Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis

Scalacci, Nicoló; Brown, Alistair K.; Pavan, Fernando Rogério; Ribeiro, Carolina Barbosa; Manetti, Fabrizio; Bhakta, Sanjib; Maitra, Arundhati; Smith, Darren; Petricci, Elena; Castagnolo, Daniele

doi:10.1016/j.ejmech.2016.12.042

Cited by 25 publications

(11 citation statements)

References 29 publications

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“…In recent years a wide range of factors has led to the resurgence of TB. The causative pathogen Mtb afflicts more frequently patients with weakened immune system and thus, TB is significantly hazardous to those who suffer from the human immune deficiency virus (HIV) [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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In vitro Controlled Release of two new Tuberculocidal Adamantane Aminoethers from Solid Pharmaceutical Formulations (II)

et al. 2017

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The aim of the present investigation was to develop matrix tablet formulations for the controlled release of two new tuberculocidal adamantane aminoethers (compounds and ), congeneric to the adamantane derivative which is in final clinical trials, and aminoethers () and (), using carefully selected excipients, such as polyvinylpyrrolidone, sodium alginate and lactose. The tablets were prepared using the direct compression method and dissolution experiments were conducted using the US Pharmacopoeia type II apparatus (paddle method) in gastric and intestinal fluids. The results suggest that both analogues, more lipophilic than and aminoethers () and (), have the requisite release characteristics for oral administration. In conclusion, these formulations merit further assessment by conducting studies, at a later stage.

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Section: Introductionmentioning

confidence: 99%

“…In addition, the high cost of conventional therapy constitutes a serious problem. Hence, it is obvious that there is an imperative need to design new agents with antitubercular activity in order not only to tackle the resistant strains of Mtb, but also to reduce the therapy period [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

In vitro Controlled Release of two new Tuberculocidal Adamantane Aminoethers from Solid Pharmaceutical Formulations (II)

et al. 2017

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“…In the context of a study to identify novel antibacterial agents designed to overcome antimicrobial resistance, a small library of diverse bioactive compounds had previously been synthesised within our team. Using the Resazurin Microtiter Assay (REMA) [14,15,16], these compounds were screened for antibacterial activity at a fixed concentration (128 μg/mL) against a range of drug-susceptible bacteria including Gram-positive, Gram-negative and mycolata bacteria (Supporting Information, Table S1) which revealed that many possessed little utility, even at these high concentrations. However, benzo-[2,1,3]-diazole architectures 1 – 12 were shown to possess antibacterial activity, including activity against mycolata bacteria and Mtb (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Benzoxa-[2,1,3]-diazole Substituted Amino Acid Hydrazides as Potential Anti-Tubercular Agents

et al. 2019

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Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection are desperately needed to tackle the continuing global burden of this disease and the efficacy and cost limitations associated with current medicines. Herein, we report the synthesis of a series of novel benzoxa-[2,1,3]-diazole substituted amino acid hydrazides in a two-step synthesis and evaluate their inhibitory activity against Mtb and selected bacterial strains of clinical importance utilising an end point-determined REMA assay. Alongside this, their potential for undesired cytotoxicity against mammalian cells was assessed employing standard MTT assay methodologies. It has been demonstrated using modification at three sites (the hydrazine, amino acid, and the benzodiazole) it is possible to change both the antibacterial activity and cytotoxicity of these molecules whilst not affecting their microbial selectivity, making them attractive architectures for further exploitation as novel antibacterial agents.

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“…However, thioridazine and other phenothiazines inhibit Ca 2ϩ ion channels and are used as antipsychotic drugs (24); hence, they have side effects and are cytotoxic at low concentrations. For example, the 50% inhibitory concentration (IC 50 ) of thioridazine for human macrophages is 5 to 8 g/ml (24,78,81). An additional cytotoxic mechanism of many drug efflux pump inhibitors is that they impair host transporter proteins (82).…”

Section: Discussionmentioning

confidence: 99%

A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis

Meikle

Mossberg

Mitra

et al. 2019

Antimicrob Agents Chemother

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Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug-resistant strains has become a major challenge for health care systems and, in some cases, has rendered TB untreatable. However, the development of new TB drugs has been plagued with high failure rates and costs. Alternative strategies to increase the efficacy of current TB treatment regimens include host-directed therapies or agents that makeM. tuberculosismore susceptible to existing TB drugs. In this study, we show that HAMLET, an α-lactalbumin–oleic acid complex derived from human milk, has bactericidal activity againstM. tuberculosis. HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured α-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sublethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics againstM. tuberculosis. For example, the minimal inhibitory concentrations of rifampin, bedaquiline, delamanid, and clarithromycin were decreased by 8- to 16-fold. HAMLET also killedM. tuberculosisand enhanced the efficacy of TB drugs inside macrophages, a natural habitat ofM. tuberculosis. Previous studies showed that HAMLET is stable after oral delivery in mice and nontoxic in humans and that it is possible to package hydrophobic compounds in the oleic acid core of HAMLET to increase their solubility and metabolic stability. The potential of HAMLET and other liprotides as drug delivery and sensitization agents in TB chemotherapy is discussed here.

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Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis

Cited by 25 publications

References 29 publications

In vitro Controlled Release of two new Tuberculocidal Adamantane Aminoethers from Solid Pharmaceutical Formulations (II)

In vitro Controlled Release of two new Tuberculocidal Adamantane Aminoethers from Solid Pharmaceutical Formulations (II)

Identification of Novel Benzoxa-[2,1,3]-diazole Substituted Amino Acid Hydrazides as Potential Anti-Tubercular Agents

A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis

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