Lead selection and characterization of antitubercular compounds using the Nested Chemical Library

Anna Sipos, János Pató, Rita Székely, Ruben C. Hartkoorn, László Kékesi, László Orfi, Csaba Szántai-Kis, Katarína Mikušová, Zuzana Svetlíková, Jana Korduláková, Valakunja Nagaraja, Adwait Anand Godbole, Natassja Bush, Frédéric Collin, Anthony Maxwell, Stewart T. Cole, György Kéri

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21 Citations (Scopus)

Abstract

Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem's Nested Chemical Library™ using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 μM and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays.

Original languageEnglish
Pages (from-to)S200-S206
JournalTuberculosis
Volume95
Issue numberS1
DOIs
Publication statusPublished - Jun 1 2015

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Keywords

  • Enzyme inhibitor
  • Kinase inhibitor
  • Phenotypical screening
  • Targeted therapy
  • Tuberculosis

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Sipos, A., Pató, J., Székely, R., Hartkoorn, R. C., Kékesi, L., Orfi, L., Szántai-Kis, C., Mikušová, K., Svetlíková, Z., Korduláková, J., Nagaraja, V., Godbole, A. A., Bush, N., Collin, F., Maxwell, A., Cole, S. T., & Kéri, G. (2015). Lead selection and characterization of antitubercular compounds using the Nested Chemical Library. Tuberculosis, 95(S1), S200-S206. https://doi.org/10.1016/j.tube.2015.02.028