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. email@example.comShow MeSH
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Mentions: The selectivity of the inhibitors was examined against other M. tuberculosis kinases and this revealed that they typically showed cross-affinity with PknF, although they displayed only modest inhibition of PknG. Aminopyrimidines featuring appended pyrazole groups have been reported in the literature as inhibitors of a number of human kinases,10 so achieving selectivity in these compounds was therefore a key consideration and their kinase selectivity against a 76-member human kinase panel was examined. Pleasingly compound 16c, containing the aminopyridine head group motif, showed an improvement in selectivity relative to 11e, which contains the aminopyrazole head group (Fig. 2). This is consistent with an expected gain in selectivity that may occur through reducing the number of H-bonds that can be formed with the kinase hinge region. Docking studies were performed using Glide™ (Schrödinger Inc.) on both the aminopyrazole and aminopyridine head group variants using the PknB crystal structure (ref: 2FUM)12 from the PDB, and the predicted binding modes of compounds 15c and 16d are shown in Figure 3. It can be seen that the aminopyrazoles can form up to 3 hydrogen bonds with the hinge region of the kinase, and the appended cyclopropyl group can form a face-on lipophilic interaction with the methionine gatekeeper residue. The cyano group on the phenyl ring points in the direction of a lysine residue. By contrast, in the aminopyridine variants two hydrogen bonds with the hinge region can be formed, and the 4-substituent on the pyridine head group is orientated in the direction of the gatekeeper.
Affiliation: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK. firstname.lastname@example.org