Synthesis and Evaluation of Pyridine-derived Bedaquiline Analogues Containing Modifications at the A-ring Subunit

Overview

Journal RSC Med Chem

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2021 Jul 5

PMID 34223160

Citations 1

Authors

Lisa Barbaro

Gayathri Nagalingam

James A Triccas

Lendl Tan

Nicholas P West

Jonathan B Baell

Daniel L Priebbenow

Affiliations

Soon will be listed here.

Abstract

Despite promising efficacy, the clinical use of the anti-tubercular therapeutic bedaquiline has been restricted due to safety concerns. To date, limited SAR studies have focused on the quinoline ring (A-ring), and as such, we set out to explore modifications within this region in an attempt to discover new bedaquiline variants with an improved safety profile. We herein report the development of unique synthetic strategies that facilitated access to novel bedaquiline analogues leading to the discovery that anti-tubercular activity could be retained following replacement of the quinoline motif with pyridine heterocycles. This discovery is anticipated to open up multiple new avenues for exploration in the design of improved anti-tubercular therapeutics.

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References

Guillemont J, Meyer C, Poncelet A, Bourdrez X, Andries K . Diarylquinolines, synthesis pathways and quantitative structure--activity relationship studies leading to the discovery of TMC207. Future Med Chem. 2011; 3(11):1345-60. DOI: 10.4155/fmc.11.79. View

Cohen J . Infectious disease. Approval of novel TB drug celebrated--with restraint. Science. 2013; 339(6116):130. DOI: 10.1126/science.339.6116.130. View

Choi P, Sutherland H, Tong A, Blaser A, Franzblau S, Cooper C . Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline containing heterocyclic B-ring units. Bioorg Med Chem Lett. 2017; 27(23):5190-5196. PMC: 5696560. DOI: 10.1016/j.bmcl.2017.10.042. View

Recanatini M, Poluzzi E, Masetti M, Cavalli A, De Ponti F . QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev. 2004; 25(2):133-66. DOI: 10.1002/med.20019. View

Svensson E, Murray S, Karlsson M, Dooley K . Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug. J Antimicrob Chemother. 2014; 70(4):1106-14. PMC: 4356204. DOI: 10.1093/jac/dku504. View

Sutherland H, Tong A, Choi P, Conole D, Blaser A, Franzblau S . Structure-activity relationships for analogs of the tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles. Bioorg Med Chem. 2018; 26(8):1797-1809. PMC: 5933462. DOI: 10.1016/j.bmc.2018.02.026. View

Kamariah N, Ragunathan P, Shin J, Saw W, Wong C, Dick T . Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design. Prog Biophys Mol Biol. 2019; 152:64-73. DOI: 10.1016/j.pbiomolbio.2019.11.006. View

Calvert M, Furkert D, Cooper C, Brimble M . Synthetic approaches towards bedaquiline and its derivatives. Bioorg Med Chem Lett. 2020; 30(12):127172. DOI: 10.1016/j.bmcl.2020.127172. View

Yu M, Nagalingam G, Ellis S, Martinez E, Sintchenko V, Spain M . Nontoxic Metal-Cyclam Complexes, a New Class of Compounds with Potency against Drug-Resistant Mycobacterium tuberculosis. J Med Chem. 2016; 59(12):5917-21. DOI: 10.1021/acs.jmedchem.6b00432. View

10.

Ang C, Tan L, Sykes M, AbuGharbiyeh N, Debnath A, Reid J . Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility. J Med Chem. 2020; 63(24):15726-15751. PMC: 7770830. DOI: 10.1021/acs.jmedchem.0c01372. View

11.

Preiss L, Langer J, Yildiz O, Eckhardt-Strelau L, Guillemont J, Koul A . Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci Adv. 2015; 1(4):e1500106. PMC: 4640650. DOI: 10.1126/sciadv.1500106. View

12.

Bahuguna A, Rawat D . An overview of new antitubercular drugs, drug candidates, and their targets. Med Res Rev. 2019; 40(1):263-292. DOI: 10.1002/med.21602. View

13.

Sarathy J, Ragunathan P, Cooper C, Upton A, Gruber G, Dick T . TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug's Uncoupler Activity. Antimicrob Agents Chemother. 2019; 64(2). PMC: 6985740. DOI: 10.1128/AAC.01540-19. View

14.

Lubanyana H, Arvidsson P, Govender T, Kruger H, Naicker T . Improved Synthesis and Isolation of Bedaquiline. ACS Omega. 2020; 5(7):3607-3611. PMC: 7045498. DOI: 10.1021/acsomega.9b04037. View

15.

Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R . Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 2007; 3(6):323-4. DOI: 10.1038/nchembio884. View

16.

Sutherland H, Tong A, Choi P, Blaser A, Franzblau S, Cooper C . Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology. Bioorg Med Chem. 2019; 28(1):115213. DOI: 10.1016/j.bmc.2019.115213. View

17.

Saga Y, Motoki R, Makino S, Shimizu Y, Kanai M, Shibasaki M . Catalytic asymmetric synthesis of R207910. J Am Chem Soc. 2010; 132(23):7905-7. DOI: 10.1021/ja103183r. View

18.

Diacon A, Donald P, Pym A, Grobusch M, Patientia R, Mahanyele R . Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012; 56(6):3271-6. PMC: 3370813. DOI: 10.1128/AAC.06126-11. View

19.

Qiao C, Wang X, Xie F, Zhong W, Li S . Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue. Molecules. 2015; 20(12):22272-85. PMC: 6331863. DOI: 10.3390/molecules201219846. View

20.

Sutherland H, Tong A, Choi P, Blaser A, Conole D, Franzblau S . 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. Bioorg Med Chem. 2019; 27(7):1292-1307. PMC: 6467547. DOI: 10.1016/j.bmc.2019.02.026. View