host cell
used in the infection protocol. Compound 33 was the most promising one with IC50 of
17,20 ± 4,37 μM against T. cruzi (Tulahuen C2C4 LacZ strain) amastigotes in vitro and
IC50 > 200 μM against host cells, then expressing 11,63 of selectivity index (SI), which is
ten times higher than that observed for curcumin (1) and other natural diarylheptanoids (2
and 3). The in silico studies were accomplished to analyze the product interactions with
tubulin (curcuminoids possible molecular target) of T. cruzi by comparative modeling and
used to investigate the possible action mechanism of products by molecular docking in
tubulin, presenting a good correlation of score results and experimental results (R = -0,76),
being able to demonstrate the mitotic catastrophe process in the parasite caused by the
product's presence. Furthermore, the product's cytotoxicity has been evaluated by
theoretical methods from ADME analysis and by the capacity to suffer Michael's reactions
at the biological environment to justify its interaction with undesirable molecular targets
that could elevate their respective cytotoxicity. These analyses can justify the biological
actions and the selectivity of the hit (33) against the parasite, highlighting it as the primary
hit in this work.

COMMITTEE MEMBERS:
Presidente - 1058758 - MARCO EDILSON FREIRE DE LIMA
Interno - 1237805 - LEONARDO SIMOES DE ABREU CARNEIRO
Interna - 1979542 - RENATA BARBOSA LACERDA
Externo à Instituição - PEDRO DE SENA MURTEIRA PINHEIRO - UFRJ
Externo à Instituição - NAILTON MONTEIRO DO NASCIMENTO JÚNIOR - UNESP