Structural Simplification of Bedaquiline: the Discovery of 3‐(4‐(N,N‐Dimethylaminomethyl)phenyl)quinoline‐Derived Antitubercular Lead Compounds

Abstract

Bedaquiline (BDQ) is a novel and highly potent last‐line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo‐structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub‐microgram per mL concentrations against both sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC‐ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower‐cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non‐ATP synthase related targets.

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

“…A new bedaquiline derivatives containing a pyrazole moiety were identified by He et al and tested for their inhibitory activities against ATP synthesis inhibition in mycobacteria. The results showed that compound 379 inhibited ATP synthesis with IC 50 > 62.9 µM [ 278 ]. Various pyrazole derivatives derived from isoniazide pharmacophore along with coumarin scaffold were investigated for their anti-mycobacterial activity against MTB H37Rv by a resazurin MIC assay.…”

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

“…A critical factor for BDQ optimization is to then get a proper balance of the lipid solubility and basicity of the terminal dimethylamino group [ 99 ]. There is a great interest in manipulating the BDQ scaffold to obtain second-generation DARQ derivatives with attenuate hERG inhibition and reduced lipophilicity [ 100 , 101 , 102 , 103 , 104 , 105 , 106 ]. A TB Global Alliance collaborative project allowed the selection of two compounds (TBAJ-876 and TBA-587, Figure 18 , Table 1 ).…”

Structural simplification: an efficient strategy in lead optimization

“…Yin et al . 124 systematically simplified the structure of bedaquiline by removing the two adjacent chiral centers, which greatly streamlined the synthetic process. Analogue 115 displayed potent in vitro antitubercular activities against both the drug-sensitive mycobacterium tuberculosis ( M. tuberculosis ) strain H37Rv (MIC = 0.43 μg/mL) and drug-resistant strain 12153 (MIC = 0.48 μg/mL).

Figure 19Structural simplification of ATP synthase inhibitors and binding mode of bedaquiline with mycobacterial ATP synthase rotor ring (PDB code: 4V1F).

…”