Despite being present in many drugs, guanylhydrazones and semicarbazones are two functional groups that have been little investigated as potential therapeutic strategies for the treatment of Alzheimer's disease (AD). For this reason, we initiated the synthesis and evaluation of these compounds as potential anticholinesterase agents, aiming to offer new alternatives for drug development against AD. In the severe phase of AD butyrylcholinesterase (BChE) becomes the main enzyme responsible for the hydrolysis of acetylcholine (ACh). Therefore, in this project, we present the results of BChE inhibitory activity, enzyme kinetics, cytotoxicity, and molecular modeling studies for three guanylhydrazone and two semicarbazone derivatives that were previously synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Among the compounds tested, guanylhydrazones (1, 2, and 3) showed inhibitory activity against BChE, exhibiting a mixed non-competitive inhibition profile. Specifically, compound 2 (phenanthrenequinone) demonstrated superior inhibitory potency with an IC50 of 0.68 μM, compared to compound 1 (acridinone) with an IC50 of 3.87 μM, and compound 3 (benzodioxole) with an IC50 of 101.7 μM. In contrast, semicarbazones (4 and 5) showed no BChE inhibition up to the highest concentration tested (300 μM). Importantly, all five compounds were found to be non-cytotoxic. Our results suggest that these compounds have potential as drug prototypes targeting different phases of AD. Compounds 3, 4, and 5 may be more effective in the early phase, when AChE activity remains high; compound 1 could be useful in the intermediate phase; and compound 2 appears particularly promising for the severe phase, when BChE plays a more dominant role.

Federal University of Maranhão Postgraduate Program in Adult Health Avenida dos Portugueses 1966 Bacanga 65080 805 São Luís Maranhão Brazil

Institute of Biosciences Federal University of the State of Rio de Janeiro Av Pasteur 296 Urca 22290 250 Rio de Janeiro Brazil

Laboratory for Applied Cancer Immunology Biological and Health Sciences Center Federal University of Maranhão Avenida dos Portugueses 1966 Bacanga 65080 805 São Luís Maranhão Brazil

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Av das Américas 28705 Área 4 23020 470 Rio de Janeiro RJ Brazil

Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense Praça General Tibúrcio 80 22290 270 Rio de Janeiro Brazil; Université de Québec INRS Centre Armand Frappier Santé Biotechnologie 531 boulevard des Prairies Laval Québec H7V 1B7 Canada; Center for Basic and Applied Research Faculty of Informatics and Management University of Hradec Kralove 50003 Hradec Kralove Czech Republic

Medicinal Chemistry Group Department of Chemistry Military Institute of Engineering Praça General Tibúrcio 80 22290 270 Rio de Janeiro RJ Brazil; Department of Chemistry Federal University of Roraima Av Cap Ene Garcês 2413 69310 000 Boa Vista Roraima Brazil

Université de Québec INRS Centre Armand Frappier Santé Biotechnologie 531 boulevard des Prairies Laval Québec H7V 1B7 Canada

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