Synthesis, central nervous system activity and structure-activity relationships of novel 1-(1-Alkyl-4-Aryl-4,5-Dihydro-1 h-Imidazo)-3-substituted urea derivatives

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 Suite (a number of rigid bonds) as described previously [2,12,13]. Drug-likeness was also evaluated with Osiris Property Explorer [16]. This approach is based on a list of about 5300 distinct substructure fragments with associated drug-likeness scores. The drug-likeness is calculated summing up score values of those fragments that are present in the molecule under investigation. ADMET parameters were calculated with Discovery Studio 3.1 (solubility, blood-brain permeation) or Osiris Property Explorer [16] (toxicity risks). The prediction of toxicity by this tool relies on a precomputed set of structural fragment that give rise to toxicity alerts in case they are encountered in the investigated structure. For structure-activity relationship studies, HOMO and LUMO energies and polarizabilty were calculated with Discovery Studio 3.1 and molar surface, volume, ovality and polar surface area were calculated with VegaZZ as reported earlier [2,12,13]. The maps of the electrostatic potential (ESP) onto a surface of the electron density were visualized with ArgusLab [48].