Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue

Qiao, Changjiang; Wang, Xiaokui; Xie, Fei; Zhong, Wu; Song, Li

doi:10.3390/molecules201219846

Cited by 13 publications

(4 citation statements)

References 31 publications

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“…Other structural moieties that play a role in anti-TB activity include the hydroxyl group, the side chain with the N,N-dimethyl amino terminus and/or the naphthalene moiety. 5,133 Several bedaquiline analogues have been synthesised with the aim of improving the antimicrobial activity and spectrum of bedaquiline, as well as the pharmacological properties of the antibiotic, however, none of these has progressed to clinical evaluation. 134,135 Antimicrobial activity of bedaquiline to bedaquiline has been associated with phenotypic variations in the F 1 /F 0 -ATP synthase enzyme, which, as described below, is the target for bedaquiline in susceptible mycobacterial species.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline

Cholo

Mothiba

Fourie

et al. 2016

J. Antimicrob. Chemother.

114

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Drug-resistant (DR)-TB is the major challenge confronting the global TB control programme, necessitating treatment with second-line anti-TB drugs, often with limited therapeutic efficacy. This scenario has resulted in the inclusion of Group 5 antibiotics in various therapeutic regimens, two of which promise to impact significantly on the outcome of the therapy of DR-TB. These are the 're-purposed' riminophenazine, clofazimine, and the recently approved diarylquinoline, bedaquiline. Although they differ structurally, both of these lipophilic agents possess cationic amphiphilic properties that enable them to target and inactivate essential ion transporters in the outer membrane of Mycobacterium tuberculosis. In the case of bedaquiline, the primary target is the key respiratory chain enzyme F/F-ATPase, whereas clofazimine is less selective, apparently inhibiting several targets, which may underpin the extremely low level of resistance to this agent. This review is focused on similarities and differences between clofazimine and bedaquiline, specifically in respect of molecular mechanisms of antimycobacterial action, targeting of quiescent and metabolically active organisms, therapeutic efficacy in the clinical setting of DR-TB, resistance mechanisms, pharmacodynamics, pharmacokinetics and adverse events.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline

Cholo

Mothiba

Fourie

et al. 2016

J. Antimicrob. Chemother.

114

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“…Treating 1d with either PhMgBr or PhLi at room temperature we noted a completely lack of reactivity, at least for the first three hours. The use of CuI/PhMgBr system furnished a complex reaction mixture. On the other hand, by activation of the epoxide with either Amberlyst 15 or BF 3 , the reaction with PhLi resulted in a mixture of products, in which the main one was diarylacetaldehyde 6 .…”

Section: Resultsmentioning

confidence: 99%

Regio‐ and Diastereoselective Organo‐Zinc‐Promoted Arylation of trans‐2,3‐Diaryloxiranes by Arylboronic Acids: Stereoselective Access to trans‐2,3‐Diphenyl‐2,3‐dihydrobenzofuran

et al. 2019

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ortho‐Oxo substituted trans 2,3‐diaryloxiranes were regio‐ and stereoselectively arylated by arylzinc reagents, obtained from the corresponding boronic acids by B–Zn exchange. The reaction was quite general, irrespective to the aryl nucleophile and proceeded via a ring opening at the α‐carbon with respect to the substituted aryl ring. The stereoselectivity was from high to complete toward the alcohol resulted from retention of configuration at the electrophilic carbon. The method allowed a direct and high yielding access to trans 2,3‐diphenyl‐2,3‐dihydrobenzofuran, which is a key structural motif in resveratrol dimers as viniferins. The use of enantioenriched starting diaryloxiranes resulted in no loss of stereochemical integrity in the final trans 2,3‐dihydrobenzofuran, which was characterized for the first time in enantioenriched form.

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“…In fact, the only report of bedaquiline analogues whereby the quinoline heterocycle was not present is a very recent publication by Li and co-workers where the nitrogen atom of the quinoline was substituted with a C-H to afford 2-methoxynaphthyl derivatives. 17 During the drug discovery phase, Janssen prepared bedaquiline analogues by employing an LDA-mediated addition of 3-benzylquinolines to ethyl-amino substituted aryl ketones. 7 Since that time, two alternative asymmetric syntheses of bedaquiline have been reported, however, these require the initial use of substituted anilines to prepare the quinoline motif from which the remainder of the molecule is constructed.…”

Section: Introductionmentioning

confidence: 99%

New synthetic approaches towards analogues of bedaquiline

2016

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Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

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Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue

Cited by 13 publications

References 31 publications

Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline

Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline

Regio‐ and Diastereoselective Organo‐Zinc‐Promoted Arylation of trans‐2,3‐Diaryloxiranes by Arylboronic Acids: Stereoselective Access to trans‐2,3‐Diphenyl‐2,3‐dihydrobenzofuran

New synthetic approaches towards analogues of bedaquiline

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