The review and summarizes own and literature data about the role of mitochondria as the important target in the search for drugs for the treatment of neurodegenerative diseases. Aging is a major risk factor for sporadic forms of various neurodegenerative diseases, including Alzheimer′s disease. One of the most argued and currently accepted theories is the Mitochondrial Free Radical Theory of Aging. Mitochondrial hypotheses of the development of sporadic forms of neurodegenerative diseases particularly Alzheimer′s disease, are closely connected with it. Impairments of mitochondrial functions lead to a decrease in their ability to regulate calcium homeostasis in the cell and to a decrease in the threshold for the induction of mitochondrial permeability transition (MPT) pores. MPT inhibitors can be considered as a promising approach to the treatment of neurodegenerative diseases, since these drugs can not only exhibit the properties of neuroprotectors, but also can provide normalization of synaptic activity due to increased calcium capacity of mitochondria. The review presents data on the number of MPT inhibitors, including endogenous compounds melatonin and N-acetylserotonin, their bioisosteric analogue Dimebon and a number of other compounds. The use of mitochondria as a basis for the formation of screening strategy for the search for compounds for the treatment of neurodegenerative diseases is of particular interest – both as a test of their potential toxicity, and as a basis for the creation of metabolic stimulants and drugs with neuroprotective and cognitive-stimulating effect.

An approach to the synthesis of adamantane derivatives with NO-generating fragment containing nitroxy group has been developed. 1-Aminoadamantane, memantine, and adamantanecarboxylic acid have been used as initial compounds. The prepared compounds have shown ability to generate nitric oxide in a system mimicking biological reactions of nitro group reduction.

Using the acylation reaction with tosyl chloride of N-aminopropyl analogues of tacrine and its cyclic homologues with different size of the aliphatic cycle (5–8), we synthesized a number of new derivatives of p-toluenesulfonamide. It is shown that the synthesized hybrid compounds of tacrine and p-toluenesulfonamide are effective inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with the preferential inhibition of BChE. They also displace propidium from the peripheral anionic site of the electric eel AChE (Electrophorus electricus). The characteristics of the efficiency and selectivity of cholinesterase inhibition by the test compounds were confirmed by the results of molecular docking.

New 5-anilino-1,2,4-thiadiazole derivatives with different substituents at position 3 were synthesized and their influence on the key binding sites of NMDA receptors, inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase, as well as antioxidant properties were studied. The compounds with a 2-aminopropyl fragment were found to be efficient blockers of allosteric modulator [3H]ifenprodil binding site of the NR2B-containing NMDA receptors and moderate butyrylcholinesterase inhibitors. Some compounds were found to be able to simultaneously block the [3H]ifenprodil and intrachannel [3H]MК-801 binding sites of NMDA receptors. Compounds containing a 2-aminopropenyl fragment did not exhibit activity against NMDA receptors and butyrylcholinesterase, but showed high radical-scavenging activity.

A method for the synthesis of prolyl-glutamate phosphoisostere by cyclic amidoalkylation of phosphonous acid containing a structural isostere of glutamic acid was developed. A combination of amide and carbonyl moieties in the 4-N-Cbz-aminobutyraldehyde molecule allows cyclization with in situ generation of a cyclic pyrrolidine Schiff base followed by its Arbuzov type phosphorylation.