Synthesis and Properties of 1,3-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: IV. 1 1
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hesis and Properties of 1,3-Disubstituted Ureas and Their Isosteric Analogs Containing Polycyclic Fragments: IV.1 1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-(fluoro, chlorophenyl)ureas D. A. Pitushkina,b, V. V. Burmistrova,b, and G. M. Butova,b,* a
Volgograd State Technical University (VSTU), Volgograd, 400005 Russia Volzhsky Polytechnic Institute, VSTU Branch, Volzhsky, 404121 Russia *e-mail: [email protected]
b
Received April 13, 2020; revised April 23, 2020; accepted April 26, 2020
Abstract—The reaction of bicyclo[2.2.1]hept-5-en-2-yl isocyanate with fluoro- and chloro-substituted anilines was used to synthesize in a yield of 25–68% a series of 1,3-disubstituted ureas containing a lipophilic group in their structure. The synthesized ureas are promising as inhibitors of RNA virus replication and human soluble epoxide hydrolase. Keywords: natural compounds, bicyclo[2.2.1]hept-5-ene, isocyanate, urea, halogen-containing anilines, soluble epoxide hydrolase, coronavirus, SARS-CoV
DOI: 10.1134/S1070428020080023 Isocyanates present interest as promising intermediates for the synthesis of biologically active substances. Ureas derived from isocyanates are versatile building blocks for heterocyclic synthesis and exhibit broad-spectrum biological activity [2]. For example, 2-({4'-[(phenylcarbamoyl)amino]-4-biphenylyl}carbonyl)cyclopentane1-carboxylic acid showed activity against rotavirus replication in cells and is considered as a potential antiviral agent [3]. A series of 1,3,3-trisubstituted ureas [ethyl 2-(4-R-1,4-diazepane-1-carboxamido)benzoates] was tested as inhibitors of RNA viruses, including SARS-CoV, and showed activity (the replication rate decreased to 7.97% of the control at a concentration of 250 μM), which makes these compounds potential antiviral agents against RNA viruses, including SARS-CoV, HIV-1, and other ARVI viruses [4]. Ureidothiophenes, the ureido group of which is linked the benzene ring, were found to act as powerful RNA polymerase inhibitors with antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 1 and 0.25 μg/mL, respectively) [5]. Over the past years 1,3-disubstituted ureas containing a highly lipophilic group have been actively explored as human soluble epoxide hydrolase [6]. 1
For communication III, see [1].
Human soluble epoxide hydrolase (sEH), an enzyme involved in the metabolism of epoxy fatty acids to the corresponding vicinal diols via the addition of a water molecule, is a promising target in the therapy of hypertensive, inflammatory, and painful conditions [7]. The inhibition of this enzyme has a positive effect has a positive effect in the treatment of hypertension and kidney diseases [8]. Essential drawback of known sEH inhibitors are their fast metabolism under the action of P450 cytochrome and poor water solubility [9]. However, for high inhibitory activity toward sEH, the urea molecule should necessarily contain a highly lipophilic fragment [10]. The above problem has been proposed to approach in different ways, including the synthe
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