What is it about?
There is a necessity for new drugs to be more efficient than today’s standard due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb). 12 new isoniazid-based adamantane derivatives were synthesized and tested for their antitubercular activity. The pharmacological test results and the aqueous dissolution profile of representative examples of the new molecules are in agreement with the computational results obtained from docking poses and molecular dynamics simulations on the tested compounds. Among their congeners, the adamantane isonicotinoyl hydrazones Ia and Ih exhibit the best antitubercular activity (MIC = 0.04 μg/ml) and the lowest cytotoxicity (selectivity index ≥2500). These results are useful for in future in vivo studies.
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Why is it important?
The pharmacological evaluation results and the aqueous dissolution profile of representative examples of the new molecules are in agreement with the computational results obtained from docking poses on the tested compounds and their molecular dynamics simulations. The more active isonicotinoyl hydrazide hydrazones Ia-h display a similar binding pose with Isoniazid. On the other hand, the inactive isomer adamantanecarbohydrazones IIa-c cannot access the isoniazid binding site and they adopt furthermore a different orientation in the binding site. The more lipohilic compounds Id and Ie display a slightly different binding pose and exhibit lower activity. The phenyl group of derivatives Ic and Ig causes steric hindrance with amino acid SER315, which blocks the access to the substrate binding site and consequently the aforementioned adducts present lower activity in comparison with compound Ia. The fact that KatG resembles a cone-shaped channel that progressively narrows toward the heme edge, allows only a single chain from both side functional chains of bis-substituted compound Ih to enter into the channel. This explains the same activity of the mono- and bis-substituted derivatives Ia and Ih, respectively.
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This page is a summary of: Synthesis, biology, computational studies and in vitro controlled release of new isoniazid-based adamantane derivatives, Future Medicinal Chemistry, September 2019, Future Science,
DOI: 10.4155/fmc-2019-0038.
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