Banca de DEFESA: AFONSO SANTINE MAGALHAES MESQUITA VELEZ

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : AFONSO SANTINE MAGALHAES MESQUITA VELEZ
DATE: 28/11/2025
TIME: 09:00
LOCAL: Defesa híbrida: Sala 50 do Instituto de Química da UFRRJ; Ambiente virtual do Google Meet
TITLE:

Molecular hybridization and dimerization of pharmacophore groups as strategies for designing new drugs to treat infections caused by trypanosomatids

KEY WORDS:

Piperine, Nitroimidazoles, Chagas disease, Sleeping sickness

PAGES: 198
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:

Diseases caused by trypanosomatid protozoa significantly impact public health worldwide, and effective long- term treatments are still lacking. Predominantly found in the Americas, Chagas disease (American trypanosomiasis), caused by the hemoflagellated protozoan Trypanosoma cruzi, affects over 7 million people globally. In Africa, sleeping sickness (Human African trypanosomiasis), caused by Trypanosoma brucei, remains a serious health threat because of its high fatality rate if not treated early. Over 55 million people live in endemic zones across Africa, facing real risks of infection. Due to the urgent need for new therapeutic options, this work emphasizes the rational design of novel molecules using two approaches. Chapter 1 details the design of hybrids based on synthetic derivatives of the natural amide piperine, extracted from dried Piper nigrum fruits, combined with pharmacophoric groups found in existing antiparasitic drugs like nitroimidazoles (which contribute to the activity of benznidazole, megazol, and metronidazole). Organic analysis techniques- including those used to investigate intermediates- were employed to synthesize and characterize these hybrids. All molecules were tested against the primary forms of T. cruzi, especially the amastigote stage (strain Tulahuen C2C4- LacZ), and evaluated for activity against T. brucei and cytotoxicity toward different mammalian cells. Molecular docking and enzymatic models of TcSDH and 14 DM of T. cruzi were used to assess the inhibitory potential of these hybrid ligands. In Chapter 2, the rational design of dimeric compounds was explored, inspired solely by the pharmacophoric core of benznidazole (2- 2-nitroimidazole), created through simple N-alkylation using bidentate alkylating agents — a promising strategy. Biological tests showed all dimeric compounds were active against T. cruzi amastigotes (Tulahuen C 2 C 4- LacZ). Notably, longer-chain dimers displayed remarkable potency (IC₅₀ < 1 1.0 µM), indicating that their activity depends on the length of the methylene spacer; longer chains interact more effectively with T. cruzi nitroreductase (TcNTR), which activates these prodrugs inside the parasite. These compounds also demonstrated significant activity against T. b. brucei (strain 427) and exhibited minimal cytotoxicity in mammalian cells, underscoring their selectivity — especially among the longer-chain dimers. The nitroimidazole pharmacophoric groups are crucial in antiparasitic therapy, which, despite limited efficacy, continues to show some success at certain stages of treatment. Overall, this study aims to enhance understanding of their mechanisms of action across different parasites and hosts. It uses multiple approaches to improve the design of new drug candidates and facilitate the development of prototype molecules active against parasitic infections.

COMMITTEE MEMBERS:
Interno - 1700480 - ARTHUR EUGEN KUMMERLE
Interna - ***.742.388-** - AUREA ECHEVARRIA AZNAR NEVES LIMA - UFRRJ
Interno - 2624418 - CLAUDIO EDUARDO RODRIGUES DOS SANTOS
Externa à Instituição - LUANA DA SILVA MAGALHÃES FOREZI - UFF
Externa à Instituição - LUCIANA POLACO COVRE - UFRJ
Externo à Instituição - LUIS OCTÁVIO REGASINI - UNESP
Presidente - 1058758 - MARCO EDILSON FREIRE DE LIMA