Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

  • J Med Chem. 2024 Nov 14;67(21):19143-19164. doi: 10.1021/acs.jmedchem.4c01594.
Matheus Andrade Meirelles  1 ,  Vitor M Almeida  2 ,  Jaryd R Sullivan  3  4  5 ,  Ian de Toledo  1 ,  Caio Vinicius Dos Reis  2 ,  Micael Rodrigues Cunha  2 ,  Rachel Zigweid  6  7 ,  Abraham Shim  6  7 ,  Banumathi Sankaran  8 ,  Elijah L Woodward  7  9 ,  Steve Seibold  7  9 ,  Lijun Liu  7  9 ,  Mohammad Rasel Mian  7  9 ,  Kevin P Battaile  10 ,  Jennifer Riley  11 ,  Christina Duncan  11 ,  Frederick R C Simeons  11 ,  Liam Ferguson  11 ,  Halimatu Joji  11 ,  Kevin D Read  11 ,  Scott Lovell  7  9 ,  Bart L Staker  6  7 ,  Marcel A Behr  3  4  5  12 ,  Ronaldo A Pilli  1 ,  Rafael M Couñago  2  13
Affiliations
  • 1. Department of Organic Chemistry, Institute of Chemistry, University of Campinas, UNICAMP, 13083-970-Campinas, SP, Brazil.
  • 2. Center of Medicinal Chemistry (CQMED), Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas, UNICAMP, 13083-886-Campinas, SP, Brazil.
  • 3. Department of Microbiology & Immunology, McGill University, Montréal H3A 2B4, Canada.
  • 4. Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal H4A 3J1, Canada.
  • 5. McGill International TB Centre, Montréal H4A 3S5, Canada.
  • 6. Center for Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, United States.
  • 7. Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, Washington 98109, United States.
  • 8. Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
  • 9. Protein Structure and X-ray Crystallography Laboratory, Del Shankel Structural Biology Center, University of Kansas, Lawrence, Kansas 66047, United States.
  • 10. New York Structural Biology Center, Upton, New York 11973, United States.
  • 11. Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry, University of Dundee, Dundee DD1 5EH, U.K.
  • 12. Department of Medicine, McGill University Health Centre, Montréal H4A 3J1, Canada.
  • 13. Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
PMID: 39468773 DOI: 10.1021/acs.jmedchem.4c01594
Abstract

Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by Antibiotics in Gram-negative Bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

Products