Elena Simoni1, Manuela Bartolini1, Izuddin F Abu2,3, Alix Blockley2, Cecilia Gotti4, Giovanni Bottegoni5, Roberta Caporaso1, Christian Bergamini1, Vincenza Andrisano6, Andrea Cavalli1,5, Ian R Mellor2, Anna Minarini1, Michela Rosini1. 1. Department of Pharmacy & Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. 2. School of Life Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK. 3. Institute of Medical Science Technology, University of Kuala Lumpur, A1-1, Jalan TKS1, Taman Kajang Sentral, Selangor, 43000 Kajang, Malaysia. 4. CNR, Institute of Neuroscience, Via Luigi Vanvitelli 32, 20129 Milano, Italy. 5. Drug Discovery & Development, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy. 6. Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.
Abstract
AIM: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. METHODS: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways. RESULTS: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation. CONCLUSION: The compounds emerged as a suitable starting point for a further optimization process.
AIM: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. METHODS: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways. RESULTS: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-β aggregation. CONCLUSION: The compounds emerged as a suitable starting point for a further optimization process.
Authors: Suresh K Bowroju; Narsimha R Penthala; Naga Rajiv Lakkaniga; Meenakshisundaram Balasubramaniam; Srinivas Ayyadevara; Robert J Shmookler Reis; Peter A Crooks Journal: Bioorg Med Chem Date: 2021-07-14 Impact factor: 3.461
Authors: Erik Andrade-Jorge; José Bribiesca-Carlos; Francisco J Martínez-Martínez; Marvin A Soriano-Ursúa; Itzia I Padilla-Martínez; José G Trujillo-Ferrara Journal: Chem Cent J Date: 2018-06-25 Impact factor: 4.215