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

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 OPEN ACCESSMolecules 2015, 20 3822 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.

Synthesis and Pharmacological Evaluation of Novel 1-(1,4-Alkylaryldisubstituted-4,5-dihydro-1H-imidazo)-3-substituted Urea Derivatives

“…Compounds 3a – m were prepared by the reactions between the respective 1-alkyl-4-aryl-4,5-dihydro-1 H -imidazol-2-amines 1a – c and the appropriate isocyanates 2 in dichloromethane (Scheme 1). We have previously reported a few series of 1-aryl-4,5-dihydro-1 H -imidazo-2-amine derivatives which do not possess a protonable nitrogen atom, but exhibit serotoninergic and antinociceptive activity mediated [2,8,10,11,12] or not [6,7] thought the opioid system.…”

“…Parameters to evaluate drug-likeness were calculated using VegaZZ v. 3.0.1 [46] (number of atoms), Discovery Studio v. 3.1. [47] (molar mass, number of rings, lipophilicity, number of rotatable bonds), ACDLabs (molar refractivity, number of hydrogen bond donors and acceptors), and the Schrödinger Suite (a number of rigid bonds) as described previously [2,6,7,8]. ADMET parameters were calculated with Discovery Studio 3.1 (solubility, blood-brain permeation) or Osiris Property Explorer [48] (toxicity risks) as previously described [2,6,7,8].…”

“…These shared structural features can be found in bezitramide, fentanyl and pethidine, and their analogues, Figure 1 [2]. Non-classical pharmacophore models explaining opioid receptor activity which consist of a base, a hydrophobic and aromatic moiety or hydrogen bond acceptor, hydrophobic, and aromatic groups were also suggested [2,5,6,7,8].…”

“…Treatment potential and demand for improved opioid analgesics have resulted in development of a number of new opioid analgesics [1]. Based on the non-classical pharmacophore models for opioid receptor activity we have previously reported a few series of compounds with antinociceptive activity mediated through the opioid system (series A–E, Figure 2), partially mediated through opioid system (series F) or with a different mechanism of antinociceptive activity (series G–P) [2,6,7,8,9,10,11,12].…”

Fragmental Method KowWIN as the Powerful Tool for Prediction of Chromatographic Behavior of Novel Bioactive Urea Derivatives

“…Substituted urea derivatives belong to important class of molecules with a large spectrum of biological properties. Basing on our previous studies, 27 synthesized N-substituted 1-alkyl-4-aryl(arylalkyl) imidazolidyn-2-ylidene ureas exhibit antinociceptive and serotonergic activity.Chromatographic experiments were conducted on octadecyl and cholesterol stationary phases. Owing to their similarity to biological membranes, both adsorbents can be utilized to anticipate affinity of analytes to the cell membranes.…”