Banca de DEFESA: LUIZ HENRIQUE DE CARVALHO OLIVETO

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : LUIZ HENRIQUE DE CARVALHO OLIVETO
DATE: 27/06/2024
TIME: 09:00
LOCAL: Sala virtual: https://meet.google.com/nvt-sdeo-hwe
TITLE:

DESIGN, SYNTHESIS, AND EVALUATION OF THE ANTI-TRYPANOSOMA CRUZI ACTIVITY OF NEW MOLECULAR HYBRIDS OF PIPERINE AND NITAZOXANIDE

KEY WORDS:

Chagas disease, molecular hybridization, nitroheterocycles, amidation reactions, anti-parasitic chemotherapy.

PAGES: 164
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:

Chagas disease (CD) is a neglected tropical disease (NTD) caused by the hemoflagellate protozoan Trypanosoma cruzi. CD has various modes of transmission, with the primary one being vectorial, through the bite of insects from the Reduviidae family (subfamily Triatominae). However, transmission can also occur vertically from mother to child, through the placenta or breastfeeding, by blood transfusion, laboratory accidents, or orally, also known as distant transmission, through consuming raw food containing contaminated insects. T. cruzihas has a complex life cycle, presenting three distinct evolutive forms (epimastigote, amastigote, and trypomastigote). The progression of the infection is divided into three phases: acute, indeterminate, and chronic. In the chronic phase, damage occurs mainly to the digestive tract and the cardiac system in approximately 30% of infected patients. Recent literature data have revealed a new form of amastigote, the dormant amastigote, which lodges in cells of deep and poorly vascularized tissues, forming nests and being capable of restarting the disease cycle at any time. It is estimated that the disease affects 6 to 8 million people worldwide and causes approximately 50,000 deaths. There are only two drugs used in the treatment of Chagas disease patients: nitroimidazole, benznidazole, and the nitrofuran derivative, nifurtimox. Due to genotoxic effects, the use of nifurtimox has been discontinued in Brazil, leaving only benznidazole as a therapeutic alternative for the chemotherapy of Chagas disease. These drugs do not show effective activity in the chronic phase of the infection, highlighting the need to develop new therapeutic alternatives for chronic Chagas disease patients. The amide piperine is a natural product that shows good in vitro activity against T. cruzi. This amide can be isolated in yields ranging from 3 to 10% from the dried fruits of Piper nigrum (black pepper). The chemical structure of piperine is divided into three main subunits: a trisubstituted aromatic ring, a conjugated diene spacer with four carbons, and a piperidinyl amide fraction. Different approaches have been employed better to understand piperine's structure-activity relationship (SAR), leading to the preparation of different families of derivatives of this essential natural amide. In this work, we propose using the molecular hybridization strategy of piperine with the nitro-thiazole nucleus, a pharmacophore present in the structure of the antiparasitic drug nitazoxanide (Annita®). Literature data demonstrate that nitro-heterocycles interfere with the redox balance of the parasite cell, which, being more sensitive to the presence of radical oxygen and nitrogen species, is more affected by them than mammalian cells. Thus, the planned compounds have great potential to present selective toxicity against parasite cells. Auspicious preliminary results obtained in vitro against amastigotes of T. cruzi (strain Tulahuen LaCZ, C2C3) of a piperine-nitazoxanide hybrid synthesized in this work validate the proposed molecular design strategy. The hybrids were prepared in yields ranging from 24 to 47% through a coupling reaction between carboxylic acids and amides in the presence of HATU. The tests in T. cruzi showed positive results, highlighting the main hybrid, LOP-04, which presented an IC50 result in the range of 2 mM. Two other compounds, ME-04 and ME-05, also showed good selectivity indices, 18.40 and 17.58, respectively. The data set allowed us to understand and outline an SAR study to analyze which portions of the molecules contributed to the antitrypanosomal activity. The results obtained herein demonstrate that this work successfully achieved the proposed objectives.

COMMITTEE MEMBERS:
Interno - 3292567 - EDUARDO HILLMANN WANDERLIND
Externa ao Programa - 1335855 - DANIELLE DE OLIVEIRA NASCIMENTO - UFRRJExterno à Instituição - EDSON FERREIRA DA SILVA - FIOCRUZ
Externo à Instituição - GUSTAVO HENRIQUE GOULART TROSSINI - USP