Journal Article
Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization
Candice, S; Lawrence, N; Boshoff, HIM; Barry, CE III; Harris, CJ; Gordon, R; Chibale, K; Feng, T; van Der Westhuyzen, R; Gessner, RK; Street, LJ; Morgans, GL; Warner, DF; Moosa, A; Naran, K; ,
Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
EISSN: 1464-3391
PERGAMON-ELSEVIER SCIENCE LTD
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. (C) 2015 Elsevier Ltd. All rights reserved.
Aminopyrazolopyrimidine; Antibacterial agent; Infectious diseases; Mycobacterium tuberculosis; 2,5 dimethyl 3 phenyl n (pyridin 2 ylmethyl)pyrazolo[1,5 a]pyrimidin 7 amine; 2,5 dimethyl 3 phenyl n (pyridin 3 ylmethyl)pyrazolo[1,5 a]pyrimidin 7 amine; 2,5 dimethyl 3 phenylpyrazolo[1,5-a]pyrimidin 7(4h) one; 3 bromo 7 chloro 2,5 dimethylpyrazolo[1,5 a]pyrimidin; 3 bromo 7 chloro 5 methylpyrazolo; 7 chloro 2,5 dimethyl 3 phenylpyrazolo[1,5 a]pyrimidine; 7 chloro 5 methylpyrazolo[1,5 a]pyridimidine; 7 chloro 5 methylpyrazolo[1,5 a]pyrimidine; aminopyrazolo[1,5 a]pyrimidine derivative; pyrimidine derivative; tert butyl (3 bromo 2,5 dimethylpyrazolo[1,5 a]pyrimidin 7 yl)(pyridin 2 ylmethyl) carbamate; tert butyl (3 bromo 5 methylpyrazolo[1,5 a]pyrimidin 7 yl)(pyridin 2 ylmethyl)carbamate; unclassified drug; pyrazole derivative; pyrazolo(1,5-a)pyrimidine; pyrimidine derivative; tuberculostatic agent; antibacterial activity; Article; concentration response; drug cytotoxicity; drug efficacy; drug solubility; drug stability; drug synthesis; human; hydrophobicity; hydroxylation; in vitro study; lipophilicity; liver microsome; methylation; minimum inhibitory concentration; Mycobacterium tuberculosis; nonhuman; structure activity relation; animal; cell survival; chemistry; CHO cell line; Cricetulus; drug design; drug effects; half life time; hamster; metabolism; microbial sensitivity test; mouse; Mycobacterium tuberculosis; rat; solubility; structure activity relation; synthesis; Animals; Antitubercular Agents; Cell Survival; CHO Cells; Cricetinae; Cricetulus; Drug Design; Half-Life; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Pyrazoles; Pyrimidines; Rats; Solubility; Structure-Activity Relationship