Tabular and image data of article "Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease"

<p>The search for novel drugs to address the medical needs of Alzheimer&rsquo;s disease (AD) is an ongoing process relying&nbsp;on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by&nbsp;developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more<br>comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase&nbsp;inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have&nbsp;paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole&nbsp;moieties to generate novel MTDLs endowed with additional properties like N-methyl-D-aspartate&nbsp;(NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked&nbsp;amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences&nbsp;with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridinebased&nbsp;drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with&nbsp;potential implications in AD therapy.</p> <p><strong>Table 1. </strong>hBChE inhibitory activities of 5c-d, 7c and 7 g and reference compounds&nbsp;(amiridine hydrochloride and THA); their cytotoxicity profile on SH-SY5Y cell&nbsp;line, and predictions of BBB penetration.</p> <p>T<strong>able 2</strong>. Relative inhibitions (RIs) of 5c-d and 7 m and reference compound memantine&nbsp;at recombinant human GluN1/GluN2B NMDA receptor expressed in HEK293&nbsp;cells.</p> <p><strong>Fig_1</strong>. Chemical structures of rivastigmine, galantamine, and tacrine as representatives of cholinesterase inhibitors. Approaches to novel drugs for AD treatment on&nbsp;the selected candidates are displayed.</p> <p><strong>Fig_2</strong>. Examples of previously published amiridine-based derivatives and design strategy applied in the current study below, using various pharmacophores.</p> <p><strong>Fig_3</strong>. Top scored docking pose of 5b (A) and 5d (B) highlighting the key findings responsible for compound activity/inactivity. For the sake of clarity, superimposed&nbsp;ligands are aligned in the Fig. C with respect to key amino acid residue W82 to demonstrate the binding difference. Compounds 5b and 5d are colored in&nbsp;salmon and yellow, respectively. Essential amino acid residues responsible for ligand anchoring are rendered in green. Important interactions of different origin are&nbsp;displayed with dashed black lines. The figure was created with The PyMOL Molecular Graphics System, v. 2.5.2.</p> <p><strong>Scheme 1</strong>. Preparation of the amiridine-based compounds 5a-d. Reagents and&nbsp;conditions: <strong>a)</strong> 2-chloroacetyl chloride (4 eq.), CHCl3, 90 ◦C, overnight, 8, 54%,&nbsp;11, 90%, 12, 52%; <strong>b)</strong> CH3CN, K2CO3, KI, reflux, 3 h, 5a, 54%, 5b, 54%; <strong>c)</strong>&nbsp;amiridine (1.1 eq), CH3CN, K2CO3, KI, reflux, overnight, 5c, 48%, 5d, 41%.</p> <p><strong>Scheme 2</strong>. Preparation of intermediate 13 and final compound 6. Reagents&nbsp;and conditions: <strong>a)</strong> potassium phthalimide, CH3CN, reflux, 3 h, then an excess of&nbsp;NH2NH2&sdot;H2O, reflux, overnight, 57%; <strong>b)</strong> DMF, TEA, BOP, room temperature, 2&nbsp;days, 86%.</p> <p><strong>Scheme 3</strong>. Preparation of amiridine-benzothiazole derivatives 7a-m. Reagents&nbsp;and conditions: <strong>a)</strong> for 7a: 2-chlorobenzothiazole, 110 ◦C, overnight, 32%; for&nbsp;7b-m: corresponding 2-chlorobenzothiazole, DIPEA, 100 ◦C, overnight,&nbsp;21&ndash;77%.</p>