Aminopyrazolo[1, 5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Soares de Melo, Candice; 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.; Harris, C. John; Gordon, Richard; Chibale, Kelly
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 22(2015)
• Page Start: 7240
• Page End: 7250
• Publication Date: 2015-11-15
• Subjects: Mycobacterium tuberculosis -- Antibacterial agent -- Aminopyrazolopyrimidine -- Infectious diseases; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.10.021
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.