| Autor: |
Andrade Meirelles, Matheus, Almeida, Vitor M., Sullivan, Jaryd R., de Toledo, Ian, dos Reis, Caio Vinicius, Cunha, Micael Rodrigues, Zigweid, Rachel, Shim, Abraham, Sankaran, Banumathi, Woodward, Elijah L., Seibold, Steve, Liu, Lijun, Mian, Mohammad Rasel, Battaile, Kevin P., Riley, Jennifer, Duncan, Christina, Simeons, Frederick R. C., Ferguson, Liam, Joji, Halimatu, Read, Kevin D., Lovell, Scott, Staker, Bart L., Behr, Marcel A., Pilli, Ronaldo A., Couñago, Rafael M. |
| Zdroj: |
Journal of Medicinal Chemistry; November 2024, Vol. 67 Issue: 21 p19143-19164, 22p |
| Abstrakt: |
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 aviumand Mycobacterium abscessus. This study underscores the potential of compound 8as a promising candidate for the in vivovalidation of DHFR as an effective treatment against NTM infections. |
| Databáze: |
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