Optimization of diarilalkynes with antiviral potential: Design, synthesis and evaluation of activity of new HsDHODH inhibitors

• Grant number: 24/23733-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: February 28, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Maria Paula Inamonico Fernandes
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Viral infections, as well as other infectious diseases, are a global public health problem due to the severity of their symptoms and the high costs associated with preventive and therapeutic measures, as observed during the SARS-CoV-2 pandemic. Regarding the available therapies, the use of antivirals stands out. However, a concern about these therapeutic agents is the development of resistance, which occurs primarily due to mutations in the viral genome and results in the emergence of drug-resistant strains. In this context, studies aimed at developing antivirals capable of evading mechanisms of resistance acquisition have begun to come into view, such as the design of drugs based on Host-Directed Therapy (HDT) approach. By targeting a host structure, any adaptative viral response is avoided. Thus, to explore this innovative approach, new fragments with 1,2-diarylethine scaffold have been reported, demonstrating potential to inhibit human dihydroorotate dehydrogenase (HsDHODH). This enzyme is involved in the de novo synthesis of pyrimidine nucleotides, which are crucial for viral replication. Despite advances, such as identifying good renal clearence and membrane permeability, low cytotoxicity, as well as strong antiviral activity, these molecules exhibit low water solubility. As this latter parameter is critical for the compound's dissolution in bodily fluids, low water solubility is considered a critical limitation in the research and development process of a future drug. Therefore, given this problem, the present work aims to continue former studies involving 1,2-diarylethynes, or diarylalkynes, optimizing their physicochemical properties to obtain fragments with improved water solubility and an antiviral profile equal or superior to the previously analyzed molecules.