Recent advances in urea- and thiourea-containing compounds: focus on innovative approaches in medicinal chemistry and organic synthesis

Abstract

Urea and thiourea represent privileged structures in medicinal chemistry. Indeed, these moieties constitute a common framework of a variety of drugs and bioactive compounds endowed with a broad range of therapeutic and pharmacological properties. Herein, we provide an overview of the state-of-the-art of urea and thiourea-containing pharmaceuticals. We also review the diverse approaches pursued for (thio)urea bioisosteric replacements in medicinal chemistry applications. Finally, representative examples of recent advances in the synthesis of urea- and thiourea-based compounds by enabling chemical tools are discussed.

Fig. 1. Example of protein–ligand interactions, 3D (left) and 2D (right), engaged by an antitumor urea-containing drug, lenvatinib (2), complexed with one of its biological targets FGFR-1 (fibroblast growth factor receptor-1, pdb code 5ZV2). The urea moiety is able to engage multiple hydrogen bond interactions (magenta dashed lines and arrows) with the carboxylic moiety of Glu531 and the Asp641 backbone nitrogen.

Fig. 2. Representative examples of urea-containing antitumor agents.

Fig. 3. Vacor metabolic pathway.

Fig. 4. Chemical structures of selected urea and thiourea compounds used in therapy as chemotherapeutic agents.

Fig. 5. Chemical structures of terminal urea-based drugs for CNS disorders.

Fig. 6. Chemical structures of other urea-based chemical tools.

Fig. 7. Chemical structures of cyclic (thio)urea-containing drugs.

Fig. 8. Thiourea bioisosteres as milestone drugs in antiulcer agent discovery.

Fig. 9. Structure of torsemide (29) and its derivatives 30–32.

Fig. 10. Examples of urea bioisosteric replacement in the neuropeptide Y1 receptor antagonist BMS-193885 (33).

Fig. 11. Squaramide moiety as a urea bioisostere.

Fig. 12. Aminopyrimidin-4-one as a urea bioisosteric group.

Fig. 13. 3-Amino-1,2,4-benzothiadiazine-1,1-dioxide scaffold as a (thio)urea bioisostere.

Fig. 14. Examples of squaramide derivatives.

Fig. 15. Structures of 2,2-diamino-1-nitroethene derivatives as factor Xa inhibitors.

Fig. 16. Urea and α-fluoroenamide groups display similar geometric and electronic properties. As an example, the unsubstituted compounds are reported together with the relevant measured angles, distance lengths (black arrows and labels) and partial charges (blue label) obtained by ab initio calculations.

Fig. 17. 2-Methylacrylamide moiety as a thiourea bioisostere.

Fig. 18. General scheme for the Curtius rearrangement of carboxylic acids and acyl chlorides under continuous flow conditions.

Fig. 19. General schematic flow set-up composed of two sequential microreactors and an in-line FT-IR spectrometer.

Fig. 20. Multicomponent continuous-flow synthesis of thioureas from isocyanides (A), amidines or amines and sulfur (B).

Fig. 21. Continuous-flow generation of a piperidin-4 one library based on a urea scaffold.

Scheme 1. Generation of a urea library by using MW-assisted Staudinger–aza-Wittig reaction. Reaction conditions: a) NaN₃, CH₃CN, 95 °C, 240 W; b) PS-PPh₂, CO₂, primary amine, 70 °C, 200 W.

Scheme 2. One-pot tandem, microwave-accelerated synthesis of diaryl ureas. Reaction conditions: DPPA, Et₃N, 100 °C, toluene.

Scheme 3. Synthesis of N-substituted ureas via reaction between potassium cyanate and different amines under microwave irradiation. Reaction conditions: H₂O, 80 °C, 1000 W.

Scheme 4. Microwave-assisted synthesis of (thio)ureas in a solventless system. Reaction conditions: MgO, 200 W.

Scheme 5. One-pot synthesis of substituted-thioureas under microwave conditions. Reaction conditions: a) CS₂, 160 °C, 150 W; b) primary amine, 160 °C, 150 W.

Scheme 6. Ultrasound-mediated synthesis of ureas. Reaction conditions: CH₂Cl₂, r.t.

Scheme 7. Synthesis of thioureas under ultrasounds. Reaction Conditions: primary amine, acetone, r.t.

Scheme 8. Ultrasound-assisted synthesis of α-ureidophosphonates. Reaction conditions: 75 °C, 40 kHz.

Scheme 9. Photocatalytic synthesis of urea. Reaction conditions: TiO₂-zeolite, Hg lamp 250 W, 1 atm, 40 °C.

Scheme 10. Synthesis of symmetrical N,N′-diaryl thioureas under sunlight. Reaction conditions: CS₂, H₂O.

Scheme 11. Oxidative desulfurization of thiocarbonyl compounds for the synthesis of urea derivatives. Reaction conditions: O₂, eosin Y, DMSO/H₂O, 12 W blue LED.

Scheme 12. Synthesis of symmetrical dialkyl ureas by electrocatalytic carbonylation of aliphatic amines. Reaction conditions: CO, Pd(PPh₃)₂Cl₂, Cu(OAc)₂, n-BuNCl₄, CH₃CN or DMF, 30 °C, 1 atm, 0.9 V.

Scheme 13. Oxidative carbonylation of aliphatic and aromatic amines for the synthesis of symmetrical ureas. Reaction conditions: CO, Pd(OAc)₂ or Pd(PPh₃)₄, n-Bu₄NBF₄, CH₃CN, NaOAc, 50 °C, 1 atm, 0.4 V.

Scheme 14. Synthesis of cyclic urea derivatives by difunctionalization of alkenes. Reaction conditions: TEMPO, H₂O, CH₃CN, 60 °C, RVC anode, Pt cathode 10 mA.

Fig. 22. A proposed mechanism for the electrosynthesis of phenylimidazolidinones.