title: Lead selection and characterization of antitubercular compounds using the Nested Chemical Library.
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.
authors: MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, Tűzoltó u. 37-47, H-1094 Budapest, Hungary; Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022 Budapest, Hungary. Electronic address: asipos@vichem.hu.
authors: Anna
authors: A
authors: Sipos
authors: Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022 Budapest, Hungary.
authors: János
authors: J
authors: Pató
authors: Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022 Budapest, Hungary; Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors: Rita
authors: R
authors: Székely
authors: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors: Ruben C
authors: RC
authors: Hartkoorn
authors: Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022 Budapest, Hungary.
authors: László
authors: L
authors: Kékesi
authors: Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022 Budapest, Hungary; Semmelweis University, Department of Pharmaceutical Chemistry, Hőgyes Endre u. 9, H-1092 Budapest, Hungary.
authors: László
authors: L
authors: Őrfi
authors: Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022 Budapest, Hungary.
authors: Csaba
authors: C
authors: Szántai-Kis
authors: Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina CH-1, Bratislava, Slovakia.
authors: Katarína
authors: K
authors: Mikušová
authors: Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina CH-1, Bratislava, Slovakia.
authors: Zuzana
authors: Z
authors: Svetlíková
authors: Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina CH-1, Bratislava, Slovakia.
authors: Jana
authors: J
authors: Korduláková
authors: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India.
authors: Valakunja
authors: V
authors: Nagaraja
authors: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560 012, India.
authors: Adwait Anand
authors: AA
authors: Godbole
authors: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH United Kingdom.
authors: Natassja
authors: N
authors: Bush
authors: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH United Kingdom.
authors: Frédéric
authors: F
authors: Collin
authors: Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH United Kingdom.
authors: Anthony
authors: A
authors: Maxwell
authors: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors: Stewart T
authors: ST
authors: Cole
authors: MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, Tűzoltó u. 37-47, H-1094 Budapest, Hungary; Vichem Chemie Research Ltd., Herman Ottó u. 15, H-1022 Budapest, Hungary. Electronic address: keri@vichem.hu.
authors: György
authors: G
authors: Kéri
mesh_terms: D000995:Antitubercular Agents / Q000302:isolation & purification*; D027081:DNA Gyrase / Q000187:drug effects; D026942:DNA Topoisomerases / Q000187:drug effects; D015195:Drug Design; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification; D006801:Humans; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors; D008826:Microbial Sensitivity Tests; D058990:Molecular Targeted Therapy / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification; D054852:Small Molecule Libraries; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000302:isolation & purification; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D059003:Topoisomerase Inhibitors; D008364:Mannosyltransferases; D026942:DNA Topoisomerases; D027081:DNA Gyrase
keywords: Enzyme inhibitor; Kinase inhibitor; Phenotypical screening; Targeted therapy; Tuberculosis