2. Academic Validation
  3. Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors

Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors

  • Eur J Med Chem. 2019 Oct 1:179:404-422. doi: 10.1016/j.ejmech.2019.06.041.
Nikolay T Tzvetkov 1,  Hans-Georg Stammler 2,  Maya G Georgieva 3,  Daniela Russo 4,  Immacolata Faraone 4,  Aneliya A Balacheva 3,  Silvia Hristova 5,  Atanas G Atanasov 6,  Luigi Milella 4,  Liudmil Antonov 5,  Marcus Gastreich 7
Affiliations

Affiliations

  • 1 NTZ Lab Ltd., Krasno selo 198, Sofia, 1618, Bulgaria. Electronic address: ntzvetkov@ntzlab.com.
  • 2 Department of Chemistry, Bielefeld University, Universitätsstr. 25, 33615, Bielefeld, Germany.
  • 3 Bulgarian Academy of Sciences, Institute of Molecular Biology "Roumen Tsanev", Department of Biochemical Pharmacology and Drug Design, Acad. G. Bonchev Str., Bl. 21, 1113, Sofia, Bulgaria.
  • 4 Department of Science, Università degli Studi della Basilicata, V.le Ateneo Lucano 10, 85100, Potenza, Italy; Spinoff BioActiPlant S.R.L. Department of Science, University of Basilicata, V.le dell'Ateneo lucano, 10, 85100, Potenza, Italy.
  • 5 Bulgarian Academy of Sciences, Institute of Organic Chemistry with Centre of Phytochemistry, Acad. G. Bonchev Str., Bl. 9, Sofia, 1113, Bulgaria.
  • 6 Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, 05-552, Jastrzebiec, Poland; Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090, Vienna, Austria; Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev str., 1113, Sofia, Bulgaria.
  • 7 BioSolveIT GmbH, An der Ziegelei 79, 53757, St. Augustin, Germany.
PMID: 31265934 DOI: 10.1016/j.ejmech.2019.06.041
Abstract

A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and Other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE Enzymes. Compound 15 was found to be the most potent and selective AChE Inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.

Keywords

(Indazole-5-yl)methanimines; MAO-B inhibitors; Molecular modeling; Parkinson's disease; X-ray.

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