Urea Derivatives Research Articles

Design and evaluation of semicarbazide-embeddedd stationary phases for liquid chromatography

Semicarbazide, as a derivative of urea, constitutes a great variety of functional molecules for different needs. Herein, novel stationary phases with an incorporated semicarbazide group were proposed. Using aliphatic (docosanoyl, C22) and aromatic (benzoyl, Bz) hydrazides, the semicarbazide-embedded ligands were synthesized before chemical modification of the silica gel, allowing for an accurate interpretation of the chromatographic properties of the corresponding packings. The new stationary phases were water-wettable, due to the presence of highly polar groups. In particular, Bz-semicarbazide (Bz-SCD) stationary phase was sufficiently hydrophilic to run in hydrophilic interaction (HILIC) mode, whilst the C22 (C22-SCD) equivalent, in spite of its reversed-phase nature, was markedly less hydrophobic than the referenced polar-embedded ones. The versatility of C22-SCD was demonstrated with a large selection of analytes, including geometric isomers and standard mixtures of polycyclic aromatic hydrocarbons, sulfonamides, sulfonylurea, substituted ureas, pyridines and carbamates, fat-soluble colorants, antifungal metabolites, angiotensin II receptor blockers and calcium channel blockers.

Discovery of novel urea derivatives as ferroptosis and autophagy inducer for human colon cancer treatment

A series of novel urea derivatives were designed, synthesized and evaluated for their inhibitory activities against HT-29 cells, and structure-activity relationships (SAR) were summarized. Compound 10p stood out from these derivatives, exhibiting the most potent antiproliferative activity. Further biological studies demonstrated that 10p arrested cell cycle at G2/M phase via regulating cell cycle-related proteins CDK1 and Cyclin B1. The underlying molecular mechanisms demonstrated that 10p induced cell death through ferroptosis and autophagy, but not apoptosis. Moreover, 10p-induced ferroptosis and autophagy were both related with accumulation of ROS, but they were independent of each other. Our findings substantiated that 10p combines ferroptosis induction and autophagy trigger in single molecule, making it a potential candidate for colon cancer treatment and is worth further development.

Manganese PNN pincer complex for hydrogenation of carbamate and urea derivatives: Reaction mechanism examined by DFT calculations

A comprehensive computational study is reported here on the mechanism of the reaction through which a Mn(I) pincer catalyst is able to assist the hydrogenation process of carbamate and urea derivatives, chosen as representative linker units of polyurethanes. Four substrate models, carbamate and urea derivatives, have been examined in order to evaluate their influence on the hydrogenation mechanism of polyurethanes to generate useful alcohols and amines organic building blocks. The outcomes of the computational exploration highlight a different behavior of the catalyst in assisting hydrogenation of carbamate or carbamide derivatives in the different steps of the whole reaction mechanism. Indeed, for the first hydrogenation step, the viability of a ligand-assisted mechanism has been found only for carbamide derivatives and involves a reversible structural change of the pincer ligand that can partially detach from the metal to favor the coordination of the molecule to be processed. The carbamate derivatives, instead, go through the formation of an intermediate in which the substrate interacts with the complex without binding. The mechanism of second hydrogenation is common to all the examined cases and requires the exploitation of the hemilabile nature of the PNN ligand. From the calculated energies put into play it clearly appears the great ability of the Mn(I) complex in catalyzing the hydrogenation of both carbamate and carbamide derivatives.

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.

Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4WT, FGFR4V550L, and FGFR4V550M with IC50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4WT, FGFR4V550L, and FGFR4V550M, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

Novel quinazolines bearing 1,3,4-thiadiazole-aryl urea derivative as anticancer agents: design, synthesis, molecular docking, DFT and bioactivity evaluations

A novel series of 1-(5-((6-nitroquinazoline-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives 8 were designed and synthesized to evaluate their cytotoxic potencies. The structures of these obtained compounds were thoroughly characterized by IR, 1H, and 13C NMR, MASS spectroscopy and elemental analysis methods. Additionally, their in vitro anticancer activities were investigated using the MTT assay against A549 (human lung cancer), MDA-MB231 (human triple-negative breast cancer), and MCF7 (human hormone-dependent breast cancer). Etoposide was used as a reference marketed drug for comparison. Among the compounds tested, compounds 8b and 8c demonstrated acceptable antiproliferative activity, particularly against MCF7 cells. Considering the potential VEGFR-2 inhibitor potency of these compounds, a molecular docking study was performed for the most potent compound, 8c, to determine its probable interactions. Furthermore, computational investigations, including molecular dynamics, frontier molecular orbital analysis, Fukui reactivity descriptor, electrostatic potential surface, and in silico ADME evaluation for all compounds were performed to illustrate the structure–activity relationship (SAR).

Novel Pyrazole Acyl(thio)urea Derivatives Containing a Biphenyl Scaffold as Potential Succinate Dehydrogenase Inhibitors: Design, Synthesis, Fungicidal Activity, and SAR.

As part of a program to discover novel succinate dehydrogenase inhibitor fungicides, a series of new pyrazole acyl(thio)urea compounds containing a diphenyl motif were designed and synthesized. Their structures were confirmed by 1H NMR, HRMS, and single X-ray crystal diffraction analysis. Most of these compounds possessed excellent activity against 10 fungal plant pathogens at 50 μg mL-1, especially against Rhizoctonia solani, Alternaria solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Cercospora arachidicola. Interestingly, compounds 3-(difluoromethyl)-1-methyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9b, EC50 = 0.97 ± 0.18 μg mL-1), 1,3-dimethyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9a, EC50 = 2.63 ± 0.41 μg mL-1), and N-((4'-chloro-[1,1'-biphenyl]-2-yl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4-carboxamide (9g, EC50 = 1.31 ± 0.15 μg mL-1) exhibited activities against S. sclerotiorum that were better than the commercial fungicide bixafen (EC50 = 9.15 ± 0.05 μg mL-1) and similar to the positive control fluxapyroxad (EC50 = 0.71 ± 0.11 μg mL-1). These compounds were not significantly phytotoxic to monocotyledonous and dicotyledonous plants. Structure-activity relationships (SAR) are discussed by substituent effects/molecular docking, and density functional theory analysis indicated that these compounds are succinate dehydrogenase inhibitors.

Novel 1-(1-Arylimiazolin-2-Yl)-3-Arylalkilurea Derivatives with Modulatory Activity on Opioid MOP Receptors.

μ-opioid receptor ligands such as morphine and fentanyl are the most known and potent painkillers. However, the severe side effects seen with their use significantly limit their widespread use. The continuous broadening of knowledge about the properties of the interactions of the MOP receptor (human mu opioid receptor, OP3) with ligands and specific intracellular signaling pathways allows for the designation of new directions of research with respect to compounds with analgesic effects in a mechanism different from classical ligands. Allosteric modulation is an extremely promising line of research. Compounds with modulator properties may provide a safer alternative to the currently used opioids. The aim of our research was to obtain a series of urea derivatives of 1-aryl-2-aminoimidazoline and to determine their activity, mechanism of biological action and selectivity toward the MOP receptor. The obtained compounds were subjected to functional tests (cAMP accumulation and β-arrestin recruitment) in vitro. One of the obtained compounds, when administered alone, did not show any biological activity, while when co-administered with DAMGO, it inhibited β-arrestin recruitment. These results indicate that this compound is a negative allosteric modulator (NAM) of the human MOP receptor.

Thermodynamic and Catalytic Insights into Non‐Reductive Transformation of CO2 with Amines into Organic Urea Derivatives

AbstractCarbon dioxide (CO2) utilization as a carbonyl source is an attractive and promising approach to yielding value‐added organic urea derivatives, which are currently produced with toxic reagents such as phosgene and carbon monoxide, along with the contribution to mitigating global warming. However, the direct intermolecular reaction between CO2 and amines into organic urea derivatives has thermodynamic limitations, and such obstacles need to be considered well in order to establish efficient reaction systems. Herein, this review describes the thermodynamic aspects for producing several organic urea compounds, viz., N,N’‐dibutylurea, N,N’‐di(tert‐butyl)urea, 2‐imidazolidinone (ethylene urea), N,N’‐dimethyl‐2‐imidazolidinone, tetrahydro‐2‐pyrimidinone (propylene urea), and N,N’‐diphenylurea, based on the results of computational calculations. Besides, a variety of the state‐of‐the‐art reaction systems with/without catalyst for synthesizing such organic urea compounds operated under pressurized CO2 have been summarized and discussed to make not only advantages but also disadvantages clear. We have also overviewed the very recently reported approaches that employ alkylcarbamic acids as substrates and instead does not require external CO2. The thermodynamic and catalytic insights garnered here could be a fruitful guideline for fairly assessing each reaction system and further improving the efficiency of CO2 utilization as a carbonyl source.

Synergistic effect of tryptamine-urea derivatives to overcome the chromosomally-mediated colistin resistance in Klebsiella pneumoniae

Colistin is considered as the last-resort antibiotics to treat multi-drug resistant Gram-negative bacterial infections in humans. However, the clinical use of colistin was limited because of the apparition of chromosomal mutations and mobile colistin resistance genes in bacterial isolates. One promising strategy is to combine existing antibiotics with promising non-antibiotics to overcome the widespread emergence of antibiotic-resistant pathogens. Moreover, colistin resistance would be regulated by two component systems PhoP/PhoQ which leads to permanent synthesis of cationic groups compensating for Mg2+ deficiency. In this study, the synthesis of a small library of tryptamine urea derivatives was carried out. In addition, antibiotic susceptibility, antibiotic adjuvant screening and checkerboard assays were used to investigate the antibacterial activity of these synthesized compounds and the potential synergistic activity of their combination with colistin. Conformational analysis of the docked binding modes of the active compound in the predicted binding pocket of bacterial response regulator PhoP were carried out, to see if the active compound inhibits PhoP which is involved in colistin resistance. Finally, hemolytic activity studies have been conducted on the most active compound.

N, N'-disubstituted Ureas as Novel Antiplatelet Agents: Synthesis, Pharmacological Evaluation and In Silico Studies.

Thrombotic disorders are among the leading causes of morbidity and mortality worldwide. Drugs used in the prevention and treatment of atherothrombosis have pharmacokinetic limitations and adverse effects such as hemorrhagic conditions, highlighting the importance of developing more effective antiplatelet agents. ethod: In this work, we synthesized N,N'-disubstituted ureas 3a-3j and evaluated their antiplatelet profiles through in vitro, ex vivo, and in silico studies. The synthesized derivatives exhibited a selective inhibitory profile against platelet aggregation induced by arachidonic acid (AA) in vitro, without significantly affecting other aspects of primary hemostasis and blood coagulation. The compounds that showed inhibition greater than 85% were submitted to the analysis of their potency by calculating the concentration required to inhibit 50% of platelet aggregation induced by AA (IC50). Urea derivative 3a was the most potent with IC50 of 1.45 μM. Interestingly, this derivative inhibited more than 90% of platelet aggregation induced by AA ex vivo, with a similar effect to acetylsalicylic acid. In the hemolysis assay, most of the urea derivatives presented values below 10% suggesting good hemocompatibility. Additionally, the compounds tested at 100 μM also showed no cytotoxic effects in HepG2 and Vero cells. The in silico results suggested that compound 3a may bind to the key residue of COX-1 similar to AA and known COX-1 inhibitors, and the results are also in agreement with our SAR, which suggests that the inhibition of this enzyme is the most likely mechanism of antiplatelet activity. Therefore, these results demonstrated that N,N'-disubstituted ureas are promising candidates for the development of novel antiplatelet agents.

Exploiting decarbonylation and dehydrogenation of formamides for the synthesis of ureas, polyureas, and poly(urea-urethanes).

Urea derivatives, polyureas, and poly(urea-urethanes) are materials of great interest. However, their current methods of synthesis involve toxic feedstocks - isocyanate and phosgene gas. There is significant interest in developing alternative methodologies for their synthesis from safer feedstocks. We report here new methods for the synthesis of urea derivatives, polyureas, and poly(urea-urethane) using a ruthenium pincer catalyst. In this approach, urea derivatives and polyureas are synthesized from the self-coupling of formamides and diformamides, respectively, whereas poly(urea-urethanes) are synthesized from the coupling of diformamides and diols. CO and H2 gases are eliminated in all these processes. Decarbonylation of formamides using such organometallic catalysts has not been reported before and therefore mechanistic insights have been provided using experiments and DFT computation to shed light on pathways of these processes.

Palladium-catalyzed ligand-regulated divergent synthesis of pyrrole[2,3-b]indoles and ureas from 2-ethynylanilines and isocyanides.

Herein, a palladium-catalyzed and ligand-controlled protocol for the divergent synthesis of pyrrole[2,3-b]indole and urea derivatives has been described. Pyrrole[2,3-b]indoles ("cyclization on" products) via tandem cyclization of o-alkynylanilines with isocyanides in the absence of a ligand and ureas ("cyclization off" products) via oxidative amination of anilines with isocyanides in the presence of a ligand were obtained both in moderate to good yields with high selectivity. In this chemistry, cyclic and acyclic products were easily accessed with the same starting materials under the regulation of the ligand.

Computational evaluation of the inhibitory potential of some urea, thiourea, and selenourea derivatives of diselenides against leishmaniasis: 2D-QSAR, pharmacokinetics, molecular docking, and molecular dynamics simulation

Leishmaniasis affects more than twelve million people globally and a further one billion people are at risk in leishmaniasis endemic areas. The lack of a vaccine for leishmaniasis coupled with the limitations of existing anti-leishmanial therapies prompted this study. Computational techniques have profound applications in screening large libraries of compounds, studying protein-ligand interactions, analyzing pharmacokinetic properties, and designing new drug entities with great speed, accuracy, and precision. This study was carried out to evaluate the anti-leishmanial potential of some diselenides by quantitative structure-activity relationship, pharmacokinetics analysis, density functional theory, molecular docking, and molecular dynamics simulation. The built quantitative structure-activity relationship model was validated (R2train = 0.7128, R2test = 0.6110, Q2LOO = 0.5018) with compounds 6 and 12 having the highest and the least predicted inhibitory activity values of 5.8335 and 4.7998 respectively. Only compounds 7 and 26 passed the drug-likeness test performed on the eight diselenides with relatively higher pEC50. The selected diselenides (7 and 26) showed good pharmacokinetic properties and bound more strongly with the target protein (6K91) than the reference drug (Pentamidine). The results of the studies; density functional theory and molecular dynamics simulation suggest the reactivity, favourability, and stability of the tested compounds in the order; compound 26 > compound 7 > Pentamidine. Conclusively, the selected diselenides could be developed as potential anti-leishmanial drug molecules and/or as useful scaffolds for designing superior anti-leishmanial agents.

Design, synthesis and biological evaluation of aryl urea derivatives of oxazole-pyrimidine as anticancer agents

A library of aryl urea oxazole-pyrimidine derivatives (12a-j) have been synthesized and investigated for their anticancer activity profile against a panel of four human cancer cell lines including breast cancer (MCF-7), lung cancer (A549), colon cancer (Colo-205) and ovarian cancer (A2780) by utilizing of MTT method, compare with etoposide used as reference drug candidate. All the examined compounds displayed potent anticancer activity with IC50 values ranges from 0.01 ± 0.0062 µM to 10.6 ± 7.43 µM, whereas, etoposide showed values ranges from 0.17 ± 0.034 µM to 3.34 ± 0.152 µM. Among the synthesized compounds, seven compounds 12a, 12b, 12d, 12e, 12f, 12 g and 12 h demonstrated most promising activity than reference drug.

Urothermal synthesis of metal–organic frameworks

The use of urea derivatives as solvents for the preparation of metal–organic frameworks is reviewed.

Switching the hydrogenation selectivity of urea derivatives via subtly tuning the amount and type of additive in the catalyst system

We have developed a triphos-Ru catalytic system that can switch the chemoselectivity in catalytic hydrogenation of urea derivatives (from N-formamides to N-monomethylamines and methanol) by changing only 0.5 mol% KOtBu (2% to 1.5%).

Mechanochemical synthesis of β-cyclodextrin urea derivatives under reactive CO2 atmosphere by Staudinger aza-Wittig reaction

Easily synthesize various ureido β-cyclodextrins with minimal environmental impact using a fast and solvent-free mechanochemical process under carbon dioxide reactive atmosphere.

Theoretical and experimental approach on investigation of ethylurea-water clusters

Abstract Alkylated urea derivatives have found wide application as starting materials for the production of many drugs, including anticancer drugs, as well as in many other areas. In this work, we studied ethylurea crystalline hydrates using a complex of theoretical and experimental methods. The nature of the intermolecular interactions between ethylurea and water molecules is investigated using topological analyses such as atoms in molecules (AIM), non-covalent interaction (NCI), reduced density gradient (RDG), electron localized functions (ELF), and localized orbital locator (LOL). The hydrogen bond energy is in the range of 1.1295–14.4327 kcal/mol. Also, a highly correlated parabolic relationship between topological parameters (E HB, ρ, and ∇2 ρ) and H-bond length was determined. According to RDG data, with an increase in the number of water molecules in ethylurea clusters, the area corresponding to hydrogen bonds increases. The initial ethylurea and its crystalline hydrate were studied by FTIR spectroscopy and X-ray diffraction. The introduction of water molecules into the ethylurea crystal was proved by IR spectroscopy by the appearance of the corresponding absorption bands. X-ray diffraction showed that the initial ethylurea has intense peaks at 11.2, 16.8, 21.4, 22.24, 25.06, 25.78° 2Ɵ, the intensity of which changes when water molecules are introduced into the crystal.

New Liquid Electrolytes Consisting of Li Salts and Urea Derivatives for Li-Ion Batteries

Deep eutectic solvents are mixtures that exhibit melting points much lower than those of the endmembers due to the molecular interactions. Deep eutectic solvents attracted attention because high melting point compounds are available as flame-resistance solvents.1 However, the stable operation of Li-ion batteries (LIBs) with deep eutectic electrolytes (DEEs) is still challenging probably due to their high protonic nature and consequent narrow potential window.2 To develop Li-ion DEEs with a wide potential window, we investigated DEEs based on lithium bis(fluorosulfonyl)amide (LiFSA) and a series of urea derivatives to clarify the correlation between compound structure and electrolyte properties. Furthermore, we examined the electrode performances of the Li4Ti5O12 (LTO) negative electrode and LiNi1/3Co1/3Mn1/3O2 (NCM) positive electrode in the DEEs.To prepare DEEs, urea derivatives, such as urea, 1-methylurea, 1,3-dimethylurea, 1,1-dimethylurea, and tetramethyl urea are mixed with LiFSA at molar ratios of 1:2 or 1:4 at room temperature. The oxidation and reduction stability was evaluated by linear sweep voltammetry (LSV) in three-electrode cells with Pt foil as the working electrode. Galvanostatic charge-discharge tests were performed in three-electrode cells with LTO or NCM working electrodes and activated carbon counter electrodes.The prepared LiFSA:urea derivative (1:4) mixtures (LiFSA:urea, LiFSA:1,3-dimethylurea, and LiFSA:tetramethylurea) became transparent liquids at room temperature. Moreover, LiFSA:1,3-dimethylurea and LiFSA:tetramethylurea were clear liquid at even in 1:2 mixtures. Using the five DEEs, we evaluated their electrolyte properties. Figure 1 shows the LSV curves of the DEEs. Among the five deep eutectic liquids, LiFSA:1,3-dimethylurea (1:2) exhibited the widest potential window of 4.49 V, showing an even wider potential window than electrolytes with non-protonic tetramethyl urea.Figure 2a displays the charge-discharge curves of LTO electrodes in the DEEs. The LiFSA:urea (1:4) electrolyte cell exhibits a large irreversible capacity, and its initial reversible capacity is 228 mAh g-1, significantly larger than the theoretical capacity. This indicates that side reactions possibly takes place in addition to the LTO charge-discharge reaction. On the other hand, the LiFSA:1,3-dimethylurea (1:2) electrolyte demonstrates stable and reversible charge-discharge for 50 cycles, with an initial discharge capacity of 179 mAh g-1, which is close to the theoretical capacity. The LiFSA:tetramethylurea cell showed lower cycle stability than the LiFSA:1,3-dimethylurea cell, possibly due to electrolyte precipitation during cycling because LiFSA:tetramethylurea (1:2) electrolyte is an almost saturated solution.Using the LiFSA:1,3-dimethylurea (1:2) DEE, we further evaluated the electrochemical performance of the NCM electrode as shown in Figure 2b. The NCM electrode showed reversible charge-discharge behavior over 10 cycles with moderate capacity of 75.7 mAh g-1. These results demonstrate the potential applicability of the DEE to 3 V-class LIBs. In the presentation, we will also discuss the optimization of LiFSA concentration to improve battery properties and the observation of the formation of surface films on the electrodes in DEEs.

A library of benzimidazole based amide and urea derivatives as supramolecular gelators – A comparative study

We present a set of alkyl chain functionalized benzimidazole based compounds containing amide and urea functional groups which were screened for their gelation behaviour. Both the sets bear similar molecular scaffolds, making them an excellent tool for determining the role of the supramolecular interactions involved in the gelation process. All the compounds were characterised using physico-chemical techniques like NMR and FT-IR. The gels were subjected to small angle neutron scattering studies (SANS), rheological studies, SEM and FT-IR. In order to rationalize the gelation behaviour, solvent parameter studies were conducted. The results show a dependence on refractive index of solvent, polarizability and dispersion interactions. The respective orientation of amide and conformation in urea based compounds were explored and studied using computational calculations and their corresponding effect on the resulting supramolecular superstructures was scrutinized. The compounds were also explored to act as chemosensor for selective detection of mercuric ions with exceptionally low LOD (limit of detection) values.