Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues

Author(s)

Meirelles, Matheus A. ; de Toledo, Ian ; Thurow, Samuel ; Barreiro, Gabriela ; Counago, Rafael M. ; Pilli, Ronaldo A.

• Document type: Journal article
• Source: Journal of Organic Chemistry; v. 88, n. 13, p. 13-pg., 2023-06-08.

Abstract

Tworoutes to the antimalarial diaminopyrimidine P218 weredeveloped based on the C-6 metalation of suitable 2,4-dichloro-5-alkoxypyrimidines using (TMP)(2)Zn center dot 2MgCl(2)center dot 2LiClbase. One approach involves a late-stage modification of the C-6 position,while the other allows for tail fragment modification of P218. Both routes have proven reliable in synthesizing P218, as well as eight analogues. These innovative strategies have thepotential to contribute to the search for new antimalarial drugs. (AU)

• FAPESP's process: 14/50897-0 - INCT 2014: Open-acess Medicinal Chemistry Centre (OpenMedChem)
• Grantee: Katlin Brauer Massirer
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/25008-0 - Design and synthesis of STK10 and VRK2 kinase inhibitors
• Grantee: Ian de Toledo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/20735-1 - Design and synthesis of dihydrofolate reductase inhibitors for nontuberculous mycobacteria
• Grantee: Matheus Andrade Meirelles
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/13104-5 - Planning and synthesis of inhibitors based on biological targets: the case of neglected kinases
• Grantee: Ronaldo Aloise Pilli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
• Grantee: Paulo Arruda
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE