title: Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization.
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.
authors.forename: Candice
authors.initials: C
authors.lastname: Soares de Melo
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Soares de Melo
authors.initials: Sde M
authors.lastname: Candice
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Tzu-Shean
authors.initials: TS
authors.lastname: Feng
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Renier
authors.initials: R
authors.lastname: van der Westhuyzen
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gessner
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.affiliation: iThemba Pharmaceuticals, Modderfontein 1609, South Africa.
authors.forename: Garreth L
authors.initials: GL
authors.lastname: Morgans
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Digby F
authors.initials: DF
authors.lastname: Warner
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Atica
authors.initials: A
authors.lastname: Moosa
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Krupa
authors.initials: K
authors.lastname: Naran
authors.affiliation: Division of Clinical Pharmacology, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Nina
authors.initials: N
authors.lastname: Lawrence
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Helena I M
authors.initials: HI
authors.lastname: Boshoff
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Cjh Consultants (Pharmaceutical R&D), Lydith, High Street, Eynsford, Kent DA4 0AB, United Kingdom.
authors.forename: C John
authors.initials: CJ
authors.lastname: Harris
authors.affiliation: Strategic Health Innovation Partnerships (SHIP), South African Medical Research Council, Parow Valley, South Africa.
authors.forename: Richard
authors.initials: R
authors.lastname: Gordon
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: kelly.chibale@uct.ac.za.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006207:Half-Life; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine
keywords: Aminopyrazolopyrimidine; Antibacterial agent; Infectious diseases; Mycobacterium tuberculosis