Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization.
Bioorg Med Chem, 2015/11/15;23(22):7240-50.
Soares de Melo C, Candice Sde M[1], Feng TS[1], van der Westhuyzen R[1], Gessner RK[1], Street LJ[1], Morgans GL[2], Warner DF[3], Moosa A[4], Naran K[4], Lawrence N[5], Boshoff HI[6], Barry CE 3rd[6], Harris CJ[7], Gordon R[8], Chibale K[9]
Affiliations
PMID: 26522089
Impact factor: 3.461
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.
Keywords: Aminopyrazolopyrimidine; Antibacterial agent; Infectious diseases; Mycobacterium tuberculosis
MeSH terms
Animals; Antitubercular Agents; CHO Cells; Cell Survival; Cricetinae; Cricetulus; Drug Design; Half-Life; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Pyrazoles; Pyrimidines; Rats; Solubility; Structure-Activity Relationship
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