Dataset Information

Novel Pyrimidines as Antitubercular Agents.

ABSTRACT: Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.

SUBMITTER: Inoyama D

PROVIDER: S-EPMC5826157 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Novel Pyrimidines as Antitubercular Agents.

Inoyama Daigo D Paget Steven D SD Russo Riccardo R Kandasamy Srinivasan S Kumar Pradeep P Singleton Eric E Occi James J Tuckman Margareta M Zimmerman Matthew D MD Ho Hsin Pin HP Perryman Alexander L AL Dartois Véronique V Connell Nancy N Freundlich Joel S JS

Antimicrobial agents and chemotherapy 20180223 3

Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines w ...[more]

PMID: 29311070

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Project description:PurposeMulti- and extensively drug-resistant tuberculosis (TB) is a global threat to human health. It requires immediate action to seek new antitubercular compounds and devise alternate strategies. Nanomaterials, in the present scenario, have opened new avenues in medicine, diagnosis, and therapeutics. In view of this, the current study aims to determine the efficacy of phytogenic metal nanoparticles to inhibit mycobacteria.MethodsSilver (AgNPs), gold (AuNPs), and gold-silver bimetallic (Au-AgNPs) nanoparticles synthesized from medicinal plants, such as Barleria prionitis, Plumbago zeylanica, and Syzygium cumini, were tested against Mycobacterium tuberculosis and M. bovis BCG. In vitro and ex vivo macrophage infection model assays were designed to determine minimum inhibitory concentration (MIC) and half maximal inhibitory concentration of nanoparticles. Microscopic analyses were carried out to demonstrate intracellular uptake of nanoparticles in macrophages. Besides this, biocompatibility, specificity, and selectivity of nanoparticles were also established with respect to human cell lines.ResultsAu-AgNPs exhibited highest antitubercular activity, with MIC of <2.56 μg/mL, followed by AgNPs. AuNPs did not show such activity at concentrations of up to 100 μg/mL. In vitro and ex vivo macrophage infection model assays revealed the inhibition of both active and dormant stage mycobacteria on exposure to Au-AgNPs. These nanoparticles were capable of entering macrophage cells and exhibited up to 45% cytotoxicity at 30 μg/mL (ten times MIC concentration) after 48 hours. Among these, Au-AgNPs synthesized from S. cumini were found to be more specific toward mycobacteria, with their selectivity index in the range of 94-108.ConclusionThis is the first study to report the antimycobacterial activity of AuNPs, AgNPs, and Au-AgNPs synthesized from medicinal plants. Among these, Au-AgNPs from S. cumini showed profound efficiency, specificity, and selectivity to kill mycobacteria. These should be investigated further to develop novel TB nanoantibiotics.

Dataset Information

Novel Pyrimidines as Antitubercular Agents.

Publications

Novel Pyrimidines as Antitubercular Agents.

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