European Society of Mycobacteriology - Instituto Nacional de Saúde ...

SCREENING OF MOLECULES WITH ANTI-TB ACTIVITY, FROM THE BRAZILIAN
CERRADO PLANTS, AND SYNTHETIC METALLO-ORGANIC COMPOUNDS
GL-13
Clarice Leite
Universidade Estadual Paulista, Faculdade de Ciências Farmacêuticas
Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death.
Among all countries in the Americas, Brazil reports the second-highest TB mortality and morbidity, comprising a prevalence
of 62/100.000. The global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of
the development of new antituberculous drugs.
Plants have provided many drugs in the past, and they remain a rich source of novel compounds. Plant extracts are among
the most attractive sources for developing new drugs and have been shown to produce promising results in the treatment
of several diseases. Our research group deals in projects that integrate the chemical and anti-TB activity of plants
that compose the bioma of the Brazilian Cerrado, a savannah like vegetation. Many of those plants are commonly used
as natural remedies by people living in these areas to treat many illnesses. To perform the phytochemical step we used
chromatographic techniques, and to determine the structure of the isolated compounds we used mainly spectrometric
methods. To evaluate the activity of the extracts, enriched fractions and pure substances against M. tuberculosis we use
the resazurin microtiter assay (REMA) and M. tuberculosis H 37
Rv ATCC 27294 strain. In total were studied 77 extracts
from 39 plants, distributed into 20 families. From all extracts assayed 23% showed promising activity, bellow or equal to
125 µg/mL. The triterpene bassic acid from B. fagifolia showed strong antitubercular activity with MIC values of 2.5 µg/mL
comparable to MICs of some first-line tuberculosis drugs. The results indicated that plants of "cerrado" present fractions
and compounds with promising anti tuberculosis activity.
By the way, the use of natural compounds from plants is problematic, due to difficulty in obtaining pure substances and
their low availability.
Within the pipeline of new synthetic compounds with potential effectiveness in the treatment of TB, there are 7 novel
compounds, which are in various stages of clinical development. Inside this group however, there are complexes that
associate metals to organic compounds. Using the thiosemicarbazones, semicarbazones and hidrazones derivates as ligands,
we proposed the complexation with Vanadium, to obtain organo-metallic compounds. We determined the anti-M.
tuberculosis activity of these compounds using REMA and the study of the citotoxicity of the ligands and complexes was
performed using murine macrophage cell line J774. We analyzed 37 compounds (14 free ligands and 23 vanadium complexes)
and from of this, 17 (46%) presented promising MIC values varying between 0.97 and 7.80 μg/mL. The vanadium
complexes of hydrazones, semicarbazones and tiossemicarbazones derivates showed high antiTB activity, most of the
time this activity was increased from 2 to 10 times when compared with the free ligands. However due to high citotoxicity
of hydrazones, semicarbazones and tiossemicarbazones derivates, the increase in the activity of the complexes didn’t
compensate the citotoxicity of the ligands.
38 ESM 2009