Ureide Research Articles

In Vitro and In Vivo Evaluation of a Novel Water-Soluble N-Glycyl Prodrug (N-GLY-CBZ) of Carbamazepine

The synthesis and characterization of N-glycyl-carbamazepine (N-Gly-CBZ), an N-acyl urea derivative of carbamazepine (CBZ) designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the glycyl-urea bond was recently reported. The rate and extent of conversion of N-Gly-CBZ to CBZ in a whole animal model is reported here along with supporting in vitro data. Pharmacokinetic parameters were determined for N-Gly-CBZ and CBZ following IV and oral administration of N-Gly-CBZ and CBZ control to rats using a crossover design. The in vivo elimination of N-Gly-CBZ following IV administration in rats was biphasic in nature with a t(1/2) of about 1.1 min, which was very similar to the t(1/2) for appearance of CBZ. The mean value for the relative AUC ratio for CBZ from N-Gly-CBZ and CBZ from a cyclodextrin solution showed that N-Gly-CBZ delivered a (± SD) 98 ± 16% (± SD) equivalent dose of CBZ in six rats. The results of the IV dosing pharmacokinetics investigation were consistent with N-Gly-CBZ acting as a prodrug with rapid and complete conversion to CBZ in vivo. The overall absolute oral bioavailability of CBZ from N-Gly-CBZ was determined to be 41 ± 14% in three rats. The relative oral bioavailability of CBZ from N-Gly-CBZ compared to an oral CBZ control was 1.72 ± 0.54. That is, the prodrug, N-Gly-CBZ, demonstrated superior oral bioavailability of CBZ over the CBZ control, which was likely due to its greater aqueous solubility.

Molecular Docking and QSAR Studies on Substituted Acyl(thio)urea and Thiadiazolo [2,3‐α] Pyrimidine Derivatives as Potent Inhibitors of Influenza Virus Neuraminidase

Surflex-Dock was employed to dock 36 thiourea and thiadiazolo [2,3-alpha] pyrimidine derivatives into neuraminidase 1a4g. Molecular docking results showed that hydrogen bonding, electrostatic, and hydrophobic features were important factors affecting inhibitory activities of these neuraminidase inhibitors. Moreover, there was a significant correlation between the predicted binding affinity (total scores) and experimental pIC50 values with correlation coefficient r=0.846 and p<0.0001. Hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis were used to develop quantitative structure-activity relationship models. Squared multiple correlation coefficients (r2) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.899, 0.878, and 0.865, respectively. Squared cross-validated correlation coefficient (q2) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models was in turn 0.628, 0.656, and 0.509. In addition, squared multiple correlation coefficients for test set (r2test) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.558, 0.667, and 0.566, respectively. The most active sample ID 2 was taken as a template molecule to design new molecules. Based on the comparative molecular field analysis model, new compounds were designed by LeapFrog. Seven new compounds with improved binding energy and predicted activities were finally obtained.

1-Ethyl-3-(3-dimethylaminopropyl) Carbodiimide Hydrochloride (EDCI×HCl)

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI˙HCl) [¹] is a white crystalline solid with a melting point of 110-115 ˚C. EDCI˙HCl is a versatile organic reagent for many reactions. It is an effective dehydrating agent commonly used in the synthesis of amides, esters and anhydrides. [²] In these reactions, an acyl urea is a byproduct, which is water-soluble. This property of ­EDCI˙HCl makes it a very important chemical in its own class, superior to other traditional coupling reagents. It can also be used in the synthesis of oxazoles, oxadiazoles, triazoles, and guanidine compounds.

Difatty Acyl Urea from Corn Oil: Synthesis and Characterization

In this study, difatty acyl urea has been successfully synthesized from corn oil using sodium ethoxide as a catalyst. Ethyl fatty ester and glycerol were produced as by-products. In this reaction, corn oil was refluxed with urea in ethanol. The highest conversion percentage (78%) was obtained when the process was carried out for 8 hours using urea to corn oil ratio of 5.6: 1.0 at 78 degrees C. Both difatty acyl urea and ethyl fatty ester have been characterized using elemental analysis, Fourier transform infrared (FTIR) spectroscopy and (1)H nuclear magnetic resonance (NMR) technique.

Lead structures for applications in photodynamic therapy. Part 2: Synthetic studies for photo-triggered release systems of bioconjugate porphyrin photosensitizers

Photodynamic therapy (PDT) selectivity and specificity can be improved by binding the photosensitizers to target receptors. One approach is to cross-link porphyrins to a biological target receptor via the photocleavable o-nitrobenzyl linker, where a controlled released of the porphyrin can be monitored upon irradiation. The synthetic pathways involved esterification of a porphyrin–carboxylic acid and a unit containing the o-nitrobenzyl alcohol moiety and the bioconjugate. Reactions of a model porphyrin and o-nitrobenzyl alcohol using the carbonyl activating carbodiimide reagent DCC gave a stable N-acyl urea porphyrin, whereas use of EDAC (1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride) gave the desired compounds. Further studies were carried out on the attachment of carbohydrates (i.e., potentially receptor binding ligands) through such a linker to porphyrins. Preliminary irradiation experiments of such a compound show that upon UV irradiation (350 nm) for 80 min, approximately 50% of the porphyrin was cleaved to release the carboxylic acid porphyrin photosensitizer indicating the utility of such systems as photosensitizers delivery systems.

Glucokinase activators as new type 2 diabetes therapeutic agents

Background: Small molecule glucokinase activators (GKAs) represent a new strategy to treat type 2 diabetes. Glucokinase (GK) primarily exerts its effect through modulatory actions in the pancreatic β-cells and the liver. It couples insulin secretion in the pancreas with plasma glucose concentration, and improves glucose utilization in the liver, thus affecting two key aspects of glucose homeostasis. Objective and method: To review currently disclosed GKA structures and to classify them based on the key structural features. For this purpose, the data from patent disclosures and publications are used. Also, published in vitro findings on related lead GKAs are used to compare their effect on GK kinetics. Results and conclusion: The most common GKA pharmacophore consists of a center, which can be a carbon or an aromatic ring, and three attachments. Two of these are hydrophobic groups, with at least one of them being an aromatic ring. The third attachment, without exception, consists of an H-bond donor–acceptor pair in the form of a heterocyclic amine, or an N-acyl urea. These structurally diverse GKAs show important differences in their effects on the kinetic properties of GK.

Thermodynamic Characterization of Allosteric Glycogen Phosphorylase Inhibitors

Glycogen phosphorylase (GP) is a validated target for the treatment of type 2 diabetes. Here we describe highly potent GP inhibitors, AVE5688, AVE2865, and AVE9423. The first two compounds are optimized members of the acyl urea series. The latter represents a novel quinolone class of GP inhibitors, which is introduced in this study. In the enzyme assay, both inhibitor types compete with the physiological activator AMP and act synergistically with glucose. Isothermal titration calorimetry (ITC) shows that the compounds strongly bind to nonphosphorylated, inactive GP (GPb). Binding to phosphorylated, active GP (GPa) is substantially weaker, and the thermodynamic profile reflects a coupled transition to the inactive (tense) conformation. Crystal structures confirm that the three inhibitors bind to the AMP site of tense state GP. These data provide the first direct evidence that acyl urea and quinolone compounds are allosteric inhibitors that selectively bind to and stabilize the inactive conformation of the enzyme. Furthermore, ITC reveals markedly different thermodynamic contributions to inhibitor potency that can be related to the binding modes observed in the cocrystal structures. For AVE5688, which occupies only the lower part of the bifurcated AMP site, binding to GPb (Kd = 170 nM) is exclusively enthalpic (Delta H = -9.0 kcal/mol, TDelta S = 0.3 kcal/mol). The inhibitors AVE2865 (Kd = 9 nM, Delta H = -6.8 kcal/mol, TDelta S = 4.2 kcal/mol) and AVE9423 (Kd = 24 nM, Delta H = -5.9 kcal/mol, TDelta S = 4.6 kcal/mol) fully exploit the volume of the binding pocket. Their pronounced binding entropy can be attributed to the extensive displacement of solvent molecules as well as to ionic interactions with the phosphate recognition site.

Assessment of synthetic methods for the preparation of N-β- d-glucopyranosyl-N′-substituted ureas, -thioureas and related compounds

Preparation of O-peracetylated N-β- d-glucopyranosyl- N′-acyl urea derivatives resulted in the formation of anomeric mixtures under the following conditions: acylation of O-peracetylated β- d-glucopyranosyl urea by acyl chlorides in the presence of ZnCl 2 in refluxing CHCl 3; addition of O-peracetylated β- d-glucopyranosylamine to acyl isocyanates in acetonitrile at rt; addition of carboxamides to in situ prepared O-peracetylated β- d-glucopyranosyl isocyanate in refluxing toluene. Deprotection of O-peracetylated N-β- d-glucopyranosyl- N′-acyl ureas either under base (NaOMe in MeOH at or below rt) or under acid (KHSO 4 or AcCl in MeOH at rt) catalyzed transesterification conditions resulted in unavoidable partial cleavage of the N′-acyl moieties. Reaction of β- d-glucopyranosylammonium carbamate with an isocyanate, isothiocyanate or isoselenocyanate in dry pyridine at rt appears as a general method for the preparation of the corresponding β- d-glucopyranosyl ureas, -thio- and -selenoureas, respectively, inclusive N′-acyl derivatives.

Novel analogs of d- e-MAPP and B13. Part 1: Synthesis and evaluation as potential anticancer agents

A series of novel isosteric analogs of the ceramidase inhibitors, (1 S,2 R)- N-myristoylamino-phenylpropanol-1 ( d- e-MAPP) and (1 R,2 R)- N-myristoylamino-4′-nitro-phenylpropandiol-1,3 (B13), with modified targeting and physicochemical properties were designed, synthesized, and evaluated as potential anticancer agents. When MCF7 cells were treated with the analogs, results indicated that the new analogs were of equal or greater potency compared to the parent compounds. Their activity was predominantly defined by the nature of the modification of the N-acyl hydrophobic interfaces: N-acyl analogs (class A), urea analogs (class B), N-alkyl analogs (class C, lysosomotropic agents), and ω-cationic- N-acyl analogs (class D, mitochondriotropic agents). The most potent compounds belonged to either class D, the aromatic ceramidoids, or to class C, the aromatic N-alkylaminoalcohols. Representative analogs selected from this study were also evaluated by the National Cancer Institute In Vitro Anticancer Drug Discovery Screen. Again, results showed a similar class-dependent activity. In general, the active analogs were non-selectively broad spectrum and had promising activity against all cancer cell lines. However, some active analogs of the d- e-MAPP family were selective against different types of cancer. Compounds LCL85, LCL120, LCL385, LCL284, and LCL204 were identified to be promising lead compounds for therapeutic development.

FR258900, a potential anti‐hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase

FR258900 has been discovered as a novel inhibitor of human liver glycogen phosphorylase a and proved to suppress hepatic glycogen breakdown and reduce plasma glucose concentrations in diabetic mice models. To elucidate the mechanism of inhibition, we have determined the crystal structure of the cocrystallized rabbit muscle glycogen phosphorylase b-FR258900 complex and refined it to 2.2 A resolution. The structure demonstrates that the inhibitor binds at the allosteric activator site, where the physiological activator AMP binds. The contacts from FR258900 to glycogen phosphorylase are dominated by nonpolar van der Waals interactions with Gln71, Gln72, Phe196, and Val45' (from the symmetry-related subunit), and also by ionic interactions from the carboxylate groups to the three arginine residues (Arg242, Arg309, and Arg310) that form the allosteric phosphate-recognition subsite. The binding of FR258900 to the protein promotes conformational changes that stabilize an inactive T-state quaternary conformation of the enzyme. The ligand-binding mode is different from those of the potent phenoxy-phthalate and acyl urea inhibitors, previously described, illustrating the broad specificity of the allosteric site.

Three-Component, One-Pot Sequential Synthesis of N-Aryl, N‘-Alkyl Barbiturates

[reaction: see text] Condensation between N-alkyl, N'-aryl carbodiimides and malonic acid monoesters leads to a high-yield formation of N-acyl urea derivatives that could be cyclized to C-monosubstituted barbiturates by addition of a suitable base in a one-pot sequential fashion. In the presence of an electrophile, the last step gives rise to a one-pot, three-component sequential synthesis of fully substituted barbiturates.

Quantitative structure–activity relationship study of acyl ureas as inhibitors of human liver glycogen phosphorylase using least squares support vector machines

An effective quantitative structure–activity relationship (QSAR) model of a series of acyl ureas as inhibitors of human liver glycogen phosphorylase a (hlGPa), was built using a modified algorithm of support vector machine (SVM), least squares support vector machines (LS-SVMs). Each compound was depicted by structural descriptors that encode constitutional, topological, geometrical, electrostatic and quantum-chemical features. The Heuristic Method (HM) was used to search the feature space and select the structural descriptors responsible for activity. The LS-SVMs and multiple linear regression (MLR) methods were performed to build QSAR models. The LS-SVMs model gives better results with the predicted correlation coefficient (R) 0.899 and mean-square errors (MSE) 0.148 for the test set, as well as that 0.88 and 0.174 in the MLR model. The prediction results indicate that LS-SVMs is a potential method in QSAR study and can be used as a tool of drug screening.

Crosslinking by polycarbodiimides

Polycarbodiimides are effective crosslinkers for carboxyl functional polymers. The reaction between carbodiimides and carboxyl groups can follow two main courses, one leading to N-acyl urea groups, and one leading to anhydride and urea groups. In this paper, we show that both routes are relevant for crosslinking of urethane resins with polycarbodiimide crosslinkers. It was found that if the concentration of carboxyl groups is high, anhydride and urea formation is the dominant route, but if the concentration of carboxyl groups is low N-acyl urea formation is dominant.

Synthesis and evaluation of a new series of substituted acyl(thio)urea and thiadiazolo [2,3- a] pyrimidine derivatives as potent inhibitors of influenza virus neuraminidase

A series of substituted acyl(thio)urea and 2 H-1,2,4-thiadiazolo [2,3- a] pyrimidine derivatives were prepared and both of their cell culture and enzymatic activity toward influenza virus were tested. Their in vitro neuraminidase inhibitory activities were in good agreement with the corresponding activities in cultured cells and they were evaluated as potent neuraminidase inhibitors. Of the analogues that demonstrated IC 50s < 0.1 μM, 16 and 60 were further investigated as candidates with the most potential for future development. The molecular docking work of the representative compound was described to provide more insight into their mechanism of action and further rationalize the observations of this new series herein, which represents a novel class of highly potent and selective inhibitors of influenza virus.

Rapid Synthesis of N-Acyl Ureas from Their Thio Analogues Using Wet Silica-Supported Permanganate Under Solvent-Free Conditions

A rapid method to N-acyl ureas from corresponding N-acyl thioureas is described. N-coumaroyl-N′-arylthioureas, which are easily prepared by the reaction of coumarin-3-carboxylic acid chloride with potassium thiocyanate and arylamines, can be expeditiously transformed into corresponding N-acyl ureas via r.t. grinding with wet silica supported potassium permanganate under solvent-free conditions in an excellent yield.

Activation of Carboxylic Acids by Burgess Reagent: An Efficient Route to Acyl Ureas and Amides.

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Activation of carboxylic acids by Burgess reagent: an efficient route to acyl ureas and amides

Carboxylic acids upon treatment with Burgess reagent are converted to novel mixed sulfocarboxy anhydrides. Subsequent treatment of such mixed anhydrides with amines at elevated temperatures yields acyl ureas and amides. The ratio of the two products appears to be temperature controlled. The method provides a simple and convenient route to diverse acyl ureas starting from carboxylic acids and amines.

Synthesis of Imides, N‐Acyl Vinylogous Carbamates and Ureas, and Nitriles by Oxidation of Amides and Amines with Dess–Martin Periodinane

Expanding our synthetic tool repertoire: The DMP-mediated oxidation of a range of amide substrates has been demonstrated, affording the corresponding imides and N-acyl vinylogous carbamates and ureas. Likewise, an array of benzylic and related amines have also been successfully converted into their nitrile counterparts (see scheme; DMP=Dess–Martin periodinane).

Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes

Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.

Crystallographic studies on acyl ureas, a new class of inhibitors of glycogen phosphorylase

Crystallographic studies on acyl ureas, a new class of inhibitors of glycogen phosphorylase