Urea Derivatives Research Articles

Design, Synthesis, and Biological Evaluation of 2-Formyl Tetrahydronaphthyridine Urea Derivatives as New Selective Covalently Reversible FGFR4 Inhibitors.

Aberrant FGF19/FGFR4 signaling is an oncogenic driver force for the development of human hepatocellular carcinoma (HCC). A series of 2-formyl tetrahydronaphthyridine urea derivatives were designed and synthesized as new covalently reversible inhibitors of FGFR4. The representative compound 9ka exhibited an IC50 value of 5.4 nM against FGFR4 and demonstrated extraordinary kinome selectivity. Compound 9ka also exhibited good oral pharmacokinetic properties with an AUC(0-t) value of 38 950.06 h·ng/mL, a T1/2 value of 3.06 h, and an oral bioavailability of 50.97%, at an oral dose of 25 mg/kg in Sprague-Dawley (SD) rats. Furthermore, compound 9ka induced significant tumor regressions in a xenograft mouse model of Hep3B2.1-7 HCC cell line without an obvious sign of toxicity upon 30 mg/kg oral administration. Compound 9ka may serve as a promising lead compound for further anticancer drug development.

Photo-on-Demand Phosgenation Reactions with Chloroform for Selective Syntheses of N-Substituted Ureas and Isocyanates.

Two new reaction processes involving the in situ oxidative photochemical conversion of CHCl3 to COCl2 allowed selective syntheses of N-substituted ureas and isocyanates from amines. (I) A CHCl3 solution containing an amine and an organic base under O2 bubbling provided the urea derivative under exposure to UV light generated from a low-pressure mercury lamp at 20–40 °C. (II) A two-step reaction involving the oxidative photodecomposition of CHCl3 at lower temperatures and subsequent sequential injections of an amine and organic base into the sample solution provided the isocyanate in high yield. The reaction processes of (I) and (II) capitalize on the solution conditions of [COCl2] < [amine] and [COCl2] > [amine], respectively, to result in 1:2 and 1:1 reactions. In general, isocyanates, especially aromatic and haloalkyl ones, readily undergo hydrolysis in the presence of an organic base. However, with the advantage of synthesizing the isocyanates in CHCl3 solvent, direct addition of monoalcohols and diols to the as-prepared sample solution containing the diisocyanate allowed the one-pot syntheses of biscarbamates and polyurethanes, respectively. The reactions developed in this study are simple, safe, and inexpensive methods of synthesizing N-substituted ureas and isocyanates, and derivatives of isocyanates such as carbamates and polyurethanes. The present new methods can replace current synthetic methods using COCl2 in both academia and industry.

Rational design and synthesis of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants

Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a–k, 8n–z, and phenyl urea 8l–m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC50 and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics.

Synthesis of novel 2-acetamide-5-phenylthio-1,3,4-thiadiazole-containing phenyl urea derivatives as potential VEGFR-2 inhibitors.

A novel series of 2-acetamide-5-phenylthio-1,3,4-thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT-29, A431, and PC3, as well as normal HDF cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4-chloro-containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl-2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR-2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three-dimensional cell culture method using the hanging drop technique.

Synthesis of diaryl urea derivatives and evaluation of their antiproliferative activities in colon adenocarcinoma

Colon cancer is one of the leading causes of cancer-related deaths today. Serious research for ideal chemotherapy continues today. In this context, newly synthesized molecules have an essential role in cancer treatment research. The effects of 5 diaryl urea derivatives synthesized within the scope of this study on the HT-29 colon cancer cell line were investigated for the first time in the literature by in-silico and in-vitro methods. Among the five compounds produced in the first stage of the study, DAU5 was found to have a cytotoxic effect on HT-29. However, it was determined that it did not show a serious cytotoxic effect on L929 (healthy fibroblast cell line) at the same doses. The efficacy of DAU5 was evaluated for expression of LC3B, an indicator of autophagy, and 8-OHdG, an indicator of oxidative stress-DNA damage. LC3B and 8-OHdG expression were lower in the DAU5 treatment group than in the control group. As a result, it was seen that DAU5, a diaryl urea derivative compound we synthesized in this study, has the potential to be a chemotherapeutic agent against colon cancer. However, our study needs to be supported by in vivo and clinical studies.

Synthesis, spectral characterization, anti-bacterial, cytotoxic evaluation and docking studies of new urea and thiourea derivatives

Isoniazid is one of the main API’s used in the combination treatment of tuberculosis recommended by the WHO. Urea and its derivatives are an important class of heterocyclic compounds that possess a wide range of therapeutic and pharmacological properties, while thiourea is an organosulphur compound in that it resembles urea except that the atom oxygen has been replaced by a Sulphur atom, but the properties of urea and thiourea are significantly different. The current work concerns the synthesis of a new class of urea and thiourea derivatives of isoniazid with various isocyanates and isothiocyanates in the presence of trimethylamine. The IR and NMR spectral data were performed for the urea and thiourea derivatives of the compounds [(3c & 3f) & (3d & 3e)], respectively. Molecular docking studies of the compounds (3a-h) revealed the binding mode involved in the active site of DNA gyrase. The synthesized urea and thiourea derivatives of isoniazid with various isocyanates and isothiocyanates were tested for their antibacterial activity against gram-positive and gram-negative bacteria using the “disc diffusion method”. Of all compounds tested, the urea derivatives (3a &3d), the thiourea derivatives (3e & 3g) showed more potent activity than the other compounds. The MTT assay revealed concentration dependent cytotoxic effects over a concentration range 25-200 µg/mL.

Selective and low-cost triterpene urea and amide derivatives of high cytotoxicity and selectivity

Phytochemicals play a vital role in drug discovery, especially for the development of anti-cancer drugs. Thereby, convenient syntheses, high cytotoxicity but also good tumor cell/non-tumor cell selectivity, are called for. An interesting group of phytochemicals is represented by pentacyclic triterpenoic acids and derivatives thereof. Herein we report the synthesis of some ursolic and oleanolic acid derived amides and urea derivatives and the results from sulforhodamine (SRB) assays to assess their cytotoxic activity for several human tumor cell lines. As a result, an ursolic acid derived benzyl urea 16 showed a rather low EC50 = 1.4 μM for A375 melanoma cell while being not cytotoxic (EC50 = 70 μM) for non-malignant fibroblasts (NIH 3T3).

Novel urea derivative-loaded PLGA nanoparticles to inhibit caries-associated Streptococcus mutans.

Caries is the most common chronic infectious disease in the human oral cavity and the existing anti-caries agents may lead to drug resistance and microecological imbalance. A novel urea derivative, 1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea, has a potentially prominent antibacterial effect on cariogenic bacterial strain Streptococcus mutans UA159. In this study, we encapsulated the water-insoluble urea derivative in poly(lactic-co-glycolic acid) (PLGA) nanoparticles, performed physicochemical characterizations and explored its potential as a caries-preventive agent. The results showed that the drug-loaded PLGA nanoparticles exhibited satisfying surface morphology, particle size, size distribution and stability. With an optimized theoretical drug loading (10%), the drug-loaded PLGA nanoparticles exhibited negligible cytotoxicity against human oral squamous cell carcinoma cells. We noticed a biphasic drug release in vitro and the rate and cumulative release was higher in an acidic environment (pH 4.5) compared to a neutral environment (pH 7.4). The drug-loaded PLGA nanoparticles significantly inhibited the growth and lactic acid production of planktonic S. mutans as well as S. mutans biofilms. Our results indicate that the novel urea derivative-loaded PLGA nanoparticles serve as a promising anti-caries agent with remarkable pharmaceutical characteristics, low cytotoxicity, and satisfying antimicrobial effect.

From amides to urea derivatives or carbamates with chemospecific C–C bond cleavage at room temperature

A general method for copper-catalyzed chemospecific C–C bond cleavage of amides to synthesize urea derivatives and carbamates at room temperature was reported.

Synthesis and Structural Studies of N-Maltosylated Aryl Thiobiurets

The derivatives of urea, thiourea and thiosemicarbazide play an important role in medicinal chemistry by influencing various pharmacological activities. The design and development of novel N-maltosides have emerged as an important class of organic compounds. A series of 1-hepta-O-benzoyl-β-D-Maltosyl- 5-aryl-2-4-thiobiurets are described in present work. By mixing hepta-O-benzoyl→D-maltosyl isocyanates with various aryl thiocarbamides, 1-hepta-O-benzoyl-β-D-maltosyl-5-aryl-2-4-thiobiurets have been synthesized. The identities of this newly synthesized 1-hepta-O-benzoyl-β-D-Maltosyl-5- aryl-2-4-thiobiurets were characterized by IR, 1H NMR and mass analyses. The compounds tested for antibacterial activity against a wide range of microorganisms, including Staphylococcus aureus, Escherichia coli, Psudomonas aeruginosa and antifungal activities against Aspergillus niger and Trichoderma. TLC confirmed the activity of these compounds.

Polymorphic solvates, ionic cocrystals and C–N bond formation to form ionic cocrystals in sulfamethoxazole and sulfathiazole-derived urea

Solvates and ionic cocrystals of two sulfa-drug based urea derivatives were studied, where also polymorphs of a solvate, thermal stability, unusual C–N bond formation and desolvation were elucidated.

Concise synthesis and biological activity evaluation of novel pyrazinyl–aryl urea derivatives against several cancer cell lines, which can especially induce T24 apoptotic and necroptotic cell death

Based on the structural modification of regorafenib, 28 pyrazinyl-aryl urea derivatives were synthesized and their in vitro antiproliferative activities were evaluated. Six compounds (5-16, 5-17, 5-18, 5-19, 5-22, and 5-23) exhibited favorable inhibitory activity against the human bladder cancer T24 cell line, and 5-23 demonstrated the strongest inhibitory activity (IC50 = 4.58 ± 0.24 μM) with high selectivity. Compound 5-23 induced apoptosis in the low concentration range (≤7.5 μM) combined with shorter incubation time (≤10 h) via the activation of caspases, while high concentrations and prolonged incubation times led to necroptotic cell death by activating the RIPK1/RIPK3/MLKL signaling pathway. Induced apoptosis and necroptosis were closely associated with intracellular reactive oxygen species generation and decreased mitochondrial membrane potential. Compared with regorafenib, 5-23 displayed improved pharmacokinetic profiles in an in vivo rat model. Molecular docking and structure-activity relationship analyses were in agreement with the biological data. Compound 5-23 may be a potent anti-bladder cancer agent and this small molecule can be considered as a promising structure for further optimization.

Docking, Synthesis and Anticancer Activity of 4-(4-(3-(4-Chloro-3-(trifluoromethyl)- phenyl)ureido)phenoxy)-N-(2-morpholinoethyl)picolinamide Derivatives

A new series of diaryl urea derivatives bearing pyridine moiety were designed, synthesized and evaluated for their biological activity. In this study, we applied the structure-based virtual screening (SBVS) on the high similar sorafenib approved drug, selected from the DrugBank database as well as on a series of derivatives, selected from the literature. Aim was to provide new potent anticancer agents. Analysis was performed using AutoDock VINA tools. Based on the ligand binding energy. Compounds will be synthesized by chlorination of pyridine acid derivative which further coupled with amine and form amide, amide further reaction with aminophenolic moiety and form ether which is react with other aromatic amine using CDI to produce final compound and these compounds characterized by IR, NMR and mass spectroscopic techniques. The synthesized derivatives have been evaluated to their anticancer activity in vitro by MTT assay using MCF-7 cell line. The anticancer activity indicates that compounds C1, C3, C6 and C9 have better anticancer activity.

Identification of Small-Molecule Urea Derivatives as Ptpc Modulators

Identification of Small-Molecule Urea Derivatives as Ptpc Modulators

Correction: Concise synthesis and biological activity evaluation of novel pyrazinyl–aryl urea derivatives against several cancer cell lines, which can especially induce T24 apoptotic and necroptotic cell death

Correction for ‘Concise synthesis and biological activity evaluation of novel pyrazinyl–aryl urea derivatives against several cancer cell lines, which can especially induce T24 apoptotic and necroptotic cell death’ by Jia-Nian Chen et al., RSC Med. Chem., 2021, DOI: 10.1039/d1md00306b.

Atom based 3D QSAR and Fingerprint based 2D QSAR of Novel Molecules as MmpL3 receptor inhibitors for Mycobacterium tuberculosis

Tuberculosis is one of the leading cause of increase in mortality rate in today’s health care scenario. Due to increase frequency of drug resistant TB it is prudent to find new targets and promising targets for anti-tubercular activity. MmpL3 (Mycobacterial Membrane Protein Large 3) is one of the most effective and promiscuous targets for development of new drug for anti-tubercular therapy due to its cross resistance inhibition property. In this study we have presented atom based 3D QSAR and finger print based 2D QSAR models to study different structural and functional groups of Adamantyl urea derivatives and their action in MmpL3 inhibitory activity which will provide us the insight for designing better and far more effective anti TB drugs.

Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile.

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

HPLC/MSn Profiling and Healing Activity of a Muco-Adhesive Formula of Salvadora persica against Acetic Acid-Induced Oral Ulcer in Rats.

Salvadora persica L. (S. persica, Siwak) is an ethnic plant that is widely used for improving oral hygiene. This study aimed to provide a phytochemical profiling of S. persica ethyl acetate fraction (SPEAF) and to evaluate the healing activity of a muco-adhesive formula of the fraction against acetic acid-induced oral ulcers in rats. HPLC-ESI-QTOF-MS-MS analysis of SPEAF resulted in the tentative identification of 56 metabolites containing fatty acids (23%), urea derivatives (10.5%) and sulphur compounds (10%), in addition to several amides, polyphenols and organic acids (6.5%, 5% and 2%, respectively). For the first time, 19 compounds were identified from S. persica. In vitro and in vivo experiments indicated that the extract is non-toxic. SPEAF exhibited superior healing activities compared to both the negative and positive control groups on days 7 and 14 of tongue ulcer induction. This was confirmed by histopathological examinations of haematoxylin and eosin-stained (H&E) and Masson’s trichrome-stained tongue sections. Moreover, SPEAF showed potent anti-inflammatory activities, as evidenced by the inhibited expression of interleukin-6 (IL-6) and tumour necrosis alpha (TNF-α). Moreover, SPEAF exhibited potent antioxidant activity, as it prevented malondialdehyde (MDA) accumulation, reduced glutathione (GSH) depletion and superoxide dismutase (SOD) exhaustion. SPEAF significantly enhanced hydroxyproline tongue content and upregulated collagen type I alpha 1 (Col1A1) mRNA expression. SPEAF also improved angiogenesis, as shown by the increased mRNA expression of the angiopoietin-1 (Ang-1). In conclusion, S. persica has a wide range of secondary metabolites and ameliorates acetic acid-induced tongue ulcers in rats. This can be attributed, at least partly, to its anti-inflammatory, antioxidant, procollagen and angiogenic activities. These findings provide support and validity for the use of S. persica as a traditional and conventional treatment for oral disorders.

Investigation of an artificial solution degradant of linagliptin: An undesired linagliptin urea derivative generates in sample preparation of linagliptin tablet treated by sonication in acetonitrile containing diluent

During the related substances testing method development for linagliptin tablet, an unknown peak was observed in HPLC chromatograms with a level exceeding the identification threshold. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, the unknown peak was rapidly identified as linagliptin urea, a solution degradant that is caused by the reaction between the API and hydrocyanic acid with sonication treatment to accelerate dissolution of the drug substance in sample preparation of linagliptin tablets, and hydrocyanic acid is a known impurity in HPLC grade acetonitrile and acetonitrile is used as part of diluent. The mechanism of the solution degradation chemistry was verified by stressing linagliptin API with trimethylsilyl cyanide (TMSCN, which can give off HCN slowly in the presence of water) treated with sonication in the sample preparation. Further investigation found that when the sonication treatment was replaced by vortex vibration in the process of the sample preparation, the RRT 1.28 species was decreased to below the level of the detection limit (0.02%). The structure of this impurity was further confirmed through the synthesis of the impurity and subsequent structure characterization by 1D and 2D NMR. Due to the presence of trace amount of HCN in HPLC grade acetonitrile, these types of solution degradation would likely occur in analysis of pharmaceutical finished products containing APIs with primary and secondary amine moieties drug product during sample preparations, particularly when sonication treatment is used to accelerate dissolution of drug substance from the finished drug product. In the GMP quality control laboratories, such events may trigger undesirable out-of-specification (OOS) events. Hence, the results of this paper can help to prevent these events from happening in the first place or resolve these OOS events in GMP laboratories.

Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer

The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.