Scouting around 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones for Single- and Multitarget Ligands Directed towards Relevant Alzheimer's Targets |
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| Authors: | Dr Rosa Purgatorio Dr Larisa N Kulikova Dr Leonardo Pisani Dr Marco Catto Dr Modesto de Candia Prof Antonio Carrieri Prof Saverio Cellamare Dr Annalisa De Palma Andrey A Beloglazkin Ghulam Reza Raesi Prof Leonid G Voskressensky Prof Cosimo D Altomare |
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| Affiliation: | 1. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy;2. Organic Chemistry Department, Peoples' Friendship University of Russia (RUDN), 6 Miklukho-Maklaya St., Moscow, 117198 Russia;3. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy |
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| Abstract: | A number of 1,2,3,4-tetrahydrochromeno3,2-c]pyridin-10-one derivatives have been synthesized and screened against different targets involved in the onset and progression of Alzheimer's disease (AD), such as acetyl- and butyrylcholinesterase (AChE and BChE), monoamine oxidases A and B (MAO A and B), aggregation of β-amyloid (Aβ) and reactive oxygen species (ROS) production. Derivatives 1 c , 3 b , 4 and 5 a showed multifaceted profiles of promising anti-AD features and returned well-balanced multitargeting inhibitory activities. Moreover, compound 1 f , a potent and selective human MAO B inhibitor (IC50=0.89 μM), proved to be a safe neuroprotectant in a human neuroblastoma cell line (SH-SY5Y) by improving viability impaired by Aβ1–42 and pro-oxidant insult. Furthermore, structure–activity relationships (SARs) and docking models were derived in order to assist further hit-to-lead optimization stage. |
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| Keywords: | Alzheimer's disease inhibitors medicinal chemistry multitarget-directed ligands tetrahydrochromenopyridinone |
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