Synthesis of 2-oxomethylcytisine derivatives with nootropic activity

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Abstract

A library of 2-oxomethylcytisine derivatives, including conjugates with a phenyl fragment linked to the starting molecule via aminomethyl, acyl, ethenyl, ethyl, thio-, and carboxamide, as well as propenone spacers, has been synthesized. This library also includes Diels–Alder adducts with N-substituted maleinimides. The nootropic activity of the synthesized compounds was studied in vivo using the CPAR test. Three samples were found to have comparable or superior activity to the reference drug Piracetam (the latent period for the first entry of laboratory animals into the dark chamber at the stage of reflex reproduction was 271.7±50.3, 288.8±50.8 and 300.0±0.0 seconds versus 270.9±29.1 seconds, respectively).

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About the authors

A. V. Koval’skaya

Ufa Federal Research Center of Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0001-7772-2894

Ufa Institute of Chemistry

Russian Federation, Ufa, 450054

V. A. Sorokina

Ufa Federal Research Center of Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0001-5311-9580

Ufa Institute of Chemistry

Russian Federation, Ufa, 450054

N. S. Makara

Ufa Federal Research Center of Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0002-1334-1504

Ufa Institute of Chemistry

Russian Federation, Ufa, 450054

R. Yu. Khisamutdinova

Ufa Federal Research Center of Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0003-3477-4250

Ufa Institute of Chemistry

Russian Federation, Ufa, 450054

S. F. Gabdrakhmanova

Ufa Federal Research Center of Russian Academy of Sciences

Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0002-6902-775X

Ufa Institute of Chemistry

Russian Federation, Ufa, 450054

I. P. Tsypysheva

Ufa Federal Research Center of Russian Academy of Sciences

Author for correspondence.
Email: tsypysheva.ip@gmail.com
ORCID iD: 0000-0002-5025-8742

Ufa Institute of Chemistry

Russian Federation, Ufa, 450054

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Supplementary files

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2. Scheme 1. 1a, R = H [(−)-cytisine] 1b, R = Me (methylcytisine) 2a, X = O, X1 = H,H, R = Me 2b, X = H,H, X1 = O, R = Me 2c, X = O, X1 = H,H, R = CH=CH(CO)Ph 2g, X = O, X1 = H,H, R = NH2 2d, X = O, X1 = H,H, R = NHCH2Ph 2е, X = O, X1 = H,H, R = NH(CO)Ph 2g, X = O, X1 = H,H,R = NH(CO)NHPh 2з, X = O, X1 = H,H,R = NH(CS)NHPh 2i, X = O, X1 = H,H,R = Ph 2k, X = O, X1 = H,H,R = CH=CHPh 2l, X = O, X1 = H,H,R = CH2CH2Ph 3a, X = O, X1 = H,H, R1 = i-Pr 3b, X = O, X1 = H,H, R1 = n-Pr 3c, X = O, X1 = H,H, R1 = Ph 3d, X = O, X1 = H,H, R1 = 2-MeO-Ph 3d: X = O, X1 = H,H, R1 = 3-MeO-Ph 3e, X = H,H, X1 = O, R1 = i-Pr

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3. Scheme 2. Reagents and conditions: i, KMnO4, acetone, 20°C; ii, 3 eq. N-isopropylmaleimide, toluene, 110°C; iii, methenamine, CF3COOH, 70°C; iv, C6H5COCH3, NaOH (10%), H2O, 20°C.

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4. Scheme 3.

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5. Scheme 4.

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