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Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC50(AChE) = 2.9–1.4 µM, IC50(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ42 aggregation. Conjugates 3 had no effect on Aβ42 self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents.

The synthesis of new hybrid compounds based on the domestic drug amiridine and a seven-membered cyclic homolog of tacrine combined by a thiourea-containing spacer was described. The synthesized conjugates were shown to be highly efficient inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with a nanomolar activity exceeding that of amyridine and tacrine, which was consistent with the molecular docking results. The conjugates also demonstrated a broader spectrum of biological activity uncharacteristic of the parent pharmacophores, namely, the ability to inhibit the AChE-induced and self-aggregation of β-amyloid and antioxidant properties.

We studied the effects of anti-Alzheimer drugs (tacrine, amiridine, and memantine) on phosphorylation of tubulin and microtubule-associated proteins isolated from rat brain, evaluated the capacity of these proteins to polymerize into microtubules after addition of study pharmacological agents, and analyzed the structure of generated microtubules. It was shown that test substances impair assembly of microtubules to a different extent. Dose-dependent effects of these agents on phosphorylation of tubulin and microtubule-associated proteins were observed. Triazolam (not approved for clinical use as anti-Alzheimer drug) in the same concentrations was used as the reference substance in the same tests. It was observed that this substance even in minimal concentration induced the most pronounced changes in microtubule structure. A direct correlation between the capacity of the test substances to modulate tubulin phosphorylation and to impair microtubule structure was found: the more the substance inhibited tubulin phosphorylation, the more it disordered microtubule structure.

In in vitro experiments, amiridine in concentration of 100, 200, and 300 µM restored disturbed structure of microtubules assembled from tubulin and microtubule-associated proteins isolated from the brain of patients with Alzheimer disease. Tacrine in a concentration of 100, 250, and 500 µM inhibited phosphorylation of tubulin and microtubule-associated proteins isolated from the brain of patients with Alzheimer disease, while memantine and amiridine in the specified concentrations had no effect on phosphorylation.

The pharmacological activity of amiridine, a drug resynthesized at the Scientific Research Institute \"Khimtekhnologiya\" (Severodonetsk, Ukraine), was studied. It was found that amiridine is a moderately toxic compound and exerts marked analgesic effects on pain of different geneses.

Acetylcholinesterase (ACE) activity and lipid peroxidation (LPO) parameters were measured in the blood of patients with Alzheimer's disease (AD) during treatment with amiridine and gliatiline. Treatment was accompanied by inhibition of ACE. There was a statistically significant relationship between clinical efficacy and changes in ACE activity. AD was charactefized by significant changes in LPO parameters, with a three-fold increase in the level of primary oxidation products on the background of a sharp (seven-fold) increase in total lipid desaturatedness. There was a statistically significant relationship between ACE activity and the levels of primary oxidation products in the RBC of patients with AD before and after treatment with amiridine and gliatiline.

It is shown that even after partial damage to the hippocampus in male rats by quinolinic acid, which causes selective degeneration of hippocampal neurons, their conditioned reflex to time remains impaired for a period of several months. Treatment with amiridine improves the learning of time-interval estimation by such rats and promotes compensatory/restorative processes in the brain. The brain contains a great diversity of connections, and their stimulation may offer an opportunity for enhancing the operation of compensatory/restorative mechanisms in it.[PUBLICATION ABSTRACT]