Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis agents

He, Chun‐Xian; Meng, Hui; Zhang, Xiang; Cui, Huaqing; Yin, Daqiang

doi:10.1016/j.cclet.2015.03.027

Cited by 22 publications

(6 citation statements)

References 22 publications

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“…The most promising of these drugs is TZ, which has a low side-effect profile, and has been found effective in mono- and combination therapy in mice ( Martins et al., 2007b ; Dutta et al., 2014a ; Dutta et al., 2014b ), as well as in limited clinical trials to treat XDR-TB ( Abbate et al., 2011 ; Udwadia et al., 2011 ). Improving upon the current state of art, a number of studies have generated novel PTZ derivatives which have lower MICs and reduced neurogenic activity ( Martins et al., 2007a ; Salie et al., 2014 ; He et al., 2015 ). However, important work remains to be done to bring PTZ compounds to the TB patient and elucidate their exact mechanism of action.…”

Section: Current State Of Bioenergetic Inhibitorsmentioning

confidence: 99%

Bioenergetic Inhibitors: Antibiotic Efficacy and Mechanisms of Action in Mycobacterium tuberculosis

Hasenoehrl

Wiggins

Berney

2021

Front. Cell. Infect. Microbiol.

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Development of novel anti-tuberculosis combination regimens that increase efficacy and reduce treatment timelines will improve patient compliance, limit side-effects, reduce costs, and enhance cure rates. Such advancements would significantly improve the global TB burden and reduce drug resistance acquisition. Bioenergetics has received considerable attention in recent years as a fertile area for anti-tuberculosis drug discovery. Targeting the electron transport chain (ETC) and oxidative phosphorylation machinery promises not only to kill growing cells but also metabolically dormant bacilli that are inherently more drug tolerant. Over the last two decades, a broad array of drugs targeting various ETC components have been developed. Here, we provide a focused review of the current state of art of bioenergetic inhibitors of Mtb with an in-depth analysis of the metabolic and bioenergetic disruptions caused by specific target inhibition as well as their synergistic and antagonistic interactions with other drugs. This foundation is then used to explore the reigning theories on the mechanisms of antibiotic-induced cell death and we discuss how bioenergetic inhibitors in particular fail to be adequately described by these models. These discussions lead us to develop a clear roadmap for new lines of investigation to better understand the mechanisms of action of these drugs with complex mechanisms as well as how to leverage that knowledge for the development of novel, rationally-designed combination therapies to cure TB.

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Section: Current State Of Bioenergetic Inhibitorsmentioning

confidence: 99%

Bioenergetic Inhibitors: Antibiotic Efficacy and Mechanisms of Action in Mycobacterium tuberculosis

Hasenoehrl

Wiggins

Berney

2021

Front. Cell. Infect. Microbiol.

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“…However, phenothiazines accumulate in macrophages and are particularly potent against intracellular M. tb [100,101]. Current efforts aim at developing new phenothiazine derivatives with improved activity against M. tb and reduced toxicity [102][103][104][105].…”

Section: Nadh Dehydrogenasesmentioning

confidence: 99%

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

2020

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New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following the FDA-approval of the ATP synthase inhibitor bedaquiline (Sirturo®), energy metabolism has become the subject of intense focus as a novel pathway to exploit for tuberculosis drug development. This enthusiasm stems from the fact that oxidative phosphorylation (OxPhos) and the maintenance of the transmembrane electrochemical gradient are essential for the viability of replicating and non-replicating Mycobacterium tuberculosis (M. tb), the etiological agent of human tuberculosis (TB). Therefore, new drugs targeting this pathway have the potential to shorten TB treatment, which is one of the major goals of TB drug discovery. This review summarises the latest and key findings regarding the OxPhos pathway in M. tb and provides an overview of the inhibitors targeting various components. We also discuss the potential of new regimens containing these inhibitors, the flexibility of this pathway and, consequently, the complexity in targeting it. Lastly, we discuss opportunities and future directions of this drug target space.

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“…On the other hand, phenothiazine, an heterocyclic structural motif owning nitrogen and sulphur heteroatoms, and their derivatives have been reported to exhibit ample of biological activities including anti‐psycosis, anti‐bacterial, anti‐viral, anti‐fungal, anti‐inflammatory, anti‐cancer, anti‐oxidant, antitubercular, anti‐MDR, calcium channel modulator, and anti‐proliferative etc. Besides their biological activities, phenothiazine decorated molecules, specifically polythiophene derivatives with phenothiazine‐vinylene conjugate side chains (PTZV‐PT) could be used in organic field effect transistors (OFETs) .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antioxidant Evaluation, Density Functional Theory Study of Dihydropyrimidine Festooned Phenothiazines

et al. 2018

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A series of dihydropyrimidine decorated phenothiazine and their derivatives 7 a‐7 i possessing a diverse range of functionalities such as isopropyl, methoxy, chloro, fluoro, nitro, naphthyl have been synthesized by adopting a multistep synthetic strategy and characterized using various physical and spectroscopic techniques. Preliminary antioxidant evaluation of all the molecules has been executed and exerted activity upto 69.34% (IC50 148 μM) with respect to the standard ascorbic acid. Computational studies of a representative molecule 7 a have also been executed and appropriate results are compared with the experimental ones. The optimized structure with their bonding features and vibrational frequencies of 7 a have been determined by employing DFT−B3LYP method with 6–311++G(d,p) basis set. The theoretically calculated and experimentally resulted vibrational frequencies of 7 a are in good harmony with each other. Further, the 1H and 13C chemical shifts of 7 a have been calculated by the Gauge Independent Atomic Orbital (GIAO) technique and compared with the experimental ones.

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Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis agents

Cited by 22 publications

References 22 publications

Bioenergetic Inhibitors: Antibiotic Efficacy and Mechanisms of Action in Mycobacterium tuberculosis

Bioenergetic Inhibitors: Antibiotic Efficacy and Mechanisms of Action in Mycobacterium tuberculosis

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

Synthesis, Antioxidant Evaluation, Density Functional Theory Study of Dihydropyrimidine Festooned Phenothiazines

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