Indole-like Trk receptor antagonists.
The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC.
University of Tartu, Institute of Chemistry, Ravila 14A, Tartu, 50411, Estonia; Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia.
Jaana
J
Tammiku-Taul
Tallinn University of Technology, Department of Gene Technology, Akadeemia 15, Tallinn, 12618, Estonia.
Rahel
R
Park
Tallinn University of Technology, Department of Gene Technology, Akadeemia 15, Tallinn, 12618, Estonia.
Kaur
K
Jaanson
Tallinn University of Technology, Department of Gene Technology, Akadeemia 15, Tallinn, 12618, Estonia.
Kristi
K
Luberg
Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia.
Dimitar A
DA
Dobchev
Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia.
Dzmitry
D
Kananovich
Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia.
Artur
A
Noole
University of Tartu, Institute of Biomedicine and Translational Medicine, Department of Pharmacology, Ravila 19, Tartu, 50411, Estonia.
Merle
M
Mandel
University of Tartu, Institute of Biomedicine and Translational Medicine, Department of Pharmacology, Ravila 19, Tartu, 50411, Estonia.
Allen
A
Kaasik
Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia.
Margus
M
Lopp
Tallinn University of Technology, Department of Gene Technology, Akadeemia 15, Tallinn, 12618, Estonia. Electronic address: tonis.timmusk@ttu.ee.
Tõnis
T
Timmusk
University of Tartu, Institute of Chemistry, Ravila 14A, Tartu, 50411, Estonia; Tallinn University of Technology, Department of Chemistry, Akadeemia 15, Tallinn, 12618, Estonia. Electronic address: mati.karelson@ut.ee.
Mati
M
Karelson
D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072417:Protein Domains; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D007211:Indoles; D020917:Receptor, trkA
2-Oxindole; Antagonist; Fragment-based QSAR; TrkA; TrkB