Derivatives of 3-Isoxazolecarboxylic Acid Esters - A Potent and Selective Compound Class against Replicating and Nonreplicating Mycobacterium tuberculosis

Lilienkampf, Annamaria; Pieroni, Marco; Franzblau, Scott G.; Bishai, William R.; Kozikowski, Alan P.

doi:10.2174/156802612799984544

Cited by 21 publications

(20 citation statements)

References 16 publications

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“…This notion may sound odd, especially if one considers the first-line antituberculosis drugs: isoniazid and pyrazinamide both have negative ClogP, whereas ClogP of ethambutol is 0.35. However, it has been deeply demonstrated that compounds with antituberculosis activity are more lipophilic than the inactive ones (Ekins et al, 2011 ), and not only in general, but also within a drug class, lipophilic derivatives are in general more active against mycobacteria than their more hydrophilic counterparts (Mao et al, 2009 ; Lilienkampf et al, 2010 , 2012 ; Pieroni et al, 2010 , 2011 , 2017 ). Below, a critical analysis of the current hot biology challenges (energy depletion, PMF, and drug transporters) and their interconnection with the lipophilicity of molecules is reported.…”

Section: State-of-the-art Of Tuberculosis Drug Discoverymentioning

confidence: 99%

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

et al. 2018

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The emergence of multi- and extensively drug resistant tuberculosis worldwide poses a great threat to human health and highlight the need to discover and develop new, effective and inexpensive antituberculosis agents. High-throughput screening assays against well-validated drug targets and structure based drug design have been employed to discover new lead compounds. However, the great majority fail to demonstrate any antimycobacterial activity when tested against Mycobacterium tuberculosis in whole-cell screening assays. This is mainly due to some of the intrinsic properties of the bacilli, such as the extremely low permeability of its cell wall, slow growth, drug resistance, drug tolerance, and persistence. In this sense, understanding the pathways involved in M. tuberculosis drug tolerance, persistence, and pathogenesis, may reveal new approaches for drug development. Moreover, the need for compounds presenting a novel mode of action is of utmost importance due to the emergence of resistance not only to the currently used antituberculosis agents, but also to those in the pipeline. Cheminformatics studies have shown that drugs endowed with antituberculosis activity have the peculiarity of being more lipophilic than many other antibacterials, likely because this leads to improved cell penetration through the extremely waxy mycobacterial cell wall. Moreover, the interaction of the lipophilic moiety with the membrane alters its stability and functional integrity due to the disruption of the proton motive force, resulting in cell death. When a ligand-based medicinal chemistry campaign is ongoing, it is always difficult to predict whether a chemical modification or a functional group would be suitable for improving the activity. Nevertheless, in the “instruction manual” of medicinal chemists, certain functional groups or certain physicochemical characteristics (i.e., high lipophilicity) are considered red flags to look out for in order to safeguard drug-likeness and avoid attritions in the drug discovery process. In this review, we describe how antituberculosis compounds challenge established rules such as the Lipinski's “rule of five” and how medicinal chemistry for antituberculosis compounds must be thought beyond such dogmatic schemes.

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Section: State-of-the-art Of Tuberculosis Drug Discoverymentioning

confidence: 99%

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

et al. 2018

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“…This method has been adapted for direct utility with M. tuberculosis and has led to the identification of a number of promising lead compounds 4 . A recent phenotypic screening of a library of 6,800 compounds identified several chemotypes with anti- M. tuberculosis activity 5–8 . We synthesized and preliminarily characterized one molecular class, indoleamides, which was active against both drug-susceptible and drug-resistant M. tuberculosis 9 .…”

Section: Introductionmentioning

confidence: 99%

Indoleamides are active against drug-resistant Mycobacterium tuberculosis

et al. 2013

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Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3 which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent anti-mycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis.

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“…8 Indeed, most of the efforts of some of the authors of this work has moved through this path. [9][10][11][12][13][14][15][16][17][18][19] While this approach has proved to be correct, it is nevertheless incomplete. It does not consider that, besides mutations, other mechanisms such as efflux play an important role in the development of resistance in M. tuberculosis.…”

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confidence: 99%

Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy

et al. 2015

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Tuberculosis, caused by Mycobacterium tuberculosis, is still one of the leading infectious diseases globally. Therefore, novel approaches are needed to face this disease. Efflux pumps are known to contribute to the emergence of M. tuberculosis drug resistance. Thioridazine has shown good anti-TB properties both in vitro and in vivo, likely due to its capacity to inhibit efflux mechanisms. Here we report the design and synthesis of a number of putative efflux inhibitors inspired by the structure of thioridazine. Compounds were evaluated for their in vitro and ex vivo activity against M. tuberculosis H37Rv. Compared to the parent molecule, some of the compounds synthesized showed higher efflux inhibitory capacity, less cytotoxicity, and a remarkable synergistic effect with anti-TB drugs both in vitro and in human macrophages, demonstrating their potential to be used as coadjuvants for the treatment of tuberculosis.

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Derivatives of 3-Isoxazolecarboxylic Acid Esters - A Potent and Selective Compound Class against Replicating and Nonreplicating Mycobacterium tuberculosis

Cited by 21 publications

References 16 publications

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

Indoleamides are active against drug-resistant Mycobacterium tuberculosis

Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy

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