Features of Conjugation of Ipidacrine Chloroalkylamides with 5-Acetyl-3-(Trifluoromethyl)Pyrazole and Its Derivatives. Study of Biological Activity

An approach to the preparation of ipidacrine conjugates with trifluoromethyl pyrazoles containing acetyl, hydrazone or oxime groups as functional substituents has been investigated. The alkylation of 5-acetyl-3-(trifluoromethyl)pyrazole with 2-chloroacetamide of ipidacrine proceeds non-regioselectively on the nitrogen atoms of the pyrazole ring, giving a mixture of 3-/5-CF-regioisomeric products. The introduction of a hydrazone/oxime substituent into the structure of CF-pyrazoles leads to the preferential formation of 3-CF-regioisomeric conjugates. In alkylation reactions, preservation of the arylhydrazone substituent in pyrazolyl-containing ipidacrines is observed, whereas the oxime group undergoes hydrolysis to the acetyl function. Conjugation of 5-(1-hydroxizimylidenethyl)pyrazole with 3-chloropropanamide of ipidacrine was accompanied by partial reduction of the hydrazone substituent. 4-Chlorobutanamide of ipidacrine in MeCN did not react with pyrazoles, and upon heating in DMF 5-(1-hydroxizimylidenethyl)pyrazole underwent transamination to form symmetric ketazine. The conjugate with the N-propanamide spacer showed moderate selective inhibitory activity towards butyrylcholinesterase (IC = 14.5 ± 0.8 μM) and towards self-aggregation of β-amyloid (1–42). The introduction of an aryl substituent into the hydrazone fragment led to an increase in the antioxidant activity of pyrazoles and to the appearance of significant antioxidant properties of the conjugates in the ABTS (TEAC = 0.47–0.56) and FRAP (0.44–0.55 TE) tests.