Diaryl Urea Research Articles

Urea Anions: Simple, Fast, and Selective Catalysts for Ring-Opening Polymerizations.

Aliphatic polyesters and polycarbonates are a class of biorenewable, biocompatible, and biodegradable materials. One of the most powerful methods for accessing these materials is the ring-opening polymerization (ROP) of cyclic monomers. Here we report that the deprotonation of ureas generates a class of versatile catalysts that are simultaneously fast and selective for the living ring-opening polymerization of several common monomers, including lactide, δ-valerolactone, ε-caprolactone, a cyclic carbonate, and a cyclic phosphoester. Spanning several orders of magnitude, the reactivities of several diaryl urea anions correlated to the electron-withdrawing substituents on the aryl rings. With the appropriate urea anions, the polymerizations reached high conversions (∼90%) at room temperature within seconds (1-12 s), yielding polymers with narrow molecular weight distributions (Đ = 1.06 to 1.14). These versatile catalysts are simple to prepare, easy to use, and exhibit a range of activities that can be tuned for the optimal performance of a broad range of monomers.

Biological evaluation, docking and molecular dynamic simulation of some novel diaryl urea derivatives bearing quinoxalindione moiety.

In this study a series of diarylurea derivatives containing quinoxalindione group were biologically evaluated for their cytotoxic activities using MTT assay against MCF-7 and HepG2 cell lines. Antibacterial activities of these compounds were also evaluated by Microplate Alamar Blue Assay (MABA) against three Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram-positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast-like fungus (Candida albicans) strain. Furthermore, molecular docking was carried out to study the binding pattern of the compounds to the active site of B-RAF kinase (PDB code: 1UWH). Molecular dynamics simulation was performed on the best ligand (16e) to investigate the ligand binding dynamics in the physiological environment. Cytotoxic evaluation revealed the most prominent cytotoxicity for 6 compounds with IC50 values of 10-18 μM against two mentioned cell lines. None of the synthesized compounds showed significant antimicrobial activity. The obtained results of the molecular docking study showed that all compounds fitted in the binding site of enzyme with binding energy range of -11.22 to -12.69 kcal/mol vs sorafenib binding energy -11.74 kcal/mol as the lead compound. Molecular dynamic simulation indicated that the binding of ligand (16e) was stable in the active site of B-RAF during the simulation.

Design, Synthesis and Structure-Activity Relationships of Novel Diaryl Urea Derivatives as Potential EGFR Inhibitors

Two novel series of diaryl urea derivatives 5a–i and 13a–l were synthesized and evaluated for their cytotoxicity against H-460, HT-29, A549, and MDA-MB-231 cancer cell lines in vitro. Therein, 4-aminoquinazolinyl-diaryl urea derivatives 5a–i demonstrated significant activity, and seven of them are more active than sorafenib, with IC50 values ranging from 0.089 to 5.46 μM. Especially, compound 5a exhibited the most active potency both in cellular (IC50 = 0.15, 0.089, 0.36, and 0.75 μM, respectively) and enzymatic assay (IC50 = 56 nM against EGFR), representing a promising lead for further optimization.

Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea

Tuberculosis is a major threat for mankind and the emergence of resistance strain of Mycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for human civilization. In this study, we have synthesized different diaryl urea derivatives targeting the inhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46, 57, 58 and 86 showed MIC values ≤ 10 μg/ml against H37Rv and mc26030 strains. The best molecule with a methyl at ortho position of the first aromatic ring and prenyl group at the meta position of the second aromatic ring showed the MIC value of 5.2 μg/ml and 1 μg/ml against H37Rv and mc26030 respectively, with mammalian cytotoxicity of 163.4 μg/ml. The effective compounds showed selective inhibitory effect on mycolic acid (epoxy mycolate) biosynthesis in 14C-radiolabelled assay. At the same time these molecules also executed their potent immunomodulatory activity by up-regulation of IFN-γ and IL-12 and down-regulation of IL-10.

Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2

EGFR and VEGFR-2 are involved in pathological disorders and the progression of different kinds of tumors, the combined blockade of EGFR and VEGFR signaling pathways appears to be an attractive approach to cancer therapy. In this work, a series of 4-anilinoquinazoline derivatives containing substituted diaryl urea or glycine methyl ester moiety were designed and identified as EGFR and VEGFR-2 dual inhibitors. Compounds 19i, 19j and 19l exhibited the most potent inhibitory activities against EGFR (IC50 = 1 nM, 78 nM and 51 nM, respectively) and VEGFR-2 (IC50 = 79 nM, 14 nM and 14 nM, respectively), they showed good antiproliferative activities as well. Molecular docking established the interaction of 19i with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.

Diaryl Urea: A Privileged Structure in Anticancer Agents.

The diaryl urea is an important fragment/pharmacophore in constructing anticancer molecules due to its near-perfect binding with certain acceptors. The urea NH moiety is a favorable hydrogen bond donor, while the urea oxygen atom is regarded as an excellent acceptor. Many novel compounds have been synthesized and evaluated for their antitumor activity with the successful development of sorafenib. Moreover, this structure is used to link alkylating pharmacophores with high affinity DNA binders. In addition, the diaryl urea is present in several kinase inhibitors, such as RAF, KDR and Aurora kinases. Above all, this moiety is used in the type II inhibitors: it usually forms one or two hydrogen bonds with a conserved glutamic acid and one with the backbone amide of the aspartic acid in the DFG motif. In addition, some diaryl urea derivatives act as Hedgehog (Hh) ligands, binding and inhibiting proteins involved in the homonymous Hh signaling pathway. In this review we provide some of the methodologies adopted for the synthesis of diaryl ureas and a description of the most representative antitumor agents bearing the diaryl urea moiety, focusing on their mechanisms bound to the receptors and structure-activity relationships (SAR). An increased knowledge of these derivatives could prompt the search to find new and more potent compounds.

Selective synthesis of ureas and tetrazoles from amides controlled by experimental conditions using conventional and microwave irradiation

An efficient synthetic procedure has been achieved for selective synthesis of 1,5-disubstituted tetrazoles and diaryl ureas from secondary amides in situ in the presence of NaN3 and POCl3 as solvent, both by conventional and microwave methods. The reaction conditions were optimized to yield selectively either tetrazoles or urea derivatives from reasonable to excellent yields. These conversions have been tested and verified with various secondary amide precursors. The synthesized compounds were characterized by 1H NMR, 13C NMR and ESI-MS spectroscopic techniques.

Discovery of novel diaryl urea derivatives bearing a triazole moiety as potential antitumor agents

Herein, we report a novel series of diaryl urea derivatives bearing a triazole moiety, from which potent antitumor agents have been identified. With a modified triazole, most compounds showed high level activity in both cellular and enzymatic assays, accompanied with a suitable ClogD7.4 value. The most active compound, 13i, effectively suppressed proliferation of HT-29, H460 and MDA-MB-231 cancer cells, with IC50 values of 0.90, 0.85 and 1.54 μM, respectively. Compound 13i also exhibited significant inhibition of tyrosine kinases including c-Kit, RET and FLT3. Furthermore, compound 13i could obviously induce apoptosis of HT-29 cells in a concentration-dependent manner. The study of structure-activity relationships also revealed that a hydrophilic tail at the 4-position of the triazole was crucial for high activity of the compound.

Calix[4]arenes containing a ureido functionality on the lower rim as highly efficient receptors for anion recognition

Calix[4]arenes bearing diaryl urea moieties with electron-withdrawing substituents on both sides can bind selected anions (AcO−, BzO−, H2PO4−) even in highly competitive solvents such as DMSO-d6.

A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors.

In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600EB-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site.

Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors

Inhibition of receptor tyrosine kinases (RTKs) continued to be a successful approach for the treatment of many types of human cancers and many potent small molecules kinase inhibitors have been discovered the last decade. In the present study, we describe the synthesis of thienopyrimidine derivatives and their pharmacological evaluation against nine kinases (EGFR, PDGFR-ß, c-Kit, c-Met, Src, Raf, VEGFR-1, -2 and -3). Most of the synthesized compounds showed from moderate to potent activities against c-Kit with IC50 values in the nanomolar range. Among them, 4-anilino(urea)thienopyrimidine analogs showed selectivity and potent c-Kit inhibition with IC50 values less than 6nM. Docking simulation was performed for the most promising compound 9 into the c-Kit active site to determine the potential binding mode. This study reveal that the 4-anilino(urea)thienopyrimidine is an interesting scaffold to design novel potent and selective c-Kit inhibitors which may make promising candidates for cancers where c-Kit receptors are overexpressed.

Design, Synthesis and Biological Evaluation of Novel Substituted N,N'-Diaryl ureas as Potent p38 Inhibitors.

A novel series of substituted N,N′-diaryl ureas that act as p38α inhibitors have been designed and synthesized based on two key residues (Gly110 and Thr106) that are different in p38α MAPK than in other kinases. Preliminary biological evaluation indicated that most compounds possessed good p38α inhibitory potencies. Among these compounds, 9g appeared to be the most powerful and is the main compound that we will study in the future.

Design, synthesis and antitumor activity of novel 6,7-dimethoxyquinazoline derivatives containing diaryl urea moiety

A series of 6,7-dimethoxyquinazoline derivatives connected by diaryl urea scaffolds was designed, synthesized and their in vitro antitumor activities were evaluated. Most of them showed an excellent potency against the four tested cancer cell lines as compared with sorafenib. Particularly, a promising compound 20 was identified, which showed the most potent antitumor activities with IC50 values of 0.08, 0.09, 0.16 and 0.19 µmol/L against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The structure-activity relationship(SAR) analysis indicated that compounds with dimethylamino or diethylamino group at the C4 position of 6,7-dimethoxyquinazoline moiety exhibited superior activities than compounds bearing morpholino groups.

An efficient and high-yielding protocol for the production of Regorafenib via a new synthetic strategy

An improved, high-yielding, and efficient protocol for the production of Regorafenib (1), a novel diaryl urea inhibitor of multiple protein kinases, is described. The highlight of the process chemistry design and development is an optimization of the route for preparing key intermediate 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (7) by O-alkylation, nitration and reduction reactions. The developed process avoids using column chromatography to isolate 7, reduces the reaction requirements and is cost-saving, resulting in an increased overall yield from 35.0 to 57.0 % and purity from 97.0 to 99.8 %.

Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents

Two series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed, synthesized and evaluated for their biological activity. The preliminary investigation showed that most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In particular, the most promising compound 29a showed the most potent antitumor activities with IC50 values of 0.081 μM, 0.058 μM, 0.18 μM, and 0.23 μM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The SAR analyses indicated that compounds with mono-halogen groups at 4-position on the terminal phenyl ring were more active than those with double-halogen groups or methyl groups. In addition, the introduction of chlorine atoms into 6,7-position of thieno[3,2-d]pyrimidine moiety led to a slight decline, but more selective activity against H460 and HT-29 cell lines.

4-Benzothiazole-7-hydroxyindolinyl diaryl ureas are potent P2Y1 antagonists with favorable pharmacokinetics: low clearance and small volume of distribution.

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y1 antagonists may have lower bleeding liabilities than P2Y12 antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7-hydroxyindolinyl diaryl ureas. When dosed orally, 4-trifluoromethyl-7-hydroxy-3,3-dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF3 group in 4 was then transformed to various groups via a novel one-step synthesis, yielding a series of potent P2Y1 antagonists. Among them, the 4-benzothiazole-substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.

2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists

Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5μM with 10μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.

Design, synthesis and evaluation of novel diaryl urea derivatives as potential antitumor agents

A novel series of diaryl ureas containing different linker groups were designed and synthesized. Their in vitro antitumor activity against MX-1, A375, HepG2, Ketr3 and HT-29 was evaluated using the standard MTT assay. Compounds having a rigid linker group such as vinyl, ethynyl and phenyl showed significant inhibitory activity against a variety of cancer cell lines. Specifically, compound 23 with a phenyl linker group demonstrated broad-spectrum antitumor activity with IC50 values of 5.17–6.46 μM against five tested tumor cell lines. Compound 23 is more potent than reference drug sorafenib (8.27–15.2 μM), representing a promising lead for further optimization.

Identification of 1-{2-[4-chloro-1′-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4′-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y1 antagonist as an antiplatelet agent

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.

ChemInform Abstract: Synthesis of New Pyrimidinylaminobenzene Derivatives and Their Antiproliferative Activities Against Melanoma Cell Line.

AbstractDiaryl amide (I) and diaryl urea (II) derivatives possessing a pyrimidinylaminobenzene scaffold are synthesized and some of them are screened for their in vitro antiproliferative activities against A375P human melanoma cell line.