The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents

Abstract

The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against H37Rv () and identified the cyclohexane-1,3-dione-based structures and as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against lead to the identification of three lead antituberculosis agents (, and). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione () showed an MIC of 2.5 μg mL, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 μM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria and even against ; thereby reflecting its highly specific antituberculosis activity.

<I>In vitro</I> evaluation of the inhibitory effect of 3, 5-dichloro-2- pyridone on <I>Mycobacterium tuberculosis</I> H37Rv

“…Minimum bactericidal concentration (MBC) refers to the lowest antimicrobial concentration which kills 99.99 % of initial bacterial population [11]. The MBCs for the standard anti-TB drugs or test compound were calculated immediately after MIC determination.…”

“…The kill curve assay was performed according to standard method [11,12]. Mycobacterium tuberculosis cells in logarithmic growth phase (1 x 10 5 CFU/mL) were challenged with the test compound based on its MIC (16-fold dilution) for 16 days in 15 mL falcon tubes.…”

Catalyst free synthesis of 2‐Aryl‐2H‐benzo[b][1,4]oxazines and 3‐Aryl‐2H‐benzo[b][1,4]thiazin‐2‐ones: An ultrasonication‐assisted strategy

“…As a part of our ongoing medicinal chemistry research program on heterocyclic bioactive entities, [30][31][32] a research endeavor was initiated to establish a flexible protocol for synthesizing 1,4-benzoxazine derivatives. Keeping in mind the acidic and basic functional groups attached to 2-aminophenol, we subjected it to react with phenacyl bromide under ultrasonication condition, 2-aryl-1,4-benzoxazine was obtained as an exclusive product.…”

Palladium‐Catalyzed Regioselective C‐H Bond ortho‐Acetylation and Oxidative Homocoupling of N‐Arylcarbamates

“…2‐Aminophenol scaffolds are becoming more and more important in medicinal and organic chemistry. They are a principle intermediate in the synthesis of heterocyclic systems such as oxyquinolines, phenoxamines, and benzoxazoles and also display a wide range of pharmacological and biological activities, such as anti‐cancer, anti‐mycobacterial, c ‐Met kinase inhibitors, anti‐tuberculosis, antibiotic, and anti‐inflammatory …”