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

Candice Soares de Melo; Tzu-Shean Feng; Renier van der Westhuyzen; Richard K Gessner; Leslie J Street; Garreth L Morgans; Digby F Warner; Atica Moosa; Krupa Naran; Nina Lawrence; Helena I M Boshoff; Clifton E Barry 3rd; C John Harris; Richard Gordon; Kelly Chibale

doi:10.1016/j.bmc.2015.10.021

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

Bioorg Med Chem. 2015 Nov 15;23(22):7240-50. doi: 10.1016/j.bmc.2015.10.021. Epub 2015 Oct 22.

Authors

Affiliations

¹ Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
² iThemba Pharmaceuticals, Modderfontein 1609, South Africa.
³ 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.
⁴ MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town, Rondebosch 7701, South Africa.
⁵ Division of Clinical Pharmacology, University of Cape Town, Rondebosch 7701, South Africa.
⁶ Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
⁷ Cjh Consultants (Pharmaceutical R&D), Lydith, High Street, Eynsford, Kent DA4 0AB, United Kingdom.
⁸ Strategic Health Innovation Partnerships (SHIP), South African Medical Research Council, Parow Valley, South Africa.
⁹ 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: [email protected].

PMID: 26522089
DOI: 10.1016/j.bmc.2015.10.021

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.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / chemistry
Antitubercular Agents / metabolism
Antitubercular Agents / pharmacology*
CHO Cells
Cell Survival / drug effects
Cricetinae
Cricetulus
Drug Design
Half-Life
Mice
Microbial Sensitivity Tests
Microsomes, Liver / metabolism
Mycobacterium tuberculosis / drug effects*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Rats
Solubility
Structure-Activity Relationship

Substances

Antitubercular Agents
Pyrazoles
Pyrimidines
pyrazolo(1,5-a)pyrimidine

Grants and funding

Intramural NIH HHS/United States