Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis.
Bottom Line: Although a significant improvement in enzyme affinity was achieved, the aminoquinazolines showed little or no cellular activity against M. tuberculosis.However, switching to an aminopyrimidine core scaffold and the introduction of a basic amine side chain afforded compounds with nanomolar enzyme binding affinity and micromolar minimum inhibitory concentrations against M. tuberculosis.Replacement of the pyrazole head group with pyridine then allowed equipotent compounds with improved selectivity against a human kinase panel to be obtained.
Affiliation: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK. firstname.lastname@example.orgShow MeSH
Related in: MedlinePlus
Mentions: Initial SAR exploration around 1 was performed via synthetic access from 2,4-dichloroquinazoline 3 (Scheme 1). Introduction of the aminopyrazole was performed by nucleophilic substitution at the 4-position, followed by either a Suzuki coupling to introduce an aryl group or a second nucleophilic substitution to introduce a second amino substituent at the 2-position.
Affiliation: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK. email@example.com