Design and synthesis of dihydrofolate reductase inhibitors for nontuberculous mycobacteria

• Grant number: 19/20735-1
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): December 01, 2019
• Effective date (End): July 31, 2022
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Ronaldo Aloise Pilli
• Grantee: Matheus Andrade Meirelles
• Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Nontuberculous mycobacteria (NTM) are opportunistic pathogens responsible for pulmonary disease in immunocompromised patients or patients with pre-existing lung conditions such as bronchiectasis, cystic fibrosis or chronic obstructive pulmonary disease. Due to bacterial resistance and inefficient drugs, the incidence and prevalence of pulmonary diseases caused by NTMs have significantly increased worldwide. Although dihydrofolate reductase (DHFR) is a well-known biological target for antibiotics development, its inhibition in NTMs has not been extensively explored. Therefore, we aim to design and synthesize new DHFR inhibitors against NTMs, particularly M. avium and M. abscessus that are responsible for most lung infections. Based on the co-crystal structure of compound P218 and M. tuberculosis DHFR, we planned four different strategies to achieve new scaffolds active against NTMs, which were validated by docking studies. The strategies planned involve modifications at the ethyl position of P218, the synthesis of macrocycles with restricted conformation compared to the parent molecule, the investigation of hybrid molecules from P218 and trimethoprim, and substitution of the carboxylic acid residue in P218 for isostereric functional groups. The project will be developed in collaboration with the Structure Genomics Consortium (SGC-Unicamp). (AU)