Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization

作者：Candice Soares de Melo; Feng Tzu Shean; van der Westhuyzen Renier; Gessner Richard K; Street Leslie J; Morgans Garreth L; Warner Digby F; Moosa Atica; Naran Krupa; Lawrence Nina; Boshoff Helena I M; Barry Clifton E III; Harris C John; Gordon Richard; Chibale Kelly^*

来源：Bioorganic & Medicinal Chemistry, 2015, 23(22): 7240-7250.

DOI：10.1016/j.bmc.2015.10.021

• Mycobacterium tuberculosis
• Antibacterial agent
• Aminopyrazolopyrimidine
• Infectious diseases

Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified.

• 出版日期2015-11-15