6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

Abstract

Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages

“…Given that total host-cell accumulation does not necessarily correlate with antibiotic efficacy against intracellular pathogens, we hypothesised that efficacy is modulated by partitioning of compounds within the host-cell (2). The anti-tubercular antibiotic Bedaquiline is highly lipophilic (3,4), a trait associated with permeability through tissue at the expense of non-specific binding and host-sequestration (5)(6)(7). We tested whether efficacy is linked to the accumulation of the drug in intracellular compartments.…”

Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

“…The electronegativity of halogen atoms renders them net electron‐withdrawing groups, which can potentially alter the electronic environment of the indole ring. We therefore sought to incorporate a bioisosteric nitrile moiety, which has also demonstrated the capacity to displace bound waters for a net entropic gain …”

“…The electronegativity of halogena toms renders them net electron-withdrawing groups,w hich can potentially alter the electronic environmento ft he indole ring. We therefore sought to incorporate ab ioisosteric nitrile moiety, [28,29] which has also demonstrated the capacity to displace bound waters for an et entropic gain. [30] Region Ca nalogues had focussed mainly on thiophenols, which had indicated firstly that para-substituted analogues are preferred for activity,w ith the strongly electron-withdrawing nitro group providing the greatest antimalarial activity.E lectron-donating groups, particularly amines, negatively influenced activity and introduced significant mammalian cytotoxicity.…”

Narrow-spectrum antibacterial agents

“…45 Bedaquiline demonstrates activity against both non-replicating and replicating mycobacteria, and against both drug-sensitive and drug resistant isolates. However, bedaquiline is subject to CYP3A4 metabolism, 46 and exhibits potent hERG channel inhibition, 47 and as such is subject to a limited indication of use in patients for which there is considerable unmet need and a positive benefit–risk balance. 44 …”