6c125e590cf26c817f54954f2a0da7ff pmc_11359831.pdf 855ca099a14252d1342eba94018be8a6ed51983c pmc_11359831.pdf 2416249a896bfb82e65f8ecf77ed7f5ebc46c8a2d4582cd069b38e3b0d7ef8ca pmc_11359831.pdf Title: Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties Subject: Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer’s disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein–huprine hybrid lead by hydroxy group removal—ring contraction—ring opening—ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 M) and A42 and tau aggregation (73% and 68% inhibition, respectively, at 10 M), favorable in vitro brain permeation, higher aqueous solubility (18 M) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC50 >> 100 M) than the initial lead, thereby confirming the successful lead optimization by structural simplification. Keywords: multitarget drugs; Alzheimer’s disease; -amyloid anti-aggregating agents; tau anti-aggregating agents; BACE-1 inhibitors; acetylcholinesterase inhibitors; butyrylcholinesterase inhibitors; zebrafish embryos; DMPK properties Author: Caterina Pont, Anna Sampietro, F. Javier Pérez-Areales, Nunzia Cristiano, Agustí Albalat, Belén Pérez, Manuela Bartolini, Angela De Simone, Vincenza Andrisano, Marta Barenys, Elisabet Teixidó, Raimon Sabaté, M. 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Info: Title: Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties Author: Caterina Pont, Anna Sampietro, F. Javier Pérez-Areales, Nunzia Cristiano, Agustí Albalat, Belén Pérez, Manuela Bartolini, Angela De Simone, Vincenza Andrisano, Marta Barenys, Elisabet Teixidó, Raimon Sabaté, M. Isabel Loza, José Brea and Diego Muñoz-Torrero Subject: Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer’s disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein huprine hybrid lead by hydroxy group removal ring contraction ring opening ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 M) and A42 and tau aggregation (73% and 68% inhibition, respectively, at 10 M), favorable in vitro brain permeation, higher aqueous solubility (18 M) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC50 >> 100 M) than the initial lead, thereby confirming the successful lead optimization by structural simplification. 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