Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.
Keywords: CFU, colony-forming units; HPLC, high-peformance liquid chromatography; LDA, lithium diisopropylamide; LORA, low oxygen recovery assay; LiTMP, lithium tetramethylpiperidide; M.tb, Mycobacterium tuberculosis; MABA, microplate alamar blue assay; MIC(90), minimum concentration for 90% inhibition; TB, tuberculosis; hERG, the alpha subunit of a K+ channel that contributes to the electrical activity of the heart.
Copyright © 2019 Elsevier Ltd. All rights reserved.