Tetrahydropyrimidine Derivatives Research Articles

Effect of Tetrahydropyrimidine Derivatives on Protein-Nucleic Acids Interaction: TYPE II RESTRICTION ENDONUCLEASES AS A MODEL SYSTEM

2-Methyl-4-carboxy,5-hydroxy-3,4,5,6-tetrahydropyri- midine (THP(A) or hydroxyectoine) and 2-methyl,4-carboxy-3,4,5, 6-tetrahydropyrimidine (THP(B) or ectoine) are now recognized as ubiquitous bacterial osmoprotectants. To evaluate the impact of tetrahydropyrimidine derivatives (THPs) on protein-DNA interaction and on restriction-modification systems, we have examined their effect on the cleavage of plasmid DNA by 10 type II restriction endonucleases. THP(A) completely arrested the cleavage of plasmid and bacteriophage lambda DNA by EcoRI endonuclease at 0.4 mM and the oligonucleotide (d(CGCGAATTCGCG))2 at about 4.0 mM. THP(B) was 10-fold less effective than THP(A), whereas for betaine and proline, a notable inhibition was observed only at 100 mM. Similar effects of THP(A) were observed for all tested restriction endonucleases, except for SmaI and PvuII, which were inhibited only partially at 50 mM THP(A). No effect of THP(A) on the activity of DNase I, RNase A, and Taq DNA polymerase was noticed. Gel-shift assays showed that THP(A) inhibited the EcoRI-(d(CGCGAATTCGCG))2 complex formation, whereas facilitated diffusion of EcoRI along the DNA was not affected. Methylation of the carboxy group significantly decreased the activity of THPs, suggesting that their zwitterionic character is essential for the inhibition effect. Possible mechanisms of inhibition, the role of THPs in the modulation of the protein-DNA interaction, and the in vivo relevance of the observed phenomena are discussed.

Electroanalytical study of salazosulfapyridine and biseptol components at the mercury electrode

The voltammetric behaviour of two sulfonamides, salazosulfapyridine (I) and sulfamethoxazol (II), and trimethoprim (III) was investigated in aqueous medium at various pH using classical and tast DC-polarography and fast scan differential pulse voltammetry (FSDPV) at a mercury dropping and a static drop electrode. Substance I, which contains an azo group, is reduced to a hydrazine derivative. The reduction of II takes place, with difficulty, by a radical mechanism. In case of III the reduction is a two- or four-electron process (depending on the acidity) that leads to the di- or tetra-hydropyrimidine derivative as a final product. The determination of these susbstances was performed using FSDPV and adsorptive stripping voltammetry (AdSV). It is dependent on the pH-value of the medium. For concentrations less than 60 ng/ml in model samples the relative standard deviations were smaller than 5% and the detection limits calculated from regression analyses were in the range 0.2–0.5 ng/ml. The determination of I–III was performed in tablets, too; the results were in accordance with data supplied by the manufacturers.

Synthesis and characterization ofN-substituted 1,4,5,6-tetrahydropyrimidine containing functional polymers as SO2 and CO2 sorbents

Novel vinyl monomers containing 1,4,5,6-tetrahydropyrimidine were prepared by the reaction of N-substituted-1,3-diaminopropane with N,N-dimethyl-formamide dimethylacetal, which gave 1-alkyl or aryl substituted 1,4,5,6-tetrahydropyrimidines, Alkylation of the tetrahydropyrimidine derivatives by chloromethylstyrene produces the N-methyl-N′-vinyl benzyl-1,4,5,6-tetrahydropyrimidinium chloride in high yields. These monomers were readily polymerized in dimethylformamide by AIBN at 80°C. Homopolymers and soluble linear copolymers were prepared and copolymerization parameters were rationalized. Further, insoluble terpolymers prepared from these monomers, styrene and divinylbenzene were tested for the sorption of the weakly acidic gases gave excellent results. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 2411–2420, 1997

Synthesis and biological characterization of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine derivatives as selective m1 agonists.

Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Asn382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.

Reaction of 3-amino-acridine with formaldehyde in acidic medium: Influence of the stoechiometry on the reaction products

3-amino-acridine 1 reacts with formaldehyde in acidic medium to give four different compounds depending on the stoechiometry of the reaction: the dihydrooxazine derivative 2, the tetrahydropyrimidine derivative 3, the Tröger's Base analogue 4 and the acridino[3,4-j]-benzo[b][1,7]phenanthroline 5. Compounds 3, 4 and 5 could be obtained selectively by using the required amount of formaldehyde. Selective synthesis of 2 was independently realized in a three step sequence. Compounds 2, 3 and 4 in solution in 12 N HCl slowly transformed to give compound 5 as a major product.

Synthesis and radical polymerization of novel vinyl monomers having the imidazoline and pyrimidine moiety

Alkylation of the methylene bridged tetrahydropyrimidine derivatives by chloromethylstyrene produces the bridged bis(4-vinylbenzyl)-1,4,5,6,-tetrahydropyrimidinium salts in high yields. Similar procedures are used to prepare 2-imidazolinium derivatives. The quaternary salts which support functional side groups of potential biomedical interest are characterized by means of spectroscopic methods. These monomers are readily polymerized free radically in solution of dimethyl formamide at moderate temperatures. The soluble and insoluble polymers containing 2-imidazolinium and 1,4,5,6-tetrahydropyrimidinium salts were found to exhibit antibacterial activites againstEscherichia coli.

Induction of synthesis of tetrahydropyrimidine derivatives in Streptomyces strains and their effect on Escherichia coli in response to osmotic and heat stress.

The metabolic responses of a number of Streptomyces strains to osmotic and heat stress were studied by 13C nuclear magnetic resonance spectroscopy. During cell growth in a chemically defined medium supplemented with 0.5 M NaCl, tetrahydropyrimidine derivatives (THPs), 2-methyl-4-carboxy-5-hydroxy-3,4,5,6-tetrahydropyrimidine [THP(A)] and, to a lesser extent, 2-methyl-4-carboxy-3,4,5,6-tetrahydropyrimidine [THP(B)], were found to accumulate in a significant amount in all bacteria examined. In addition, when the growth temperature was shifted from 30 to 39 degrees C, the intracellular concentration of THP(A) increased significantly. Moreover, exogenously provided THP(A) or THP(B) or both reversed inhibition of Escherichia coli growth caused by osmotic stress and increased temperature. Although the ability of Streptomyces strains to tolerate high concentrations of NaCl is well known, very little is known about the osmoregulatory strategy in Streptomyces strains. Similarly, the mechanism by which compatible solutes accumulate in a variety of microorganisms is not understood. Our findings suggest the possibility of a novel mechanism of protection of DNA against salt and heat stresses involving the THPs.

Tetrahydropyrimidine derivatives inhibit binding of a Tat-like, arginine-containing peptide, to HIV TAR RNA in vitro

The ability of a small molecule, 2-methyl,4-carboxy,5-hydroxy-3,4,5,6-tetrahydropyrimidine (THP(A)), which accumulates intracellularly in various streptomyces, to inhibit the interaction of Tat peptide (R52) with TAR RNA is presented. Using gel-shift assay, we found that the inhibition constant K i of THP(A) is 50–100 nM, which is in the range of the binding constants of Tat peptide and protein. THP(A) is ∼ 10 6 times more tightly bound than the free l-arginine. The high binding affinity may be attributed to the special delocalized positive charge on the NCN group and the hydroxyl group at the 5 position of this molecule. A model for THP(A)-TAR interaction, analogous to the arginine guanidinum group-TAR interaction, is presented. The relatively high uptake of THP(A) by mammalian cells warrants in vivo Tat/TAR inhibition studies.

Untersuchungen zur Struktur und Derivatisierung von Kondensationsprodukten der 2,4-Diaminobuttersäure mit anderen Aminosäuren / Investigations Regarding Structure and Derivatization of the Condensation Products of 2,4-Diaminobutyric Acid with Other Amino Acids

Condensation of 2,4-diaminobutyric acid (Dab) with other amino acids yields tetrahydropyrimidine derivatives. Such condensation products can be constituents of the peptide chain of pyoverdins and ferribactins (the siderophors of fluorescent pseudomonads). Synthesis of several representatives and model substances allows to confirm earlier structural conclusions based mainly on NMR evidence. Apparent anomalies accompanying the derivatization for GC/MS analysis could be clarified.

ChemInform Abstract: Dichloromethane as a Reactant in the Synthesis of 1,2,3,4‐ Tetrahydropyrimidine Derivatives.

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Some New Data Concerning The Chromatographic Purity Test for Nifedipine

Abstract The analysis of different Nifedipine commercial samples indicated the presence of impurities other than the nitroso- and nitrophenylpyridine analogues of Nifedipine generally are included in the pharmacopoeia-monographs. Besides the two latter photodegradation products isonifedipine and a tetrahydropyrimidine derivative as by products of nifedipine-synthesis were identified. HPLC procedure is suitable for the separation Nifedipine and all of the four contaminants is published.

Effect of tetrahydropyrimidine derivatives on the cardiovascular system

The dp/dt values and peripheral resistance were calculated by the Wigers method [3]: P = D/MO.1322, where P is the peripheral resistance (in dynes'sec'cm-S), D is the average arterial pressure (in mm Hg), and MV is the heart output (in ml/sec); RCV-D/CF, where RCV is coronary vessel resistance, D is the average arterial pressure (in mm Hg), and CF is the coronary flow (in ml/min); RFV = D/FF, where RFV is the resistance of the femoral vessels, D is the average arterial pressure (in mm Hg), and FF is the femoral flow rate (in ml/min).

The structure and biosynthesis of new tetrahydropyrimidine derivatives in actinomycin D producer Streptomyces parvulus. Use of 13C- and 15N-labeled L-glutamate and 13C and 15N NMR spectroscopy.

Two novel compounds, 2-methyl, 4-carboxy, 5-hydroxy-3,4,5,6-tetrahydropyrimidine (THP(A] and 2-methyl, 4-carboxy-3,4,5,6-tetrahydropyrimidine (THP(B] have been identified in the pool of Streptomyces parvulus by in vivo and in vitro studies. 13C and 15N were introduced into the compounds by feeding S. parvulus with 15N- and 13C-labeled L-glutamate. High resolution 13C and 15N NMR have been applied to elucidate their structure and biosynthesis in S. parvulus. The splitting patterns and coupling constants of adjacent nitrogen-carbon molecular fragments enable us to unravel their molecular structure. Two different glutamate pools are responsible for their biosynthesis, THP(A) carbon skeleton derives from the extracellular L-[13C]glutamate, whereas THP(B) stems from D-fructose via the intracellular glutamate. During cell growth, THP(A) is synthesized and becomes the major constituent of the intracellular pool. It is consumed after THP(B) is accumulated intracellularly. The onset of THP(A) and -(B) synthesis seems correlated to the time of actinomycin D synthesis. Their high cellular concentrations during actinomycin D synthesis suggest that they may function as nitrogen storage. Other possible functions of THP molecules within the cell are discussed.

ChemInform Abstract: Synthesis and Antidepressant Properties of Novel 2‐Substituted 4,5‐Dihydro‐1H‐imidazole Derivatives.

AbstractReaction of the benzo‐fused cycloalkanones (I) with the phosphonates (II) gives the intermediates (III) which react with the diamines (IV) and (VII), yielding the imidazolines (V) and the tetrahydropyrimidine derivative (VIII).

Studies on the Pyrimidine and Related Compounds. XXXVI. Infrared Spectra of 1-(and 3)-Substituted 3, 4-dihydro-2(1H)-pyrimidinone Derivatives and Some Reactions of These Compounds

The correlation was seen between the positions of NH groups and the NH stretching pattern in infrared spectra of 1-substituted tetrahydropyrimidine derivatives and 3-substituted compounds. The measurement of the infrared spectra of these compounds in Nujol mull is useful to assign their structures. Differences in the reactivities between 1-NH and 3-NH groups were recognized by several reactions. Addition of dihydropyran to I occurred at 3-NH and the Michaeltype addition reaction proceeded giving N-1-adducts and N-1, 3-di-adducts.

Tetrahydropyrimidine derivatives as potential foliage fungicides.

Tetrahydropyrimidine derivatives as potential foliage fungicides.