Alzheimer´s disease

Alzheimer´s disease (AD) is one the most increasingly appearing health issues in the case of the elderly population. Our team focuses on several strategies to combat AD. One of them is searching for mitochondrial targets involved in the pathogenesis of AD, where amyloid-binding alcohol dehydrogenase (ABAD) has been found and is thoroughly studied. Up to now, we have developed and prepared plenty of small molecules able to inhibit ABAD, we are studying its activity in living cells. Additionally, the multitarget-directed ligands are researched, and their mode of action against various targets is studied. Our team has prepared a huge amount of small molecules aimed towards e.g., cholinesterases, monoamine oxidases, or mitochondrial targets.

Projects

• COST CA15135 – Multi-target paradigm for innovative ligand identification in the drug discovery process (MuTaLig)
• COST CM1103 – Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain
• LD14009 – Synthesis of compounds affecting mitochondrial enzymes as potential drugs for Alzheimer disease

Publications

• Benek, O.; Hroch, L.; Aitken, L.; Dolezal, R.; Guest, P.; Benkova, M.; Soukup, O.; Musil, K.; Kuca, K.; Smith, T.K.; Gunn-Moore, F.*; Musilek, K.* 6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17β-HSD10 and potential drugs for Alzheimer’s disease treatment: Design, synthesis and in vitro evaluation. Medicinal Chemistry 2017, vol. 13, no. 4, p. 345-358. DOI: 10.2174/1573406413666170109142725
• Hroch, L.; Guest, P.; Benek, O.; Soukup, O.; Janockova, J.; Dolezal, R.; Kuca, K.; Aitken, L.; Smith, T.K.; Gunn-Moore, F.; Zala, D.; Ramsay, R.*; Musilek, K.* Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer’s disease treatment. Bioorganic & Medicinal Chemistry 2017, vol. 25, no. 3, p. 1143–1152. DOI: 10.1016/j.bmc.2016.12.029
• Hroch, L.; Benek, O.; Guest, P.; Aitken, L.; Soukup, O.; Janockova, J.; Musil, K.; Dohnal,V.; Dolezal, R.; Kuca, K.; Smith, T.K.; Gunn-Moore, F.; Musilek, K.* Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment. Bioorganic & Medicinal Chemistry Letters. 2016, vol. 26, no. 15, p. 3675-3678. DOI: 10.1016/j.bmcl.2016.05.087
• Benek, O.; Soukup, O.; Pasdiorova, M.; Hroch, L.; Sepsova, V.; Jost, P.; Hrabinova, M.; Jun, D.; Kuca, K.; Zala, D.; Ramsay, R.R.; Marco-Contelles, J.*; Musilek, K.* Design, synthesis and in vitro evaluation of indolotacrine analogues as multi-target-directed ligands for the treatment of Alzheimer’s disease. ChemMedChem, 2016, vol. 11, no. 12, p. 1264-1269. DOI: 10.1002/cmdc.201500383
• Valko, M.*; Jomova, K.; Rhodes, C.J.; Kuca, K.; Musilek, K. Redox- and non-redox metal induced formation of free radicals and their role in human disease. Archives of Toxicology, 2016, vol. 90, no. 1, p. 1-37. DOI: 10.1007/s00204-015-1579-5
• Benek, O.; Aitken, L.; Hroch, L.; Kuca, K.; Gunn-Moore, F.; Musilek, K.* A Direct interaction between mitochondrial proteins and amyloid-β peptide and its significance for the progression and treatment of Alzheimer’s disease. Current Medicinal Chemistry. 2015, vol. 22, no. 9, p. 1056-1085. DOI: 10.2174/0929867322666150114163051
• Hroch, L.; Aitken, L.; Benek, O.; Dolezal, M.; Kuca, K.; Gunn-Moore, F.; Musilek, K.* Benzothiazoles: Scaffold of interest for CNS targeted drugs. Current Medicinal Chemistry. 2015, vol. 22, no. 6, p. 730-747. DOI: 10.2174/0929867322666141212120631