title: Synthesis and Biological Evaluation of Hybrid 1,5- and 2,5-Disubstituted Indoles as Potentially New Antitubercular Agents.
abstract: 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 H37Rv strain.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: LAQV@REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Soares
authors.affiliation: LAQV@REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal.
authors.forename: Monica S
authors.initials: MS
authors.lastname: Estevao
authors.affiliation: Department of Chemistry, Faculty of Science and Technology, New University of Lisbon, Campus de Caparica, 2829-516 Caparica, Portugal.
authors.forename: Maria M B
authors.initials: MMB
authors.lastname: Marques
authors.affiliation: Institute of Bioorganic Chemistry & Petroleum Chemistry, National Ukrainian Academy of Sciences, Kyiv-94, 02660, Murmanskaya 1, Ukraine.
authors.forename: Vasily
authors.initials: V
authors.lastname: Kovalishyn
authors.affiliation: Environmental Chemistry, Eawag, Uberlandstrasse 133, P.O. Box 611, 8600 Dubendorf, Switzerland.
authors.forename: Diogo A R S
authors.initials: DARS
authors.lastname: Latino
authors.affiliation: LAQV@REQUIMTE,Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal.
authors.forename: Joao
authors.initials: J
authors.lastname: Aires-de-Sousa
authors.affiliation: Unidade de Microbiologia Médica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100,1349-008 Lisboa, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ramos
authors.affiliation: Unidade de Microbiologia Médica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100,1349-008 Lisboa, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal.
authors.forename: Filomena
authors.initials: F
authors.lastname: Martins
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D000069550:Machine Learning; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D016571:Neural Networks, Computer; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: C000622914:5-(benzyloxy)-1-(pyridin-2-ylmethyl)-1H-indole; D000995:Antitubercular Agents; D007211:Indoles; D011725:Pyridines; D007538:Isoniazid
keywords: Antitubercular agents; QSARs; biological evaluation; hybrid structures; indole derivatives; synthesis