Antitubercular and antibacterial activities of isoxazolines derived from natural products: Isoxazolines as inhibitors of Mycobacterium tuberculosis InhA

Isoxazoline derivatives of the natural products eugenol, 1’- S-acetoxychavicol acetate and sclareol are prepared through 1,3-dipolar cycloaddition reactions in an aqueous buffered system. The compounds are evaluated for their antitubercular and antibacterial activities. Compounds 2, 2a and 3f display strong antitubercular activity with minimum inhibitory concentration values of 26.68, 17.89 and 14.58 µM, respectively. Furthermore, derivative 3f exhibits antibacterial activity against Bacillus cereus (minimum inhibitory concentration value of 29.16 µM). Isoxazoline derivatives of 1’- S-acetoxychavicol acetate demonstrate improvements in cytotoxicity, and derivative 3f of sclareol demonstrates improved antitubercular and antibacterial activities. Isoxazolines derived from natural products exhibit Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) inhibitory activity, and molecular modelling predicts that they form hydrogen bonding and hydrophobic interactions with NADH and with the key residues of the InhA binding site.

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Synthesis of carbohydrate-substituted isoxazoles and evaluation of their antitubercular activity

Heterocyclic Communications ◽

10.1515/hc-2016-0185 ◽

2017 ◽

Vol 23 (3) ◽

pp. 225-229 ◽

Cited By ~ 3

Author(s):

Khaoula Hajlaoui ◽

Ahlem Guesmi ◽

Naoufel Ben Hamadi ◽

Moncef Msaddek

Keyword(s):

Mycobacterium Tuberculosis ◽

Minimum Inhibitory Concentration ◽

Bacterial Strain ◽

Inhibitory Concentration ◽

Cycloaddition Reaction ◽

Antitubercular Activity ◽

Antimycobacterial Activity ◽

Dipolar Cycloaddition ◽

Nitrile Oxides ◽

Mycobacterium Tuberculosis H37rv

AbstractEight new sugar-substituted isoxazoles were synthesized by a 1,3-dipolar cycloaddition reaction of aromatic nitrile oxides with carbohydrate-substituted alkynes. Products were screened for antimycobacterial activity against the Mycobacterium tuberculosis H37Rv strain. Four compounds, 5e–h, significantly inhibit growth of the bacterial strain with a minimum inhibitory concentration (MIC) of 3.125 μg/mL.

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Synthesis and Antitubercular Activity of Heteroaromatic Isonicotinoyl and 7-Chloro-4-Quinolinyl Hydrazone Derivatives

The Scientific World JOURNAL ◽

10.1100/tsw.2010.124 ◽

2010 ◽

Vol 10 ◽

pp. 1347-1355 ◽

Cited By ~ 14

Author(s):

Marcelle de L. Ferreira ◽

Raoni S.B. Gonçalves ◽

Laura N. de F. Cardoso ◽

Carlos R. Kaiser ◽

Andre L.P. Candéa ◽

...

Keyword(s):

Antibacterial Activity ◽

Mycobacterium Tuberculosis ◽

Minimum Inhibitory Concentration ◽

Rational Design ◽

Inhibitory Concentration ◽

Antitubercular Activity ◽

First Line ◽

Starting Point

Two series ofN’(E)-heteroaromatic-isonicotinohydrazide derivatives (3a-f and 4a-b) and 1-(7-chloroquinolin-4-yl)-2-[(heteroaromatic)methylene]hydrazone derivatives (5a-f and 6a-b) have been synthesized and evaluated for theirin vitroantibacterial activity againstMycobacterium tuberculosisH37Rv. Several compounds were noncytotoxic and exhibited significant minimum inhibitory concentration (MIC) activity (3.12, 2.50, 1.25, or 0.60 μg/mL), which can be compared to that of the first-line drugs ethambutol (3.12 μg/mL) and rifampicin (2.0 μg/ml). These results can be considered an important starting point for the rational design of new leads for anti-TB compounds.

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Anti-TB Evaluation of Novel 2,3-Dihydroquinazolin-4(1H)-Ones and in Silico Studies of The Active Compounds

10.21203/rs.3.rs-341353/v1 ◽

2021 ◽

Author(s):

Apurba Dutta ◽

Priyanka Trivedi ◽

Dipshikha Gogoi ◽

Pankaj Chetia ◽

Vinita Chaturvedi ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Molecular Docking ◽

Minimum Inhibitory Concentration ◽

Active Site ◽

In Silico ◽

Inhibitory Concentration ◽

Acyl Carrier Protein ◽

Carrier Protein ◽

In Silico Studies

Abstract In vitro anti-tubercular activity of a series of 15 novel 2,3-dihydroquinazolin-4(1H)-one analogues were evaluated against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, seven compounds showed moderate to good anti-TB activity with minimum inhibitory concentration (MIC) values ranging from 25.0-12.5 μg/mL. Further, in silico experiments were carried out to identify the probable ligand-protein interaction. Molecular docking of the target compounds into the active site of enzymes 1DQY Antigen 85C from Mycobacterium Tuberculosis and 2NSD Enoyl Acyl Carrier Protein Reductase reveals notable information on the possible binding interactions.

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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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New Groups of Potential Antituberculotics: Bis(1-aryltetrazol-5-yl) Disulfides. Structure Activity Relationship

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19940234 ◽

1994 ◽

Vol 59 (1) ◽

pp. 234-238 ◽

Cited By ~ 7

Author(s):

Karel Waisser ◽

Jiří Kuneš ◽

Alexandr Hrabálek ◽

Želmíra Odlerová

Keyword(s):

Mycobacterium Tuberculosis ◽

Minimum Inhibitory Concentration ◽

Inhibitory Concentration ◽

Antimycobacterial Activity ◽

Activity Relationship ◽

Active Derivative ◽

Structure Activity ◽

Medium Activity ◽

Substituent Constants ◽

Atypical Strains

Oxidation of 1-aryltetrazole-5-thiols afforded bis(1-aryltetrazol-5-yl) disulfides. The compounds were tested for antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. avium and M. fortuitum. In the case of M. tuberculosis, the logarithm of minimum inhibitory concentration showed a parabolic dependence on hydrophobic substituent constants. Although the compounds exhibited low to medium activity, the most active derivative, bis(4-chlorophenyltetrazol-5-yl) disulfide (III) was more effective against atypical strains than are the commercial tuberculostatics used as standards.

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Two New Piperazine-Triones from a Marine-Derived Streptomycetes sp. Strain SMS636

Marine Drugs ◽

10.3390/md17030186 ◽

2019 ◽

Vol 17 (3) ◽

pp. 186 ◽

Cited By ~ 3

Author(s):

Xiuli Xu ◽

Jiahui Han ◽

Rui Lin ◽

Steven Polyak ◽

Fuhang Song

Keyword(s):

Staphylococcus Aureus ◽

Minimum Inhibitory Concentration ◽

Secondary Metabolites ◽

Deep Sea ◽

Spectroscopic Analysis ◽

Inhibitory Concentration ◽

2D Nmr ◽

Antibacterial Activities ◽

Bacillus Calmette Guerin ◽

Methicillin Resistant

Two new piperazine-triones lansai E and F (1, 2), together with four known secondary metabolites lansai D (3), 1-N-methyl-(E,Z)-albonoursin (4), imidazo[4,5-e]-1,2,4-triazine (5), and streptonigrin (6) were isolated from a deep-sea-derived Streptomycetes sp. strain SMS636. The structures of the isolated compounds were confirmed by comprehensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR. Compound 4 exhibited moderate antibacterial activities against Staphylococcus aureus and methicillin resistant S. aureus (MRSA) with Minimum Inhibitory Concentration (MIC) values of 12.5 and 25 μg/mL, respectively. Compound 6 displayed significant antibacterial activities against S. aureus, MRSA and Bacillus Calmette-Guérin (BCG) with MIC values of 0.78, 0.78 and 1.25 μg/mL, respectively.

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The Chemical Composition and Anti-mycobacterial Activities of Trachyspermum copticum and Pelargonium graveolens Essential Oils

Recent Patents on Anti-Infective Drug Discovery ◽

10.2174/1574891x14666191028113321 ◽

2020 ◽

Vol 15 (1) ◽

pp. 68-74 ◽

Cited By ~ 1

Author(s):

Jalil Kardan-Yamchi ◽

Mohaddese Mahboubi ◽

Hossein Kazemian ◽

Gholamreza Hamzelou ◽

Mohammad M. Feizabadi

Keyword(s):

Mycobacterium Tuberculosis ◽

Chemical Composition ◽

Minimum Inhibitory Concentration ◽

Essential Oil ◽

Essential Oils ◽

Inhibitory Concentration ◽

Mycobacterium Fortuitum ◽

Drug Resistant ◽

Pelargonium Graveolens ◽

Trachyspermum Copticum

Background: Microbial resistance to antibiotics and their adverse effects related to these antibiotics are a matter of global public health in the 21th century. The emergence of drug-resistant strains, has gained the interest of the scientists to discover new antimicrobial agents from the essential oil of medicinal plants. Methods: Anti-mycobacterial effects of Trachyspermum copticum and Pelargonium graveolens essential oils were determined against multi-drug resistant clinical strains of Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium fortuitum and standard strain of Mycobacterium tuberculosis H37Rv by a Broth micro-dilution method. Pelargonium graveolens plant named Narmada was discovered by Kulkarni R.N et al. (Patent ID, USPP12425P2) and a formulation comprising thymol obtained from Trachyspermum is useful in the treatment of drug-resistant bacterial infections (Patent ID, US6824795B2). The chemical composition of hydro-distilled essential oils was determined by GC and GC-MS. Results: Minimum Inhibitory Concentration (MIC) values for T. copticum essential oil against tested isolates were ranged from 19.5 µg/mL to 78 µg/mL. The least minimum inhibitory concentration of P. graveolens extract against M. Kansasii and MDR-TB was 78 µg/ml. Conclusion: The results of the present research introduced T. copticum and P. graveolens essential oils as a remarkable natural anti-mycobacterial agent, but more pharmacological studies are required to evaluate their efficacy in animal models.

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Antibacterial Activities of 5-Nitro-2-uryl and 5-Nitro-2-Imidazolyl Derivatives of 1,3,4-Thiadiazole

Internal Medicine And Medical Investigation Journal ◽

10.24200/imminv.v4i2.213 ◽

2019 ◽

Vol 4 (2) ◽

Author(s):

Mohammad Hassan Moshafi ◽

Ali Peymani ◽

Alireza Foroumadi ◽

Mohammad Reza Zabihi ◽

Farzad Doostishoar

Keyword(s):

Minimum Inhibitory Concentration ◽

Antimicrobial Agents ◽

Inhibitory Concentration ◽

Positive Control ◽

Klebsiella Pneumonia ◽

Bacterial Strains ◽

Antibacterial Effects ◽

Gram Positive ◽

Gram Negative ◽

Derivatives Of

Introduction: Nitrofurans and nitroimidazoles are broad-spectrum antimicrobial agents, which affect the microbial DNA. The aim of the present study was to evaluate the new derivatives of these two groups of antimicrobials against certain Gram-positive and Gram-negative bacterial strains. Materials and Methods: Seven new derivatives of nitrofurans and nitroimidazoles were synthesized, and 6.4 mg of each derivative was dissolved in dimethyl sulfoxide. Then, 8 serial dilutions (0.5, 1, 2, 4, 8, 16, 32, and 64 μg/ml) of each derivative was prepared using Muller-Hinton broth, and the minimum inhibitory concentration for each derivative was measured and compared to ciprofloxacin (standard). Results: All the derivatives had no antibacterial effects against Gram-negative bacteria (minimum inhibitory concentration > 64 μg/ml); only 2-(5-nitro-2-furyl)-5-(n-pentylsulfunyl)-1,3,4-thiadiazole exhibited mild antibacterial effects against Klebsiella pneumonia (minimum inhibitory concentration of 16-32 μg/ml). The antibacterial effects of the derivatives against Gram-positive bacteria also showed variations from complete inhibition of the growth of Staphylococcus epidermidis and Bacillus subtilis (minimum inhibitory concentration < 0.5 μg/ml) by 2-(5-nitro-2-furyl)-5-(n-buthylthio)-1,3,4-thiadiazole to no inhibition of S. epidermidis and streptococcus pyogenes. Conclusion: These compounds have weak antibacterial effects; only two derivatives showed antibacterial effects similar to that of the positive control.

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Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

10.7287/peerj.preprints.502v1 ◽

2014 ◽

Author(s):

N. Susantha Chandrasekera ◽

Mai A Bailey ◽

Megan Files ◽

Torey Alling ◽

Stephanie K Florio ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Minimum Inhibitory Concentration ◽

Mode Of Action ◽

Drug Targets ◽

Inhibitory Concentration ◽

Eukaryotic Cells ◽

Structure Activity ◽

Novel Drug ◽

Further Development ◽

Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

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Synthesis and in vitro Antibacterial Activity of Quaternization 10-Methoxycanthin-6-one Derivatives

10.20944/preprints201902.0248.v1 ◽

2019 ◽

Author(s):

Na Li ◽

Jiang-Kun Dai ◽

Dan Liu ◽

Jin-Yi Wang ◽

Jun-Ru Wang

Keyword(s):

Antibacterial Activity ◽

Natural Products ◽

Minimum Inhibitory Concentration ◽

Pathogenic Bacteria ◽

Antibacterial Agents ◽

Inhibitory Concentration ◽

Dilution Method ◽

In Vitro Antibacterial Activity

Natural products are an important source of antibacterial agents. Canthin-6-one alkaloids have displayed potential antibacterial activity based on our previous work. In order to improve the activity, twenty-two new 3-N-benzylated 10-methoxy canthin-6-ones were designed and synthesized through quaternization reaction. The in vitro antibacterial activity against three bacteria was evaluated by double dilution method. Four compounds (6f, 6i, 6p and 6t) displayed 2-fold superiority (minimum inhibitory concentration (MIC) = 3.91 µg/mL) against agricultural pathogenic bacteria R. solanacearum and P. syringae than agrochemical propineb. Moreover, the structure–activity relationships (SARs) were also carefully summarized in order to guide the development of antibacterial canthin-6-one agents.

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