Cyclic Urea Research Articles

Structural studies of cyclic ureas: 3. Enthalpy of formation of barbital

A thermochemical and thermophysical study has been carried out for crystalline barbital [5,5′-diethylbarbituric acid]. The thermochemical study was made by static bomb combustion calorimetry, from which the standard ( p ∘ = 0.1 MPa ) molar enthalpy of formation of the crystalline barbital, at T = 298.15 K, was derived as −(753.0 ± 1.8) kJ · mol −1. The thermophysical study was made by differential scanning calorimetry over the temperature interval (265 to 470) K. A solid–solid phase transition was found at T = 413.3 K. The vapour pressures of the crystalline barbital were measured at several temperatures between T = (355 and 377) K, by the Knudsen mass-loss effusion technique, from which the standard molar enthalpy of sublimation, at T = 298.15 K was derived as (117.3 ± 0.6) kJ · mol −1. The combination of the experimental results yielded the standard molar enthalpy of formation of barbital in the gaseous phase, at T = 298.15 K, as −(635.8 ± 1.9) kJ · mol −1. This value is compared and discussed with our theoretical calculations by several methods (Gaussian- n theories G2 and G3, complete basis set CBS-QB3, density functional B3P86 and B3LYP) by means of atomization and isodesmic reaction schemes.

Molecular recognition by artificial enzymes: Cyclic urea mimetics of alpha chymotrypsin

Molecular mechanics calculations are used to investigate the degree of structural preorganization and electrostatic complementarity for substrate binding exhibited by the cyclic urea mimetics of alpha chymotrypsin. The Amber molecular mechanics force field is used to calculate the “native” and complexed structures of a cation-binding mimetic precursor compound, as well as the structure of the cyclic urea compound containing an m-methylenehydroxy phenyl substituent, which mimics the action of the serine 195 residue in alpha chymotrypsin. Comparison of the native and complexed structures of the cation-binding precursor compound shows that this cyclic urea compound undergoes little conformational change upon substrate binding. Addition of the m-methylenehydroxy phenyl group is found to have little effect on the conformation of the macrocycle. Molecular electrostatic potential maps calculated in planes parallel to the average plane of the oxygen atoms of the macrocycle indicate that the orientation of the oxygen atoms directs the cationic end of the substrate into the electron-rich center of the macrocycle. The m-methylenehydroxy phenyl substituent affects the electrostatic potential pattern by pulling some of the electron density away from the center of the macrocycle. Similar structural and electrostatic comparisons are made with models of the active site of alpha chymotrypsin taken from the X-ray data.

ChemInform Abstract: Novel Synthesis of N,N′‐Dialkyl Cyclic Ureas Using Sulfur‐Assisted Carbonylation and Oxidation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Intermolecular Hydroamination of Ethylene and 1-Alkenes with Cyclic Ureas Catalyzed by Achiral and Chiral Gold(I) Complexes

Reaction of 1-methyl-imidazolidin-2-one (1) with 1-octene (10 equiv) catalyzed by a 1:1 mixture of (2b)AuCl [2b = 2-di-tert-butylphosphino-1,1'-binaphthyl] and AgSbF(6) in dioxane at 100 degrees C for 24 h led to isolation of 1-methyl-3-(octan-2-yl)imidazolidin-2-one in 96% yield as a single regioisomer. A range of unactivated 1-alkenes and ethylene underwent gold(I)-catalyzed intermolecular hydroamination at or below 100 degrees C in excellent yield with high regioselectivity. Reaction of 1-alkenes with substituted imidazolidin-2-ones catalyzed by chiral bis(gold) phosphine complexes led to enantioselective intermolecular hydroamination with up to 78% ee.

Novel Quantitative Structure-Activity Studies of HIV-1 Protease Inhibitors of the Cyclic Urea Type Using Descriptors Derived from Molecular Dynamics and Molecular Orbital Calculations

Human immunodeficiency virus type 1 protease (HIV-1 PR) is an essential enzyme for the replication cycle of HIV-1. HIV-1 PR inhibitors have been extensively investigated as anti-AIDS drugs. For developments of HIV-1 PR inhibitors more promising than those utilized at the moment, the construction of reliable QSAR models that can elucidate the inhibitory mechanism as consistently as possible should be one of the most significant issues. Garg, Kurup, and their groups published comprehensive QSAR studies using past structure-activity data for HIV-1 PR inhibitors, and summarized some physicochemical structural factors of inhibitors that govern variations in the inhibitory activity for various structural types. There seem to exist much to be clarified further, especially for effects of electronic structure of inhibitors. It is also expected to incorporate structural and physicochemical information about the enzyme protein into the QSAR model. In this article, we reviewed our own QSAR study on a series of cyclic urea inhibitors with newly proposed QSAR descriptors. We performed molecular dynamics simulations of HIV-1 PR-inhibitor complexes to provide the accurate geometry to the fragment molecular orbital (FMO) calculations as well as to the estimation of an accessible surface area descriptor for inhibitors and amino acid residues. With the FMO procedure to cover full electronic feature of three-dimensional structure of protease-inhibitor complexes, we derived electronic descriptors for inhibitors and amino acid residues. The successful results are believed to provide a new insight into QSAR and understanding of binding mechanism of inhibitors with HIV-1 PR at atomic and electronic levels.

Synthesis of new camptothecin analogs with improved antitumor activities

Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.

Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings

Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl-sultam cappings were selected for further SAR development. Modification at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall profile in potency and PK profile: excellent K i ∗ of 5.3 nM and activity in replicon (EC 90) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 μM h.

Novel synthesis of N,N′‐dialkyl cyclic ureas using sulfur‐assisted carbonylation and oxidation

AbstractThe first example of cyclic urea synthesis from secondary amines by the use of sulfur‐assisted carbonylation and oxidation was established. By combined sulfur‐assisted carbonylation of secondary α,ω‐diamines under an ambient pressure of carbon monoxide at 20°C with oxidation by molecular oxygen (0.1 MPa, 20°C), a facile synthetic method for N,N′‐dialkyl cyclic ureas including 1,3‐dimethyl‐2‐imidazolidinone was developed. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:64–68, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20508

Properties of Waterborne Polyurethane Adhesives: Effect of Chain Extender and Polyol Content

A series of waterborne polyurethane (WBPU) adhesives were prepared with various ratios of polyol, poly(tetramethylene oxide glycol) (PTMG), and chain extender, ethylene diamine (EDA), at a fixed content of diisocyanate, 4,4-dicyclohexylmethane diisocyanate (H12MDI) and hydrophilic agent, 2,2-dimethylol propionic acid (DMPA). WBPU adhesives were characterized by IR and 1H-NMR spectroscopies, X-ray diffraction (XRD) and gel permeation chromatography (GPC). It was found that the extent of hydrogen bonds between hard–hard segment (i.e., hydrogen bonds between the NH and carbonyl groups) increased with increasing chain extender content (decreasing polyol content). Moreover, the disordered hydrogen bond of carbonyl group (hydrogen bond of urethane groups in the interfacial region) increased with increasing chain extender content (decreasing polyol content). The cyclic urea and allophanate group, which are attributed to the side reaction and cross-linking reaction, respectively, were found above a molar ratio 0.17 of chain extender to diisocyanate. The adhesive strength was maximum with 0.95 wt% and 63.10 wt% chain extender and soft segment (PTMG), respectively (H2 sample) at room temperature for the WBPU adhesive. However, with increasing application temperature the adhesive strength decreased for all samples.

QSAR Modeling of HIV‐1 Protease Inhibition on Six‐ and Seven‐membered Cyclic Ureas

AbstractA Quantitative Structure–Activity Relationship (QSAR) analysis was carried out on a dataset of 135 six‐ and seven‐membered cyclic urea‐based Human Immunodeficiency Virus Type 1 (HIV‐1) protease inhibitors. Using a larger and more diverse dataset than previous studies reported in literature allowed a more comprehensive analysis. A large set of molecular descriptors, calculated with CODESSA PRO, was used in Multiple Linear Regression (MLR) analysis and the resulting four‐parameter model enabled accurate prediction of inhibitory activity for the structures both in training and external validation sets. The squared correlation coefficient for both sets combined is 0.824. Descriptors in the final model characterize the size and shape of the molecule and its charge distribution. Non‐linear relationships between the HIV‐1 protease inhibition activity and some descriptors are significant and described with simple non‐linear transformations. After the model development, another dataset of 45 compounds was collected and additional external validation was performed.

Hydrogen-Bonded Networks Constructed with 5-Nitrobarbiturate

A series of nine compounds including tetra-alkylammonium 5-nitrobarbiturates and their urea and thiourea adducts have been obtained and characterized by single crystal X-ray analysis. The hydrogen-bonded networks in these compounds feature three different kinds of dimeric 5-nitrobarbiturate linkages (para-to-para, ortho-to-ortho and para-to-ortho), which are stabilized by formation of the cyclic urea dimer supramolecular synthon. In four thiourea complexes, the 5-nitrobarbiturate dimer is the dominant building unit, while in the urea complexes no such dimer is present due to the comparable hydrogen bonding capability of urea and 5-nitrobarbiturate. The main connection modes in the urea complexes are the traditional head-to-tail and shoulder-to-shoulder types, as well as a specific nitro-urea hydrogen motif. In [2(CH3)4N+]·[2(C4H2N3O5)−]·(NH2)2CS (3), the thiourea molecule uses its syn and anti hydrogen atoms as a clamp and strut, respectively, to connect two nearly parallel hydrogen-bonded 5-nitrobarbitur...

Syntheses of aza and fluorine-substituted 3-(piperidin-4-yl)-4,5-dihydro-1 H-benzo[ d][1,3]diazepin-2(3 H)-ones

A practical and expedient synthesis of the title compounds is described. They were prepared by Stille reaction of nitro halopyridines 4 or nitro fluro-halobenzenes 10, followed by Michael addition of tert-butyl 4-aminopiperidine-1-carboxylate to the resulting activated vinyl compounds 5 and 11, hydrogenation (–NO 2→–NH 2), cyclic urea formation, Boc removal, and HCl salt formation. However, N3 and F1 analogs could not be made by this general strategy. Activated vinyl compounds 5a and 5d when reacted with tert-butyl 4-aminopiperidine-1-carboxylate did not stop at the desired Michael addition stage; but proceeded to produce azaindolines 8 and 9. Michael addition did not occur to compound 11d; instead, the fluorine atom was displaced.

Prediction and analysis of binding affinities for chemically diverse HIV‐1 PR inhibitors by the modified SAFE_p approach

One of the biggest challenges in the "in silico" screening of enzyme ligands is to have a protocol that could predict the ligand binding free energies. In our group we have developed a very simple screening function (referred to as solvent accessibility free energy of binding predictor, SAFE_p) which we have applied previously to the study of peptidic HIV-1 protease (HIV-1 PR) inhibitors and later to cyclic urea type HIV-1 PR inhibitors. In this work, we have extended the SAFE_p protocol to a chemically diverse set of HIV-1 PR inhibitors with binding constants that differ by several orders of magnitude. The resulting function is able to reproduce the ranking and in many cases the value of the inhibitor binding affinities for the HIV-1 PR, with accuracy comparable with that of costlier protocols. We also demonstrate that the binding pocket SAFE_p analysis can contribute to the understanding of the physical forces that participate in ligand binding. The analysis tools afforded by our protocol have allowed us to identify an induced fit phenomena mediated by the inhibitor and have demonstrated that larger fragments do not necessarily contribute the most to the binding free energy, an outcome partially brought about by the substantial role the desolvation penalty plays in the energetics of binding. Finally, we have revisited the effect of the Asp dyad protonation state on the predicted binding affinities.

Interactions of different inhibitors with active‐site aspartyl residues of HIV‐1 protease and possible relevance to pepsin

The importance of the active site region aspartyl residues 25 and 29 of the mature HIV-1 protease (PR) for the binding of five clinical and three experimental protease inhibitors [symmetric cyclic urea inhibitor DMP323, nonhydrolyzable substrate analog (RPB) and the generic aspartic protease inhibitor acetyl-pepstatin (Ac-PEP)] was assessed by differential scanning calorimetry. DeltaT(m) values, defined as the difference in T(m) for a given protein in the presence and absence of inhibitor, for PR with DRV, ATV, SQV, RTV, APV, DMP323, RPB, and Ac-PEP are 22.4, 20.8, 19.3, 15.6, 14.3, 14.7, 8.7, and 6.5 degrees C, respectively. Binding of APV and Ac-PEP is most sensitive to the D25N mutation, as shown by DeltaT(m) ratios [DeltaT(m)(PR)/DeltaT(m)(PR(D25N))] of 35.8 and 16.3, respectively, whereas binding of DMP323 and RPB (DeltaT(m) ratios of 1-2) is least affected. Binding of the substrate-like inhibitors RPB and Ac-PEP is nearly abolished (DeltaT(m)(PR)/DeltaT(m)(PR(D29N)) > or = 44) by the D29N mutation, whereas this mutation only moderately affects binding of the smaller inhibitors (DeltaT(m) ratios of 1.4-2.2). Of the nine FDA-approved clinical HIV-1 protease inhibitors screened, APV, RTV, and DRV competitively inhibit porcine pepsin with K(i) values of 0.3, 0.6, and 2.14 microM, respectively. DSC results were consistent with this relatively weak binding of APV (DeltaT(m) 2.7 degrees C) compared with the tight binding of Ac-PEP (DeltaT(m) > or = 17 degrees C). Comparison of superimposed structures of the PR/APV complex with those of PR/Ac-PEP and pepsin/pepstatin A complexes suggests a role for Asp215, Asp32, and Ser219 in pepsin, equivalent to Asp25, Asp25', and Asp29 in PR in the binding and stabilization of the pepsin/APV complex.

ChemInform Abstract: First Palladium‐ and Nickel‐Catalyzed Oxidative Diamination of Alkenes: Cyclic Urea, Sulfamide, and Guanidine Building Blocks

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

D 2O–H 2O solvent isotope effects on the thermodynamic properties of 1,3-dimethyl-2-imidazolidinone hydration between 288.15 and 318.15 K

The enthalpies of solution of 1,3-dimethyl-2-imidazolidinone or N, N′-dimethylethyleneurea in H 2O and D 2O were measured at 288.15, 298.15, 308.15, and 318.15 K. Standard enthalpies, heat capacities and entropies of solution (hydration), along with D 2O–H 2O solvent isotope effects on the quantities in question, were computed. The enthalpies of the solute dissolution as well as corresponding solvent isotope effects were found to be negative and decreasing in magnitude with increasing temperature. It was concluded that, in spite of forming the “heterocomponent” H(D)-bonds in aqueous solutions of the cyclic methyl-substituted urea derivative studied, hydrophobic hydration is the predominant type of the solute hydration and it is enhanced in D 2O.

Discovery of a novel, potent and orally active series of γ-lactams as selective NK 1 antagonists

Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious γ-lactam series of selective NK 1 antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.

Structural studies of cyclic ureas: 2. Enthalpy of formation of parabanic acid

Thermophysical and thermochemical studies have been carried out for crystalline parabanic acid. The thermophysical study was made by differential scanning calorimetry, DSC, over the temperature interval between T = (263 and 473) K. Two phase transitions were found: at T = (392.3 ± 1.6) K with the enthalpy of transition of (2.1 ± 0.4) kJ · mol −1 and at T = (509.8 ± 1.5) K, when the compound was scanned to its fusion temperature. The standard ( p ∘ = 0.1 MPa) molar enthalpy of formation, at T = 298.15 K, for crystalline parabanic acid was determined using static-bomb combustion calorimetry as −(590.2 ± 1.0) kJ · mol −1. The standard molar enthalpy of sublimation, at T = 298.15 K, was derived from the variation of their vapour pressures, measured by the Knudsen-effusion method, with the temperature. These two thermochemical parameters yielded the standard molar enthalpy of formation in the gaseous phase, at T = 298.15 K, as −(470.8 ± 1.2) kJ · mol −1.

Interaction of HIV-1 aspartic protease with its inhibitor, by molecular dynamics andab initiofragment molecular orbital method

For the three complex crystal structures of HIV-1 aspartic protease (an enzyme of AIDS) with its inhibitor in the Protein Data Bank, molecular dynamics of the generalized Born surface area and the ab initio fragment molecular orbital of an ABINIT-MP calculation was performed to obtain the binding free energy, the molecular orbital energy, the interaction energy of residues with an inhibitor and the charge transfer at the active site. The inhibitors are five symmetric cyclic ureas, of which three were modelled, and an asymmetric dipeptide. The interaction energy of the inhibitor at the active sites of aspartic acid is as great as 50 kcal mol(-1), coinciding with a tetrahedral transition state. For the inhibitor with a higher affinity, charge was transferred to the inhibitor from the active site. The difference in symmetry of the inhibitor was not evident. Binding free energy corresponds to the experimental value of the binding constant, while molecular orbital energy does not always, which is considered to be an entropy effect.

Synthesis, SAR, and X-ray structure of human BACE-1 inhibitors with cyclic urea derivatives

We describe synthesis and evaluation of a series of cyclic urea derivatives with hydroxylethylamine isostere. Modification of P3, P1, and P2' and combination of SAR display a >100-fold increase in potency with good cellular activity (IC(50)=0.15microM) relative to the previously reported compound 3.