Synthesis, Biological Assessment and Molecular Modeling of Racemic QuinoPyranoTacrines for Alzheimer's Disease Therapy

Abstract

In this report we describe the synthesis, biological evaluation and molecular modeling of new tacrine analogues such as QuinoPyranTacrines (QPTs), designed by juxtaposition of 1,4‐naphthoquinone and tacrine. From these results we have identified QPT16 as a permeable, selective human acetylcholinesterase inhibitor [IC50= 1.1 ± 0.15 μM], 3.5‐fold less‐hepatotoxic than tacrine at 1000 μM concentration, and consequently, a potential new hit‐compound for further investigation targeted to find a new agent for AD therapy.

Merged Tacrine-Based, Multitarget-Directed Acetylcholinesterase Inhibitors 2015–Present: Synthesis and Biological Activity

“…Pentacylcic pyranotacrines bearing a fused naphthalene, quinoline, or naphthoquinone moiety ( Scheme 3 A) have shown diverse anti-AD activity, including AChE inhibition, BACE1 inhibition, ROS scavenging, and metal chelation [ 71 , 72 , 73 , 74 ]. The pyranoquinoline tacrines were designed to incorporate the hydroxyquinoline moiety of cliquinol, a known antioxidant and Cu-chelator [ 72 , 75 ], while the pyranonaphthoquinone tacrines were designed to incorporate the known 1,4-naphthoquinone BACE1i scaffold [ 73 , 76 ].…”

“…The pyranoquinoline tacrines were designed to incorporate the hydroxyquinoline moiety of cliquinol, a known antioxidant and Cu-chelator [ 72 , 75 ], while the pyranonaphthoquinone tacrines were designed to incorporate the known 1,4-naphthoquinone BACE1i scaffold [ 73 , 76 ]. The compounds were prepared through closely related two-step sequences relying on 4 H -pyran construction from malononitrile, aryl aldehydes, and either 2-naphthol, 1-naphthol, 8-hydroxyquinoline, or 2-hydroxy-1,4-naphthoquinone to give intermediates 12 [ 71 ], 13a , c , e – p [ 71 , 72 ], and 14a – t [ 73 , 74 ] ( Scheme 3 B). In all cases, a subsequent Friedländer reaction with the appropriate cycloalkanone and AlCl 3 gave the target compounds 9a – c , 10a – p , and 11a – t as racemic mixtures.…”

“…The pyranonaphthoquinone tacrines 11a – t showed significantly less inhibition of AChE than tacrine. The 3-nitrophenyl substituted 11n ( Ee AChE IC 50 = 860 nM) was 17-fold less potent than tacrine ( Ee AChE IC 50 = 50 nM) [ 73 ], and the 4-methoxyphenyl substituted 11t ( h AChE IC 50 = 1.10 µM) was 8.5-fold less potent than tacrine ( h AChE IC 50 = 130 nM) [ 74 ]. 11n and 11t showed a mixed-type inhibition by the Lineweaver-Burk plot analysis, while molecular modeling with Tc AChE showed a similar interaction for both compounds with CAS and PAS residues.…”

Journey on Naphthoquinone and Anthraquinone Derivatives: New Insights in Alzheimer’s Disease

“…In plants, AQ metabolites are present in a wide range of species, predominantly the families of Rubiaceae, Polygonaceae, and Rhamnaceae. These compounds are structura Figure 9A) by means of a 4H-pyran ring, bearing at position 4 an aromatic ring variously decorated with electron-withdrawing (F, NO 2 ) and electron-donor (OCH 3 ) groups [131]. In the initial screening phase, all the compounds were tested for their potential hepatotoxicity, resulting non-hepatotoxic in the majority of cases.…”

Tacrines as Therapeutic Agents for Alzheimer's Disease. V. Recent Developments

“…Racemic quinonepyranotacrines ( QPT , II ) are tacrine analogues designed by juxtaposition of tacrine and 1,4‐napthoquinone (Figure 1), both motifs linked by a 4 H ‐pyrane ring, bearing two different electron withdrawing groups (NO 2 and F) and an electron donating group (OMe) in the aromatic ring located at the central pyran ring. Ten members of this family ( QPT1 ‐ 10 ) (Figure 3) were prepared from easily available precursors in good overall yield [30] …”