Synthesis, Functionalization and Incorporation of Aryl-Mimetics with High sp3 Character in Molecules with Anti-chagasic Activity: A Viability Study of Potential Drug-Likeness Modulators in Bioactive Compounds

• Grant number: 24/20141-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: February 28, 2030
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Luiz Carlos Dias
• Grantee: João Pedro Nogueira Bonesconto
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

Chagas disease is caused by the parasitic protozoan Trypanosoma cruzi and is classified by the World Health Organization as a Neglected Tropical Disease (NTD), affecting over 6 million people, especially in Latin America. Considering the low investment from major pharmaceutical companies in NTDs, the Drugs for Neglected Diseases initiative (DNDi), in partnership with Unicamp and USP, established the collaborative consortium LOLA to promote Drug Discovery and Development (DDD) in endemic regions. From this consortium, the chemical series 66939 emerged, a group of molecules with high anti-chagasic potential discovered by DNDi - but needing optimization of their drug-likeness, i. e. the similarity between their ADME (Absorption, Distribution, Metabolism, and Excretion) properties and those of approved drugs. In this context, the present project aims not only to optimize the drug-like properties of the presented chemical series through the non-classical bioisosterism of arenes and piperidines with high sp3 character but also to compare the feasibility of using these bioisosteres in the academic context of medicinal chemistry for NTDs. Thus, cubanes and (hetero)bicycles will be synthesized, functionalized, and incorporated into the molecular scaffold to assess their ADME and antiparasitic properties. In parallel, the project seeks to develop a simpler and more direct synthetic methodology aimed at democratizing the use of azaspiroheptanes in DDD campaigns.