Urea Derivatives in Modern Drug Discovery and Medicinal Chemistry

Abstract

The urea functionality is inherent to numerous bioactive compounds, including a variety of clinically approved therapies. Urea containing compounds are increasingly used in medicinal chemistry and drug design in order to establish key drug-target interactions and fine-tune crucial drug-like properties. In this perspective, we highlight physicochemical and conformational properties of urea derivatives. We provide outlines of traditional reagents and chemical procedures for the preparation of ureas. Also, we discuss newly developed methodologies mainly aimed at overcoming safety issues associated with traditional synthesis. Finally, we provide a broad overview of urea-based medicinally relevant compounds, ranging from approved drugs to recent medicinal chemistry developments.

Figure 1.

Structures of urea and selected urea derivatives.

Figure 2.

Possible resonance structures for the urea moiety.

Figure 3.

Conformations of N,N′-diphenyl urea, N-methyl-N,N′-diphenyl urea, and N,N′-dimethyl-N,N′-diphenyl urea.

Figure 4.

HOMO and LUMO overlap in substituted diarylureas.

Figure 5.

Formation of π-stacked aromatic arrays using substituted diarylureas.

Figure 6.

Stereoselective reduction of acylurea 11 containing a chiral sulfinyl group.

Figure 7.

(A) Association pattern of N,N′-disubstituted ureas; (B) proposed association pattern for DIPPU (14).

Figure 8.

Construction of pseudoring systems exploiting intra-molecular hydrogen bonding.

Figure 9.

Disruption of the planarity of urea derivatives through urea alkylation.

Figure 10.

Disruption of urea planarity by introduction of orthosubstituents at the aryl urea system.

Figure 11.

(A) Representation of the stacking interaction between Trp6 and urea; (B) NH-π interaction between the tryptophan 6 side-chain and urea. Part of the Trp-cage miniprotein is shown in magenta; carbon atoms, nitrogen, and hydrogen atoms are shown in green, blue, and yellow, respectively. The figure is modified based upon published structures.

Figure 12.

Structure of HIV-1 protease inhibitor 23 and highlight of the interaction with protease. Hydrogen bonding interactions are shown by blue dotted lines.

Figure 13.

X-ray structure of urea derivative 24 and HIV-1 protease complex (pdb code: 1DMP). Hydrogen bonding interactions are shown by black dotted lines.

Figure 14.

X-ray structure of sorafenib (25) and VEGFR2 complex (pdb code: 4ASD). Hydrogen bonding interactions are shown by black dotted lines.

Figure 15.

X-ray structure of lenvatinib (26) and VEGFR2 complex (pdb code: 3WZD). Hydrogen bonding interactions are shown by black dotted lines.

Figure 16.

X-ray structure of MAP kinase inhibitor BIRB 796 (27) with human p38 MAP kinase (PDB code: 1KV2). Hydrogen bonding interactions are shown by black dotted lines.

Figure 17.

(A) Transition state for sEH-catalyzed oxirane ring opening; (B) Interaction of inhibitor 28 in the enzyme active site.

Figure 18.

Mechanism of FAAH inhibition by urea derivative PF-04457845 (29).

Figure 19.

Structures of urea containing FDA approved drugs.

Figure 20.

EGFR inhibitor 108 and urea-containing EGFR inhibitors 109 and 110.

Figure 21.

Urea-containing multikinase inhibitors 111–113.

Figure 22.

Urea-containing VEGFR-2 inhibitors 114–116.

Figure 23.

Urea-containing kinase inhibitors as antitumor agents 117–120.

Figure 24.

Urea derivatives as kinase inhibitors 121–123.

Figure 25.

Urea-containing microtubule targeting agents 124–127.

Figure 26.

Urea containing anticancer agents 128–131.

Figure 27.

Urea derivatives 132–134 for neurodegenerative diseases.

Figure 28.

Urea derivatives 135–137 for neurodegenerative diseases.

Figure 29.

Urea derivatives 138–140 for neurobiological and neurodegenerative diseases.

Figure 30.

Urea derivatives 141 and 142 for neurodegenerative diseases.

Figure 31.

Urea-containing antiviral agents 143 and 144.

Figure 32.

Urea-derivatives 145–147 as antibacterial agents.

Figure 33.

Urea-containing antibacterial agents 148–150.

Figure 34.

Urea-containing antimalarial agents 151–153.

Figure 35.

Urea-containing antitripanosomal agents 47, 154, and 155.

Scheme 1.

Traditional Methodologies for the Synthesis of Ureas

Scheme 2.

Formation of Urea-Containing MAGL Inhibitor 43 Using Phosgene

Scheme 3.

Formation of the Urea Derivative 47 Using Triphosgene

Scheme 4.

Formation of Urea Derivative 51 Using CDI (50)

Scheme 5.

Formation of Urea Derivatives Using 1,l′-Carbonylbisbenzotriazole (53)

Scheme 6.

Formation of Urea Derivatives through Aminolysis of Carbamates

Scheme 7.

Synthesis of Urea Derivatives Using Carbamoylimidazolium Salts

Scheme 8.

Synthesis of Urea Derivatives Using S,S-Dimethyl Dithiocarbonate (63)

Scheme 9.

Synthesis of Urea Derivatives Using Phenyl 4,5-Dichloro-6-oxopyridazine-1(6H)-carboxylate (68)

Scheme 10.

Synthesis of Urea Derivatives 71–73 Using CDI in Water Medium

Scheme 11.

Synthesis of Urea Derivatives Using Bis(2,2,2-trifluoroethyl) Carbonate 76

Scheme 12.

Formation of the Urea Derivative 81 Using a Key Hofmann Rearrangement

Scheme 13.

Formation of Urea Derivative 83 Using the Curtius Rearrangement

Scheme 14.

Formation of Urea Derivative 86 Using the Lossen Rearrangement

Scheme 15.

Synthesis of Urea Derivatives Using CDI-Mediated Lossen Rearrangement

Scheme 16.

Synthesis of Urea Derivatives Using a Lossen Rearrangement Mediated by 1-Propanephosphonic Acid Cyclic Anhydride (87, T3P)

Scheme 17.

Synthesis of Urea Derivatives Using a Lossen Rearrangement Mediated by 2-Cyano-2-(4-nitrophenylsulfonyloxyimino)acetate (88, 4-NBsOXY)

Scheme 18.

Synthesis of Urea Derivatives Using Curtius Rearrangement via Formation of the Azidoformate

Scheme 19.

Synthesis of Urea Derivatives 91 and 93 Using Curtius Rearrangement under Ultrasonication Conditions

Scheme 20.

Synthesis of Urea Derivatives Using Curtius Rearrangement under Microwave Conditions

Scheme 21.

PhIO-Induced Hofmann Rearrangement

Scheme 22.

Synthesis of Urea Derivatives Using Tienmann Rearrangement

Scheme 23.

Synthesis of Urea Derivatives Using Snieckus-Fries-Type Rearrangement

Scheme 24.

Dicobalt Octacarbonyl Promoted Generation of Urea Derivatives

Scheme 25.

Generation of Urea Derivatives from Nitroarenes

Scheme 26.

Synthesis of Urea Derivatives Using Cross Coupling of Aryl Chlorides and Triflates with Sodium Cyanate in the Presence of Ligand 101

Scheme 27.

Pd-Catalyzed Reductive Alkylation of Urea Derivatives with Aldehydes ^aSolvent free conditions.

Scheme 28.

Pd/C-Catalyzed Carbonylation of Benzyl, Alkyl, and Aryl Azides with XPhos ^aPhMe, 60 °C, 12 h. ^b5% nBu₄NCl, H₂O/PhMe 20:1, rt, 24 h.

Scheme 29.

Synthesis of Urea Derivatives by Oxidative Carbonylation Using PdI₂ and KI

Scheme 30.

Synthesis of Urea Derivatives by Carbonylation with Mo(CO)₆

Scheme 31.

Synthesis of Urea Derivatives Using Ruthenium Pincer Complex (104, Ru-MACHO-BH) as the Precatalyst

Scheme 32.

Synthesis of Urea Derivatives Using Ruthenium Pincer Complex 105 and DMF

Scheme 33.

Synthesis of Urea Derivatives Using a Copper-Catalyzed Reaction

Scheme 34.

One-Pot Synthesis of Urea Derivatives from Boc-Amines and Cbz-Amines

Scheme 35.

Synthesis of Urea Derivatives by a Continuous-Flow Process

Scheme 36.

Synthesis of Ureas from Isonitriles via the Intermediate Isocyanates

Scheme 37.

Synthesis of Urea Derivatives Using Oximes

Scheme 38.

Synthesis of Urea Derivatives via Carbamic Acids