Novel Tuberculostatic Agents Suitable for Treatment of Mycobacterium tuberculosis Infections of the Central Nervous System.
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Date
2014-06
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Abstract
Aims: To demonstrate the efficacy of five small molecule compounds for inhibiting the
growth of Mycobacterium tuberculosis. To present evidence that these compounds will
penetrate into the central nervous system.
Study Design: Five small molecule compounds bearing a hydrazide group were
synthesized utilizing microwave excitation. These compounds were then placed into tissue
culture with Mycobacterium tuberculosis at various concentrations for evaluation of
bacterial growth inhibition.
Place and Duration of Study: The compounds to be tested were prepared at the
University of Nebraska Chemistry Department August 2013. The evaluation of antibacterial
activity was determined at the Texas A&M Health Science Center during October to
December of 2013.
Methodology: Applying microwave excitation for generation of hydrazide groups within
the structure of small molecule carboxylic acids, five agents were prepared for evaluation of bacterial growth inhibition. These agents were dissolved into tissue culture media at
various concentrations. Having various levels of tuberculostatic agents, then tuberculosis
bacteria were added to determine level of growth inhibition. Growth inhibition of the
bacteria was achieved and measured by compound concentration for comparison and
evaluation.
Results: Five compounds having a hydrazide functional group greatly inhibited the growth
of Mycobacterium tuberculosis. All five agents had molecular weight less than 215
grams/mole and polar surface area of less than 70 Angstroms2. Values of Log P ranged
from -0.226 to 0.998. Values of Log BB (Log [Cbrain/Cblood]) ranged from -0.711 to - 0.525,
with a range in central nervous system penetration Cbrain/Cblood of 0.195 to 0.299. All
compounds showed zero violations of the Rule of 5. Substantial inhibition of bacterial
growth was observed at concentrations as low as 30 micrograms/mL, as measured by
optical density and colony forming units.
Conclusion: These five hydrazide compounds substantially decreased the proliferation of
tuberculosis bacteria at concentrations as low as 30 micrograms/mL. In addition, their
physicochemical properties are shown to allow high levels of penetration into the central
nervous system.
Description
Keywords
Tuberculosis, Mycobacterium tuberculosis, tuberculostatic, isoniazid
Citation
Bartzatt Ronald, Sule Preeti, Cirillo Suat L G, Cirillo Jeffrey D. Novel Tuberculostatic Agents Suitable for Treatment of Mycobacterium tuberculosis Infections of the Central Nervous System. British Journal of Pharmaceutical Research. 2014 June; 4(12): 1535-1551.