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Development of HuperTacrines as Non-Toxic, Cholinesterase Inhibitors for the Potential Treatment of Alzheimer’s Disease

[ Vol. 15 , Issue. 8 ]

Author(s):

Mourad Chioua, Marta Pérez, Oscar M. Bautista-Aguilera, Matilde Yañez, Manuela G. López, Alejandro Romero, Ramón Cacabelos, Raimon Puig de la Bellacasa, Simone Brogi, Stefania Butini, José I. Borrell and Jose Marco-Contelles   Pages 648 - 658 ( 11 )

Abstract:


This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer’s disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.

Keywords:

ADMET, Alzheimer’s disease, cholinesterase inhibitors, hupertacrines, kinetic analysis, molecular modeling, toxicity.

Affiliation:

European Research Centre for Drug Discovery and Development (NatSynDrugs) and Department of Biotechnology, Chemistry and Pharmacy, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy., Grup d’Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain., Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain.



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