In vitro Antitubercular Activity of Dihydropyridine-Dicarboxamide and Pyrazole Derivatives against Mycobacterium tuberculosis

ABSTRACT Mycobacterium tuberculosis enoyl-acyl-ACP reductase (InhA) has been demonstrated to be the primary target of isoniazid (INH). Recently, it was postulated that M. tuberculosis dihydrofolate reductase (DHFR) is also a target of INH, based on the findings that a 4R-INH-NADP adduct synthesized from INH by a nonenzymatic approach showed strong inhibition of DHFR in vitro, and overexpression of M. tuberculosis dfrA in M. smegmatis conferred a 2-fold increase of resistance to INH. In the present study, a plasmid expressing M. tuberculosis dfrA was transformed into M. smegmatis and M. tuberculosis strains, respectively. The transformant strains were tested for their resistance to INH. Compared to the wild-type strains, overexpression of dfrA in M. smegmatis and M. tuberculosis did not confer any resistance to INH based on the MIC values. Similar negative results were obtained with 14 other overexpressed proteins that have been proposed to bind some form of INH-NAD(P) adduct. An Escherichia coli cell-based system was designed that allowed coexpression of both M. tuberculosis katG and dfrA genes in the presence of INH. The DHFR protein isolated from the experimental sample was not found bound with any INH-NADP adduct by enzyme inhibition assay and mass spectroscopic analysis. We also used whole-genome sequencing to determine whether polymorphisms in dfrA could be detected in six INH-resistant clinical isolates known to lack mutations in inhA and katG, but no such mutations were found. The dfrA overexpression experiments, together with the biochemical and sequencing studies, conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH.

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Synthesis and in vitro antitubercular activity of 4-aryl/alkylsulfonylmethylcoumarins as inhibitors of Mycobacterium tuberculosis

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2012.05.054 ◽

2012 ◽

Vol 22 (14) ◽

pp. 4807-4809 ◽

Cited By ~ 23

Author(s):

Malaichamy Jeyachandran ◽

Penugonda Ramesh ◽

Dharmarajan Sriram ◽

Palaniappan Senthilkumar ◽

Perumal Yogeeswari

Keyword(s):

Mycobacterium Tuberculosis ◽

Antitubercular Activity

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Isoniazid-Isatin Hydrazone Derivatives: Synthesis, Antitubercular Activity and Molecular Docking Studies

Trends in Sciences ◽

10.48048/tis.2021.39 ◽

2021 ◽

Vol 18 (21) ◽

pp. 39

Author(s):

Mardi Santoso ◽

Muhammad Riza Ghulam Fahmi ◽

Yehezkiel Steven Kurniawan ◽

Taslim Ersam ◽

Sri Fatmawati ◽

...

Keyword(s):

Hydrogen Bonding ◽

Mycobacterium Tuberculosis ◽

Molecular Docking ◽

Active Site ◽

Antitubercular Activity ◽

Docking Study ◽

Positive Control ◽

Tuberculosis H37rv ◽

Molecular Docking Study

This study examined the synthesis of isoniazid-isatin hydrazone derivatives 5-7, followed by an investigation on the in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, and molecular docking. A yield of 81 - 92 % of these compounds was achieved, with structural characterization by spectroscopic methods (FTIR, NMR, HRMS). The in vitro antitubercular activity was evaluated against M. tuberculosis H37Rv, and the highest effect was observed in compound 7, with a minimum inhibitory concentration (MIC) of 0.017 mM, lower than rifampicin (MIC 0.048 mM), which served as the positive control. In addition, the molecular docking of 5-7 was performed to visualize the interaction of isoniazid-isatin hydrazone derivatives with the active site of InhA receptor, which was in agreement with the experimental data. The hydrogen bonding with Ser94 and pi-pi interaction with Phe41 and/or Phe97 on the InhA active site was pivotal for the antitubercular activity. HIGHLIGHTS Tuberculosis caused by Mycobacterium tuberculosis is one of the top ten leading causes of death globally The first and second lines of antituberculosis drugs are the prevalent treatment for this disease, but they show several drawbacks and are exacerbated by the occurrence of drug resistance The isoniazid-isatin hydrazone derivatives were designed through molecular hybridization and synthesized effectively and exhibited moderate to high activity against tuberculosis H37Rv Molecular docking study demonstrated that the hydrogen bonding with Ser94 and the pi-pi interaction with Phe41 and/or Phe97 are important for antitubercular activity GRAPHICAL ABSTRACT

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in silico Design, ADME Prediction, Molecular Docking, Synthesis of Novel Triazoles, Indazoles & Aminopyridines and in vitro Evaluation of Antitubercular Activity

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22790 ◽

2020 ◽

Vol 32 (11) ◽

pp. 2713-2721

Author(s):

S. Triveni ◽

C. Naresh Babu ◽

E. Bhargav ◽

M. Vijaya Jyothi

Keyword(s):

Mycobacterium Tuberculosis ◽

Molecular Docking ◽

Drug Design ◽

In Silico ◽

Antitubercular Activity ◽

Docking Studies ◽

Luciferase Reporter ◽

Assay Method ◽

Adme Prediction

To design and synthesize novel triazoles, indazoles and aminopyridines from various (thiophene-2-yl)prop-2-en-1-one derivatives as antitubercular leads by in silico and in vitro methods. in silco Drug design, ADME prediction and molecular docking studies were performed to assess drug likeliness and antitubercular potential of all 30 novel triazoles, indazoles and aminopyridines. in silico Drug design studies revealed that the synthetic routes applied were appropriate according to the calculations of Swiss-ADME that measure synthetic accessibility. Most of the synthesized compounds found to have considerable binding score with enoyl ACP reductase enzyme of Mycobacterium tuberculosis. All the synthesized compounds were evaluated for antitubercular potential against Drug Resistant Mycobacterium tuberculosis H37Rv strain by Luciferase reporter assay method. Most of the synthesized compounds exhibited remarkable antitubercular potential against resistant strain.

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SYNTHESIS AND ANTITUBERCULAR ACTIVITY OF PIPERIDINE AND MORPHOLINE 1, 8 NAPHTHYRIDINE ANALOGUES

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2016v8i12.13503 ◽

2016 ◽

Vol 8 (12) ◽

pp. 252 ◽

Cited By ~ 2

Author(s):

Muwaffag Badawneh ◽

Jalal Aljamal

Keyword(s):

Mycobacterium Tuberculosis ◽

Inhibitory Concentration ◽

Antitubercular Activity ◽

Antimycobacterial Activity ◽

Significant Activity ◽

Reference Drug ◽

Novel Drugs ◽

Elemental Analyses ◽

Antimycobacterial Agents

Objective: The search for new, potentially useful antimycobacterial agents. In continuation with our previous screening for the discovery of novel drugs for tuberculosis, a new series of 1,8-naphthyridines derivatives were synthesized and evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis H37Rv.Methods: Several 4-morpholinomethyl-1.8-naphthyridine derivatives have been synthesized in excellent yields. The synthesized compounds were characterized by spectroscopic methods as well as elemental analyses. They were screened for their antimycobacterial activity. The growth was monitored radiometrically in 7H12 broth with the BACTEC 460 TB system. The minimum inhibitory concentration (MIC) was determined for compounds that demonstrated ≥ 90% growth inhibition in the primary screening.Results: The obtained data suggested that all compounds showed significant activity against Mycobacterium tuberculosis H37Rv compared to the standard reference drug. Analogues (6-11) having heterocyclic groups in position 7 were the most potent of those we tested.Conclusion: These findings clearly identify the 1,8-naphthyridine analogue (10) with a 6-amino-2-(4'-methoxy benzylamine-4-morpholinomethyl-7-morpholino-substituent as promising anti-tubercular agents possessing significant activity against Mycobacterium tuberculosis H37Rv

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Synthesis of Tetrahydro-2H-[1,3,5]thiadiazine-5-(4-pyridylcarboxamido)-2-thione with antitubercular activity

Scientia Pharmaceutica ◽

10.3797/scipharm.aut-04-04 ◽

2004 ◽

Vol 72 (1) ◽

pp. 35-41 ◽

Cited By ~ 7

Author(s):

D. Sriram ◽

K. Jyothi Mallika ◽

P. Yogeeswari

Keyword(s):

Mycobacterium Tuberculosis ◽

Antitubercular Activity ◽

Antimycobacterial Activity ◽

Therapeutic Use ◽

Tuberculosis H37rv ◽

Mycobacterium Tuberculosis H37rv ◽

Radiometric System ◽

Elemental Analyses ◽

Derivatives Of

3-Substituted-5-(4-pyridylcarboxamide)tetrahydro-2H-[1,3,5]thiadizine-2-thione derivatives (1-9) were synthesized as derivatives of isoniazid (INH) to overcome the resistance developed with its therapeutic use. The structures were confirmed by their spectral and elemental analyses data. These derivatives revealed higher lipophilicity compared with INH. The antimycobacterial activity of the synthesized compounds and INH was evaluated in vitro against Mycobacterium tuberculosis H37Rv at 6.25 µg/ml in BACTEC 12B medium using the BACTEC 460 radiometric system. The derivatives exhibited antitubercular activity.

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ChemInform Abstract: Synthesis and in vitro Antitubercular Activity of 4-Aryl/Alkylsulfonylmethylcoumarins as Inhibitors of Mycobacterium tuberculosis.

ChemInform ◽

10.1002/chin.201247129 ◽

2012 ◽

Vol 43 (47) ◽

pp. no-no

Author(s):

Malaichamy Jeyachandran ◽

Penugonda Ramesh ◽

Dharmarajan Sriram ◽

Palaniappan Senthilkumar ◽

Perumal Yogeeswari

Keyword(s):

Mycobacterium Tuberculosis ◽

Antitubercular Activity

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Synthesis and evaluation of β-hydroxytriazoles and related compounds as antitubercular agents

French-Ukrainian Journal of Chemistry ◽

10.17721/fujcv3i1p82-96 ◽

2015 ◽

Vol 3 (1) ◽

pp. 82-96 ◽

Cited By ~ 1

Author(s):

Christophe Menendez ◽

Giorgia Mori ◽

Mathilde Maillot ◽

Isabelle Fabing ◽

Chantal Carayon ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Antitubercular Activity ◽

Propargyl Bromide ◽

Antitubercular Agents ◽

Oxidation Reactions ◽

Mycobacterium Tuberculosis H37rv ◽

Barbier Reaction ◽

New Compounds ◽

Related Compounds

A new series of β-hydroxytriazoles were synthesized and evaluated as Mycobacterium tuberculosis inhibitors. Our strategy implied the synthesis of alkyne precursors through a Barbier reaction between benzaldehydes and propargyl bromide followed by click chemistry to afford substituted β-hydroxyl benzyltriazoles. These compounds are also key intermediates either for oxidation reactions leading to α,β-diketotriazoles or for elimination reactions affording styryl triazoles. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv resulted in compounds with MIC up to 7 μM.

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