BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
Synthesis and Biological Evaluation of Hybrid 1,5- and 2,5-Disubstituted Indoles as Potentially New Antitubercular Agents

Participants in the publication
Ana Soares (Author)
Monica S. Estevao (Author)
Maria M.B. Marques (Author)
Vasily Kovalishyn (Author)
Diogo A.R.S. Latino (Author)
Joao Aires-de-Sousa (Author)
Jorge Ramos (Author)
Miguel Viveiros (Author)
Filomena Martins (Author)
Dep. Química e Bioquímica
CQB

Summary
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.\n\nMethods: 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 H37Rv strain.\n\nResults: 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.\n\nConclusion: 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.


Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Where published
Medicinal Chemistry

Publication Identifiers
ISSN - 1573-4064

Publisher
Bentham Science Publishers Ltd.



Document Identifiers
DOI - https://doi.org/10.2174/1573406413666170209144003
URL - http://dx.doi.org/10.2174/1573406413666170209144003

Rankings
SCIMAGO Q3 (2017) - 0.372 - Drug Discovery
SCOPUS Q3 (2017) - 0.372 - Drug Discovery
Web Of Science Q3 (2017) - 2.631 - CHEMISTRY, MEDICINAL - SCIE

Keywords
Antitubercular agents indole derivatives hybrid structures QSARs synthesis biological evaluation