Synthesis, central nervous system activity and structure-activity relationships of novel 1-(1-Alkyl-4-aryl-4,5-dihydro-1H-imidazo)-3-substituted urea derivatives

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Elżbieta SzacońD Matosiuk

Abstract

A series of 10 novel urea derivatives has been synthesized and evaluated for their central nervous system activity. Compounds 3a-3h were prepared in the reaction between the respective 1-alkyl-4-aryl-4,5-dihydro-1H-imidazol-2-amines 1a and 1b and appropriate benzyl-, phenethyl-isocyanate or ethyl 4-isocyanatobenzoate and ethyl isocyanatoacetate 2 in dichloromethane. Derivatives 4c and 4g resulted from the conversion of 3c and 3g into the respective amides due to action of an aqueous ammonia solution. The results obtained in this study, based on literature data suggest a possible involvement of serotonin system and/or the opioid system in the effects of tested compounds, and especially in the effect of compound 3h. The best activity of compound 3h may be primarily attributed to its favourable ADMET properties, i.e., higher lipophilicity (related to lower polar surface area and greater molecular surface, volume and mass than for other compounds) and good blood-brain permeation. This compound has also the greatest polarizability and ovality. The HOMO and LUMO energies do not seem to be directly related to activity.

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Citations

May 6, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Elżbieta SzacońDariusz Matosiuk
Jul 2, 2016·Expert Opinion on Drug Delivery·Flavia Maria SuteraLibero Italo Giannola
Jul 8, 2016·Expert Opinion on Therapeutic Patents·Franciszek SączewskiŁukasz Balewski

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Methods Mentioned

BETA
NMR

Software Mentioned

Compass Data Analysis
PREADMET
LigPrep
Schrödinger Suite
ArgusLab
Discovery Studio
Epik
VegaZZ
Osiris Property Explorer

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