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

The search for novel drugs to address the medical needs of Alzheimer’s disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology morecomprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-D-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridinebased drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

Table 1. hBChE inhibitory activities of 5c-d, 7c and 7 g and reference compounds (amiridine hydrochloride and THA); their cytotoxicity profile on SH-SY5Y cell line, and predictions of BBB penetration.

Table 2. Relative inhibitions (RIs) of 5c-d and 7 m and reference compound memantine at recombinant human GluN1/GluN2B NMDA receptor expressed in HEK293 cells.

Fig_1. Chemical structures of rivastigmine, galantamine, and tacrine as representatives of cholinesterase inhibitors. Approaches to novel drugs for AD treatment on the selected candidates are displayed.

Fig_2. Examples of previously published amiridine-based derivatives and design strategy applied in the current study below, using various pharmacophores.

Fig_3. 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 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 salmon and yellow, respectively. Essential amino acid residues responsible for ligand anchoring are rendered in green. Important interactions of different origin are displayed with dashed black lines. The figure was created with The PyMOL Molecular Graphics System, v. 2.5.2.

Scheme 1. Preparation of the amiridine-based compounds 5a-d. Reagents and conditions: a) 2-chloroacetyl chloride (4 eq.), CHCl3, 90 ◦C, overnight, 8, 54%, 11, 90%, 12, 52%; b) CH3CN, K2CO3, KI, reflux, 3 h, 5a, 54%, 5b, 54%; c) amiridine (1.1 eq), CH3CN, K2CO3, KI, reflux, overnight, 5c, 48%, 5d, 41%.

Scheme 2. Preparation of intermediate 13 and final compound 6. Reagents and conditions: a) potassium phthalimide, CH3CN, reflux, 3 h, then an excess of NH2NH2⋅H2O, reflux, overnight, 57%; b) DMF, TEA, BOP, room temperature, 2 days, 86%.

Scheme 3. Preparation of amiridine-benzothiazole derivatives 7a-m. Reagents and conditions: a) for 7a: 2-chlorobenzothiazole, 110 ◦C, overnight, 32%; for 7b-m: corresponding 2-chlorobenzothiazole, DIPEA, 100 ◦C, overnight, 21–77%.