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Tuberculosis (Edinburgh, Scotland) Mar 2019To complement the development of new or repurposed drugs for improving the treatment outcomes of drug-susceptible and drug-resistant tuberculosis, current insight also... (Review)
Review
To complement the development of new or repurposed drugs for improving the treatment outcomes of drug-susceptible and drug-resistant tuberculosis, current insight also focuses on the use of host-directed therapy. Metformin, a drug often used in the management of type 2 diabetes mellitus, has attracted attention by virtue of its favourable activity as an adjunctive agent against tuberculosis, discovered through laboratory and clinical studies. To definitively establish its role as a host-directed therapeutic in tuberculosis, more preclinical and clinical research is still required to better delineate its mechanism(s) of action and optimal clinical use.
Topics: Animals; Antitubercular Agents; Autophagy; Drug Interactions; Drug Therapy, Combination; Forecasting; Host-Pathogen Interactions; Humans; Immunity, Cellular; Latent Tuberculosis; Macrophages; Metformin; Mice; Mycobacterium tuberculosis; Oxidative Stress; Tuberculosis
PubMed: 30948180
DOI: 10.1016/j.tube.2019.02.004 -
Synthesis and antitubercular screening of [(2-chloroquinolin-3-yl)methyl] thiocarbamide derivatives.Chemical Biology & Drug Design Nov 2014A series of 1-(substituted-phenyl)-1-[(2-chloroquinolin-3-yl)methyl]thiocarbamide and 1-(substituted-phenyl)-1-[(2-chloroquinolin-3-yl)methyl]methylthiocarbamide...
A series of 1-(substituted-phenyl)-1-[(2-chloroquinolin-3-yl)methyl]thiocarbamide and 1-(substituted-phenyl)-1-[(2-chloroquinolin-3-yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, (1)H and (13)C-NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC-25177) in Lowenstein-Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g, 3h, 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity.
Topics: Administration, Oral; Antitubercular Agents; Biological Availability; Chemistry Techniques, Synthetic; Chloroquinolinols; Drug Evaluation, Preclinical; Ethionamide; Humans; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Thiourea
PubMed: 24750991
DOI: 10.1111/cbdd.12339 -
Dermatologic Therapy 2008Cutaneous tuberculosis (TB) is an extrapulmonary form of tuberculosis, which may be classified based on the immunologic state of the host. Chemotherapy still remains the... (Review)
Review
Cutaneous tuberculosis (TB) is an extrapulmonary form of tuberculosis, which may be classified based on the immunologic state of the host. Chemotherapy still remains the treatment of choice. The management of cutaneous TB follows the same guidelines as that of TB of other organs, which can be treated with a short course four-agent chemotherapeutic regimen given for 2 months followed by a two-drug regimen for the next 4 months. This chapter highlights current treatment recommendations for cutaneous TB. The important factors to consider in the choice of optimal treatment includes the type of cutaneous involvement, stage of the disease, level of immunity, and general condition of the patient. The highest priority in any cutaneous TB control program is the proper, accurate, and rapid detection of cases and the availability of chemotherapy to all tuberculosis patients until cure. Contact tracing is also an important component of efficient tuberculosis control.
Topics: Adult; Antitubercular Agents; Child; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Immunocompromised Host; Infant; Male; Middle Aged; Patient Compliance; Risk Factors; Skin; Tuberculosis, Cutaneous
PubMed: 18564245
DOI: 10.1111/j.1529-8019.2008.00186.x -
Molecular Microbiology Dec 2006For decades after its introduction, the mechanisms of action of the front-line antituberculosis therapeutic agent isoniazid (INH) remained unclear. Recent developments... (Review)
Review
For decades after its introduction, the mechanisms of action of the front-line antituberculosis therapeutic agent isoniazid (INH) remained unclear. Recent developments have shown that peroxidative activation of isoniazid by the mycobacterial enzyme KatG generates reactive species that form adducts with NAD(+) and NADP(+) that are potent inhibitors of lipid and nucleic acid biosynthetic enzymes. A direct role for some isoniazid-derived reactive species, such as nitric oxide, in inhibiting mycobacterial metabolic enzymes has also been shown. The concerted effects of these activities - inhibition of cell wall lipid synthesis, depletion of nucleic acid pools and metabolic depression - drive the exquisite potency and selectivity of this agent. To understand INH action and resistance fully, a synthesis of knowledge is required from multiple separate lines of research - including molecular genetic approaches, in vitro biochemical studies and free radical chemistry - which is the intent of this review.
Topics: Antitubercular Agents; Isoniazid; Mycobacterium tuberculosis; NAD
PubMed: 17074073
DOI: 10.1111/j.1365-2958.2006.05467.x -
ChemMedChem Feb 2016Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents...
Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non-enzymatic, in mycobacteria prior to binding to the target of interest. From a whole-cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) of Mycobacterium tuberculosis (Mtb). The lead was found to be mutagenic to start with. Our efforts to mitigate mutagenicity resulted in the identification of 6-methyl-7-nitro-5-(trifluoromethyl)-1,3-benzothiazoles (cBTs), a novel class of antitubercular agents that are non-mutagenic and exhibit an improved safety profile. The methyl group ortho to the nitro group decreases the electron affinity of the series, and is hence responsible for the non-mutagenic nature of these compounds. Additionally, the co-crystal structure of cBT in complex with Mtb DprE1 established the mode of binding. This investigation led to a new non-mutagenic antitubercular agent and demonstrates that the mutagenic nature of nitroarenes can be solved by modulation of stereoelectronic properties.
Topics: Antitubercular Agents; Benzothiazoles; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Mutagens; Mycobacterium tuberculosis; Nitro Compounds; Stereoisomerism; Structure-Activity Relationship
PubMed: 26751718
DOI: 10.1002/cmdc.201500462 -
European Journal of Medicinal Chemistry Dec 2019Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become the world's leading killer disease due to a single infectious agent which survives in the host...
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become the world's leading killer disease due to a single infectious agent which survives in the host macrophage for the indefinite period. Hence, it is necessary to enhance the efficacy of the clinically existing antitubercular agents or to discover new anti antitubercular agents. Here, we report the synthesis, characterization and antimycobacterial evaluation of protein-drug conjugates. A carrier protein, Transferrin (Tf) was covalently conjugated to isoniazid (INH) utilizing hydrazone and amide linkers. The purity of the reactions was confirmed by SDS-PAGE while conjugation was confirmed by UV-visible spectrophotometry, MALDI-TOF analysis, and FTIR spectrophotometry. The in vitro antitubercular assay result showed that the inhibitory activity of the parent drug was conserved in both the conjugates. The conjugates were effective against intracellular Mtb H37Rv and were devoid of cytotoxic effect at therapeutic concentration.
Topics: Antitubercular Agents; Drug Stability; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Transferrin; Tuberculosis
PubMed: 31557610
DOI: 10.1016/j.ejmech.2019.111713 -
Progress in Biophysics and Molecular... May 2020Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), kills more people than any other bacterium. TB control is threatened by the continued spread... (Review)
Review
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), kills more people than any other bacterium. TB control is threatened by the continued spread of drug resistance; multi-drug and extensively drug resistant Mtb require longer, more costly, treatment with multiple drugs causing worse side effects and have a lower likelihood of treatment success. The urgent need for better treatment options for drug resistant Mtb has led the World Health Organization to prioritize development of not only new individual antitubercular agents, but also new drug regimens. This introductory chapter of the special issue Novel insights into TB research and drug discovery within Progress in Biophysics and Molecular Biology, gives a short overview about the general problems of TB and the treatment of this disease today, and introduces the review topics within this issue.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Discovery; Drug Resistance; Humans; Mycobacterium tuberculosis; Signal Transduction; Tuberculosis; World Health Organization
PubMed: 32087187
DOI: 10.1016/j.pbiomolbio.2020.02.003 -
Bioorganic & Medicinal Chemistry Letters Sep 2022Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to...
Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).
Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary
PubMed: 35777718
DOI: 10.1016/j.bmcl.2022.128871 -
Bioorganic & Medicinal Chemistry Letters Sep 2022Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for...
Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).
Topics: Animals; Antitubercular Agents; Long QT Syndrome; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35636648
DOI: 10.1016/j.bmcl.2022.128824 -
Bioorganic & Medicinal Chemistry Dec 2020In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of...
In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M.tuberculosis H37Rv. In the present study we report the structure-activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.
Topics: Amides; Animals; Antitubercular Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Stability; Female; Half-Life; Humans; Mice; Mice, Inbred BALB C; Microsomes; Mycobacterium tuberculosis; Structure-Activity Relationship; Thiazoles; Tuberculosis
PubMed: 33075682
DOI: 10.1016/j.bmc.2020.115797