Background: Tuberculosis (TB) is the second leading cause of mortality worldwide being
a highly contagious and insidious illness caused by Mycobacterium tuberculosis, Mtb. Additionally,
the emergence of multidrug-resistant and extensively drug-resistant strains of Mtb, together
with significant levels of co-infection with HIV and TB (HIV/TB) make the search for new
antitubercular drugs urgent and challenging.
Methods: This work was based on the hypothesis that an active compound could be obtained if
substituents present in some other active compounds were attached on a core of an important
structure, in this case the indole scaffold, thus generating a hybrid compound. A QSAR-oriented
design based on classification and regression models along with the estimation of physicochemical
and biological properties have also been used to assist in the selection of compounds. Chosen
compounds were synthesized using various synthetic procedures and evaluated against M. tuberculosis
Results: Selected compounds possess substituents at positions C5, C2 and N1 of the indole ring.
The substituents involve p-halophenyl, pyridyl, benzyloxy and benzylamine groups. Four compounds
were synthesised using suitable synthetic procedures to attain the desired substitution at
the indole core. From these, three compounds are new and have been fully characterized, and
tested in vitro against the H37Rv ATCC27294T Mtb strain, using isoniazid as a control. One of
them, compound 2, with the pyridyl group at N1, has an experimental log (1/MIC) very close to 5
and can be considered as being (weakly) active. In fact, it is more active than 64% of all indole
molecules in our data sets of experimental results from literature. The most active indole in this
data sets has log (1/MIC)=5.93 with only 6 compounds with log (1/MIC) above 5.5.
Conclusion: Despite the lower activity found for the tested compounds, when compared to other
reported indole-derivatives, these structures, which rely on a hybrid design concept, may constitute
interesting scaffolds to prepare a new family of TB inhibitors with improved activity.