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

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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Synthesis and Preliminary Evaluation of Benzofuran-Oxadiazole Conjugates as Potential Antitubercular Agents

Asian Journal of Chemistry ◽

10.14233/ajchem.2019.21831 ◽

2019 ◽

Vol 31 (4) ◽

pp. 965-970 ◽

Cited By ~ 1

Author(s):

Veerabhadrayya S. Negalurmath ◽

Obelannavar Kotresh ◽

Mahantesha Basanagouda

Keyword(s):

Mycobacterium Tuberculosis ◽

Spectral Data ◽

13C Nmr ◽

Antitubercular Activity ◽

Preliminary Evaluation ◽

Antitubercular Agents ◽

Mass Spectral Data ◽

Mass Spectral ◽

Mycobacterium Tuberculosis H37rv ◽

Mycobacterium Phlei

In the present study, a series of benzofuran-oxadiazole conjugates 7(a-o) was designed, synthesized and characterized through IR, 1H NMR, 13C NMR and mass spectral data. All the compounds were screened for preliminary antitubercular activity against Mycobacterium phlei and Mycobacterium tuberculosis H37RV. Among all the target compounds, the compound possessing chlorine (7k, MIC 1.56 μg/mL) and bromine (7m, MIC 1.56 μg/mL) on 6th position of benzofuran showed highest activity against Mycobacterium phlei. Whereas, bromine on either 5th position (7l, MIC 3.125 μg/mL) or 6th position (7m MIC 3.125 μg/mL) on benzofuran exhibited highest activity for Mycobacterium tuberculosis (H37 RV).

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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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Design, Synthesis and Antitubercular Evaluation of New Benzimidazole Scaffolds

Anti-Infective Agents ◽

10.2174/2211352518666200108091454 ◽

2021 ◽

Vol 18 (4) ◽

pp. 375-383

Author(s):

Smriti Yadav ◽

Bharath Kumar Inturi ◽

Shrinidhi B.R ◽

Pooja H.J ◽

Neenu Ganesh ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Cell Lines ◽

Normal Cell ◽

Acyl Carrier Protein ◽

Antitubercular Activity ◽

Resistance Mechanisms ◽

Docking Studies ◽

Chemical Library ◽

Activity Data ◽

Mycobacterium Tuberculosis H37rv

Background: To overcome one of the resistance mechanisms of Isoniazid (INH), there is a need for an antitubercular agent that can inhibit InhA enzyme by circumventing the formation of INH-NAD+ adduct. Objective: The objective of the study is the development of novel antitubercular agents that target Mycobacterium tuberculosis InhA (Enoyl Acyl Carrier Protein Reductase). Methods: A small-molecule chemical library was used for the identification of the novel InhA inhibitors using primary screening and molecular docking studies followed by the scaffold hopping approach. The designed molecules, 2-(2-(hydroxymethyl)-1H- benzo[d] imidazole-1-yl)- N- substituted acetamides were synthesized by reacting (1H- benzo[d]imidazole -2-yl)methanol with appropriate 2-chloro-N-substituted acetamides / dialkylamino carbonyl chlorides respectively in good yields (42-65%). The antitubercular activity of synthesized compounds was determined by Microplate Alamar Blue Assay (MABA) against Mycobacterium tuberculosis H37Rv strain. The selected compounds were screened for cytotoxicity on normal cell lines. Results: The antitubercular activity data revealed that the 4-chlorophenyl substituted derivative (3b) showed good MIC value at 6.25 μg/mL and, dimethylacetamide substituted derivative (3i) showed MIC at 25 μg/mL among the tested compounds. The substitution of dimethylacetamide (3i) group on the 1st position of benzimidazole has good antitubercular activity (25μg/mL) in comparison to the diethyl acetamide group (3j, 100μg/mL). Conclusion: The antitubercular activity data indicated that the tested compounds exhibited well to moderate inhibition of the H37Rv strains. The compounds (3b) with electronegative substitution on the phenyl moiety exhibited better antitubercular activity than that of the other substitutions. The active compounds have displayed a good safety profile on normal cell lines.

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e-Pharmacophore model-guided design of potential DprE1 inhibitors: synthesis, in vitro antitubercular assay and molecular modelling studies

Chemical Papers ◽

10.1007/s11696-021-01743-3 ◽

2021 ◽

Author(s):

Avinash Kumar ◽

Revathi Rajappan ◽

Suvarna G. Kini ◽

Ekta Rathi ◽

Sriram Dharmarajan ◽

...

Keyword(s):

Pharmacophore Model ◽

Antitubercular Activity ◽

Stable Complex ◽

Dilution Method ◽

Agar Dilution Method ◽

Standard Drug ◽

Docking Score ◽

Mycobacterium Tuberculosis H37rv ◽

Cytotoxicity Studies

AbstractTuberculosis continues to wreak havoc worldwide and caused around 1.4 million deaths in 2019. Hence, in our pursuit of developing novel antitubercular compounds, we are reporting the e-Pharmacophore-based design of DprE1 (decaprenylphosphoryl-ribose 2′-oxidase) inhibitors. In the present work, we have developed a four-feature e-Pharmacophore model based on the receptor–ligand cavity of DprE1 protein (PDB ID 4P8C) and mapped our previous reported library of compounds against it. The compounds were ranked on phase screen score, and the insights obtained from their alignment were used to design some novel compounds. The designed compounds were docked with DprE1 protein in extra-precision mode using Glide module of Maestro, Schrodinger. Some derivatives like B1, B2, B4, B5 and B12 showed comparable docking score (docking score > − 6.0) with respect to the co-crystallized ligand. The designed compounds were synthesized and characterized. In vitro antitubercular activity was carried out on Mycobacterium tuberculosis H37Rv (ATCC27294) strain using the agar dilution method, and minimum inhibitory concentration (MIC) was determined. The compound B12 showed a MIC value of 1.56 μg/ml which was better than the standard drug ethambutol (3.125 μg/ml). Compounds B7 and B11 were found to be equipotent with ethambutol. Cytotoxicity studies against Vero cell lines proved that these compounds were non-cytotoxic. Molecular dynamic simulation study also suggests that compound B12 will form a stable complex with DprE1 protein and will show the crucial H-bond interaction with LYS418 residue. Further in vitro enzyme inhibition studies are required to validate these findings.

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Synthesis of Substituted -N-(5-((7-Methyl-2-Oxo-2H-Chromen-4-yl)-Methyl)-1,3,4-Thiadiazol-2-yl)-Benzamide Derivatives Using TBTU As Coupling Agent And Their Evaluation For Anti Tubercular Activity

Letters in Organic Chemistry ◽

10.2174/1570178618666210602160849 ◽

2021 ◽

Vol 18 ◽

Author(s):

Monika Kakadiya ◽

Yunus Pasha ◽

Malleshappa Noolvi ◽

Ashish Patel

Keyword(s):

Antitubercular Activity ◽

Side Chain ◽

Antitubercular Agents ◽

Facile Synthesis ◽

Aromatic Side Chain ◽

Reaction Conditions ◽

Coupling Reagent ◽

H37rv Strain ◽

Benzamide Derivatives

: Tuberculosis remains a highly infectious disease across the world. In the identification of new antitubercular agents, coumarin clubbed thiadiazole amides have been synthesized and evaluated for in vitro antitubercular activity. Due to the growing concern about chemicals and their impact on the environment, greener and faster reaction conditions needed to be incorporated. Therefore, we used TBTU as a coupling reagent for efficient and facile synthesis of substituted-N-(5-((7-methyl-2-oxo-2H-chromes-4-yl)-methyl)-1,3, 4 - thiadiazol-2-yl)-benzamide 4a-j with good yields up to 95% in mild reaction condition. All the synthesized compounds were evaluated in vitro for antitubercular activity against the H37Rv strain of M.Tuberculosis. Compounds 4c, 4f, and 4j were found active at 25 µg/mL against M. tb H37Rv. Electron withdrawing substituents present on aromatic side-chain showed promising anti-tubercular activity.

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Efficient synthesis and in vitro antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.10.048 ◽

2011 ◽

Vol 21 (24) ◽

pp. 7273-7276 ◽

Cited By ~ 64

Author(s):

Poovan Shanmugavelan ◽

Sangaraiah Nagarajan ◽

Murugan Sathishkumar ◽

Alagusundaram Ponnuswamy ◽

Perumal Yogeeswari ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Antitubercular Activity ◽

Efficient Synthesis

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SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW 1,3,4- OXADIAZOLES, 1,2,4-TRIAZOLES AND 1,3,4-THIADIAZOLES

INDIAN DRUGS ◽

10.53879/id.53.06.10489 ◽

2016 ◽

Vol 53 (06) ◽

pp. 18-23

Author(s):

U. V. Laddi ◽

◽

S. R. Desai

Keyword(s):

Escherichia Coli ◽

Antimicrobial Activity ◽

Mycobacterium Tuberculosis ◽

Antitubercular Activity ◽

Tuberculosis H37rv ◽

Research Centre ◽

Methyl Ethyl ◽

Rhizoctonia Bataticola ◽

Mycobacterium Tuberculosis H37rv ◽

H37rv Strain

Some new 5-[(((α-phenyl/methyl)benzylidene)amino)oxy]methyl/ethyl-2-[4-(substituted aryl)/allyl)] amino-1,3,4-oxadiazoles (4a-p), 3-[(((α-phenyl/methyl)- benzylidene) amino)oxy]methyl/ethyl-4-(4- substitutedaryl)/allyl-5-mercapto-1,2,4-triazoles (5a-p) and 5-[(((α-phenyl/methyl)-benzylidene)amino) oxy]- methyl/ethyl-2-[4-(substituted aryl)/allyl)]amino-1,3,4-thiadiazoles (6a-p) were prepared starting from α/β-[((α-(phenyl/methyl)benzylidene)amino)oxy acetic/propionic acid hydrazides (1a-d). The structures of all the compounds have been established by elemental and spectral (IR, 1HNMR and mass) analysis. All the newly synthesised compounds have been screened for their antimicrobial activity against Escherichia coli, Bacillus cirroflagellosus, Aspergillus niger and Rhizoctonia bataticola. Some of the newly synthesised compounds have been evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv strain by BACTEC radiometric system at Southern Research Institute, Birmingham, AL and Frederick Research Centre, Frederick, MD. Significant antimicrobial activity is observed against Escherichia coli and Rhizoctonia bataticola. A few compounds also exhibited interesting antitubercular activity against Mycobacterium tuberculosis H37Rv strain.

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