Molecular construction of multitarget neuroprotectors 4.* Synthesis and biological activity of conjugates of carbazoles and tetrahydrocarbazoles

Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment

“…An important contribution to the neuroprotective potential can also be made by the ability of the compounds (C-2g) to diminish, in the dose-dependent manner, the calcium-induced swelling of isolated mitochondria, which may indicate the properties of this compound and its derivatives as inhibitors of mitochondrial permeability transition38. This specific process plays a key role in the cell death cascade in both the physiological cell apoptosis and various neurotoxic scenarios (glutamate excitotoxicity, amyloid toxicity, etc .).…”

“…The synthesis of compounds combining two pharmacophores, aminoadamantane and carbazole ones, linked by a 2-hydroxypropylene spacer (Fig. 1) was reported in our previous papers323338.…”

“…For the most active compounds with the ability to influence some mitochondrial parameters38, their effects on cellular neurotoxicity were evaluated.…”

Molecular design of multitarget neuroprotective agents 5. Modification with pharmacologically active fragments of 4,4- and 1,4-dipropargyl-5-methyl-2-phenylpyrazol-3-one

“…78-79 °C. 1 Synthesis of 4,4-di(prop-2-yn-1-yl)pyrazolone 3 from methanesulfonylpyrazolone 5. Propargyl bromide 2 (5 (А) or 11 mmol (B)) was added to a solution of mesylpyrazolone 5 (5 mmol) and K 2 CO 3 (12 mmol) in Pr i OH (20 mL) with stirring at 20 °C.…”

“…Earlier, we have proposed various options for modifi cation of biologically active structures with additional pharmacophores expanding the spectrum of biological activity of the target structures. [7][8][9] In the present work, we describe the conjugation of the drug Edaravone (1) with various pharmacologically active fragments based on bispropargylation of compound 1 and the subsequent click-reaction of copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition in order to design new potential multitarget drugs for treatment of neurodegenerative diseases. The chosen farmacoactive fragments include 1-aminoadamantane derivatives, the known drugs for treatment of neurodegenerative diseases Amantadine and Memantine, carbazole and tetrahydrocarbazole derivatives, a heterocyclic base, for example, of the drug Carprofen, and tetrahydro-γ-carboline derivatives, a fragment of the known drugs Diazolin and Dimebon, as well as many representatives of neuroprotectors.…”