Synthesis and Structure–Activity Relationships for the Anti-Mycobacterial Activity of 3-Phenyl-<i>N</i>-(Pyridin-2-ylmethyl)Pyrazolo[1,5-<i>a</i>]Pyrimidin-7-Amines

Abstract

Pyrazolo[1,5-a]pyrimidines have been reported as potent inhibitors of mycobacterial ATP synthase for the treatment of Mycobacterium tuberculosis (M.tb). In this work, we report the design and synthesis of approximately 70 novel 3,5-diphenyl-N-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amines and their comprehensive structure–activity relationship studies. The most effective pyrazolo[1,5-a]pyrimidin-7-amine analogues contained a 3-(4-fluoro)phenyl group, together with a variety of 5-alkyl, 5-aryl and 5-heteroaryl substituents. A range of substituted 7-(2-pyridylmethylamine) derivatives were also active. Some of these compounds exhibited potent in vitro M.tb growth inhibition, low hERG liability and good mouse/human liver microsomal stabilities, highlighting their potential as inhibitors of M.tb.

Keywords

• pyrazolopyrimidines
• structure–activity relationships
• synthesis
• tuberculosis
• ATP synthase