The first 13-vinyl derivatives of berberine: synthesis and antimicrobial activity
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The first 13-vinyl derivatives of berberine: synthesis and antimicrobial activity Oleg D. Demekhin1, Aleksander D. Zagrebaev1, Oleg N. Burov1*, Mikhail E. Kletskii1, Natal'ya V. Pavlovich2, Elena A. Bereznyak2, Marina V. Tsimbalistova2, Sergey V. Kurbatov1 1
Southern Federal University, 7 Zorge St., Rostov-on-Don 344090, Russia; e-mail: [email protected] 2 Federal Government Health Institution ''Rostov-on-Don Plague Control Research Institute'', Federal Service for Surveillance in the Sphere of Consumers Rights Protection and Human Welfare 117/40 M. Gor'kogo St., Rostov-on-Don 344002, Russia; e-mail: [email protected] Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2019, 55(11), 1128–1130
Submitted July 16, 2019 Accepted after revision September 26, 2019
A method for the synthesis of berberine 13-vinyl derivatives has been developed consisting of an initial reaction of triethyl orthoformate with CH acids in the presence of catalytic amounts of p-toluenesulfonic acid followed by the reaction of electrophilic ethoxyethylenes with dihydroberberine. 13-Vinyldihydroberberines are resistant to spontaneous oxidation or disproportionation and can be oxidized to the corresponding 13-substituted ionic forms with silver chloride. The synthesized vinyl berberines were demonstrated to inhibit the development of a number of especially dangerous microorganisms. Keywords: activated ethylenes, berberine, dihydroberberine, antimicrobial activity, electrophilic substitution.
The synthesis of compounds capable of acting against bacteria by influencing the key mechanisms of drug resistance is an extremely urgent task of medicinal chemistry.1–4 It is advisable to search for such structures among derivatives of berberine, which has a fairly high antibacterial effect, is well coordinated with cell walls,1–3 and therefore it was widely tested as an antibiotic against a wide range of infections.4–7 It is known that when substituents are introduced into the C-13 position of reduced berberine (dihydroberberine (1), Scheme 1), derivatives with antibacterial activity can be obtained.8 Earlier, we proposed a method for introducing nitroaryl fragments into the C-13 position of reduced forms of berberine with the formation of new C(13)–C(Ar) bonds.9,10 If these substituents are electron-withdrawing, then the target products are highly stable in reduced forms. We report the first use of ethylene as a C(sp2)-electrophile which contains electron-withdrawing groups and an ethoxy 0009-3122/19/55(11)-1128©2019 Springer Science+Business Media, LLC
group as a nucleofuge. When reacting triethyl orthoformate with dimethylbarbituric acid or malonodinitrile in the presence of catalytic amounts of p-toluenesulfonic acid, we obtained electrophilic ethylenes 2, 3, corresponding to those previously described.11,12 The reaction of ethoxyethylenes 2, 3 with dihydroberberine (1) was carried out in a triethyl orthoformate medium without a catalyst at 45–50°С for 45 min (Scheme 1). A feature of 13-vinylberberines 4a,b is their structural stability – spontan
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