Synthesis of 5-(4-substituted benzyl)-2,4-diaminoquinazolines as inhibitors of candida albicans dihydrofolate reductase

Several 5-(4-substituted benzyl)-2,4-diaminoquinazolines were prepared as potentially selective inhibitors of Candida albicans dihydrofolate reductase. These compounds were synthesized by a novel route, which included as a key step the displacement of a fluoro group in 2,6-difluorobenzonitrile by the anions of ethyl or methyl 4-substituted phenylacetates. The resultant diarylacetates were saponified and decarboxylated to the 2-fluoro-6-(4-substituted phenyl)benzonitriles. Ring closure of these benzonitriles with guanidine carbonate gave the 5-(4-substituted benzyl)-2,4-diaminoquinazolines.     

Selectivity analysis of 5-(arylthio)-2,4-diaminoquinazolines as inhibitors of Candida albicans dihydrofolate reductase by molecular dynamics simulations

A series of 5-(arylthio)-2,4-diaminoquinazolines are known as selective inhibitors of dihydrofolate reductase (DHFR) from Candida albicans. We have performed docking and molecular dynamics simulations of these inhibitors with C. albicans and human DHFR to understand the basis for selectivity of these agents. Study was performed on a selected set of 10 compounds with variation in structure and activity. Molecular dynamics simulations were performed at 300 K for 45 ps with equilibration for 10 ps. Trajectory data was analyzed on the basis of hydrogen bond interactions, energy of binding and conformational energy difference. The results indicate that hydrogen bonds formed between the compound and the active site residues are responsible for inhibition and higher potency. The selectivity index, i.e the ratio of I₅₀ against human DHFR to I₅₀ against fungal DHFR, is mainly determined by the conformation adapted by the compounds within the active site of two enzymes. Since the human DHFR active site is rigid, the compound is trapped in a higher energy conformation. This energy difference between the two conformations E mainly governs the selectivity against fungal DHFR. The information generated from this analysis of potency and selectivity should be useful for further work in the area of antifungal research.     

Reactions of aromatic and heteroaromatic compounds bearing electron-acceptor substituents

The specificity of the nitration and bromination of dimethyl(2-thienyl)sulfonium salts was studied. It was found that, in contrast to methyl 2-thienyl sulfide, which reacts to form 3- and 5-substituted derivatives, the sulfonium salts give a mixture of 4- and 5-substituted products. Total suppression of the activity of the position under the influence of the sulfonium grouping is not observed.See [1] for communication VIII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 310–314, March, 1972.     

Reactions of aromatic and heteroaromatic compounds bearing electron-acceptor substituents

Dimethyl(2-thienyl)sulfonium salts were synthesized for the first time. The corresponding triiodomercurates were obtained by the reaction of methyl 2-thienyl sulfide or its substituted derivatives with methyl iodide and mercuric iodide. Sulfonium perchlorates are formed as a result of the reaction of thiophene compounds with dimethyl sulfoxide in the presence of POCl₃ and perchloric acid. The HgI₃ ^– anion was replaced by NO₃ ^– by means of an anion-exchange resin. The methods for the dimethylation of sulfonium salts with conversion of them to the corresponding sulfides were studied; the conditions for obtaining quantitative yields from these reactions by means of an anion exchange resin in the acetate form were found.See [1] for communication VII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 165–168, February, 1972.     

Reactions of aromatic and heteroaromatic compounds bearing electron-acceptor substituents

Complexing with aluminum chloride can change the specificity of the bromination of furfural in such a way that the major product becomes 4-bromofurfural. Consequently, as in the thiophene series, reinforcement of the electron-acceptor capacity of the carbonyl group by means of the complexing deactivates the free 5 position so much that the 4 position of the furan ring becomes the most active.See [1] for communication X.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 597–600, May, 1972.     

Synthesis of aromatic isothiourea compounds containing substituents in the benzene ring

Conclusions Arylation of thiourea with aryldiazonium borofluorides containing substituents in the benzene ring yielded isothiourea compounds containing halogen atoms, the nitro group, and the isothiourea group in the ring.Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 8, pp. 1910–1913, August, 1968.     

Efficient solid-phase synthesis of quinazoline-2,4-diones with various substituents on aromatic rings

We have developed a method for the solid-phase synthesis of quinazoline-2,4-diones with various substituents on the aromatic ring. Although there have been numerous reports of the solid-phase synthesis of quinazoline-2,4-diones, they were not applicable to the synthesis of the quinazoline-2,4-diones with electron-withdrawing substituents on the aromatic ring. Considering the poor nucleophilicity of the amino group of anthranilic acids, coupling of anthranilic acids to solid-supported amines was investigated without protecting the amino group. Various anthranilamides were prepared using anthranilic acids with electron-withdrawing substituents because a wide range of anthranilic acids are commercially available. These anthranilamides were successfully cyclized with carbonyldiimidazole to give quinazoline-2,4-diones with high purity.     

Molecular orbital study of the ring nitrogen basicity of various dihydrofolate reductase inhibitors

We present molecular orbital (CNDO /2) calculations on the key fragments of different dihydrofolate reductase inhibitors. Distance geometry analysis, physicochemical parameter dependent QSAR , and molecular shape analysis raised some questions regarding the basicity of the ring nitrogen (N1) in these inhibitors and the effect of the various substituents on the basicity. We show that the ring nitrogen N1 of methotrexate has a considerably higher tendency to be protonated compared to that of folic acid. However, not all 2,4-diamino inhibitors are equally basic. Even 2-amino-4-hydroxyquinazoline is sufficiently basic to be protonated, but not the 2,4-diamino-5-sulfonyl derivatives. The pyrimidinium ion seems to be highly solvated, since in spite of its high protonation energy it is strongly basic. Triazines were found to be the most basic of all the classes studied.     

Synthesis of steroidal saponins bearing an aromatic E ring

A facile synthetic approach toward the steroidal saponins bearing an aromatic E ring was developed starting from the readily available spirostan saponin.     

Influence of the aromatic ring substituents on phase equilibria of vanillins in binary systems with CO2

Solid–liquid phase transitions of vanillin, ethylvanillin, o-vanillin and o-ethylvanillin in presence of compressed CO₂ were determined with the modified capillary method. Furthermore, the solubilities of the above mentioned vanillins in supercritical CO₂ were measured at 313.2, 333.2 and 353.2 K and in the pressure range 8–30 MPa using a static–analytic method. The experimental equilibrium solubility data have been fitted to the Peng–Robinson equation in combination with two parameter van der Waals mixing rules and binary parameters were determined from the best fit. Results showed that the phase equilibria of vanillins in dense CO₂ are influenced by the position of the hydroxyl group bound to the aromatic ring. Under the pressure of CO₂ the melting point depression and also the solubility of both o-vanillins was higher than those of p-vanillins. Oppositely, the alchoxy group (methoxy or ethoxy) showed no significant influence on the solubility of vanillins.     

Inhibition of human placenta aldose reductase by tannic acid

Tannic acid was found to be a highly potent inhibitor of human placenta aldose reductase. The most potent inhibitory component of the tannic acid was isolated and identified as penta-O-galloyl-beta-D-glucose, which showed an IC50 value of 70 nM. The inhibition by the gallotannin was reversible and of mixed type with respect to DL-glyceraldehyde as the varied substrate.     

高效毛细管电泳法测定二氢叶酸还原酶活力的研究

通过胶束电动毛细管电泳法研究分离二氢叶酸还原酶体系中二氢叶酸、四氢叶酸、 NADP、 NADPH和酶5种组分,在含0.002%Brij-35的pH 9.18 50 mmol/L 的硼砂缓冲溶液中,5种组分在18min内得到基线分离.通过对其产物四氢叶酸峰面积的定量测定,计算出二氢叶酸还原酶的米氏常数,建立了毛细管电泳法对二氢叶酸还原酶活力的测定方法.     

Radioenzymatic determination of subpicomole quantities of folic acid and dihydrofolate based on differential reduction by dihydrofolate reductase

A sensitive method for the determination of folic acid in the presence of dihydrofolate has been described. The analysis is based on the difference in reactivity of dihydrofolate reductase toward folic acid and dihydrofolate. The tetrahydrofolate formed was measured by stoichiometric entrapment into a covalent, ternary complex with thymidylate synthase and [³H]fluorodeoxyuridylate. Differentiation between folic acid and dihydrofolate was accomplished by the use of two levels of dihydrofolate reductase. Recovery of both folic acid and dihydrofolate was quantitative in the range of 0.1 to 2.0 pmol.     

Synthesis of 2,4-diaminoquinazolines and tricyclic quinazolines by cascade reductive cyclization of methyl N-cyano-2-nitrobenzimidates

An efficient route to N(4)-substituted 2,4-diaminoquinazolines has been developed by employing tandem condensation of cyanoimidate-amine and reductive cyclization in iron-HCl system. This method is tolerant of a following intramolecular N-alkylation and produces two fused heterocycles in a one-pot procedure. This protocol is a facile two-step synthesis of tricyclic quinazolines, which is effected by potent cyanoimidation and tandem reductive cyclization from 2-nitrobenzaldehydes. Moreover, the forming process of tricyclic quinazolines has been investigated from the ring-opening/ring-closing cascade point of view. It is found that the preparation of tricyclic quinazolinones in good yields relies on the selective hydrolysis of tricyclic quinazolines in base or acid system.     

Transmission of the electronic effects of substituents by the thiophene ring

The shifts in the frequencies of the stretching vibrations of the hydroxyl group of phenol and pentachlorophenol that arise during the formation of hydrogen bonds with a number of substituted acetophenones and 2-acetylthiophenes, 2-acetylfuran, and 2-acetylselenophene and the frequencies of the stretching vibrations of the carbonyl group of the latter were subjected to a correlation analysis (with the Hammett, Brown, Taft, Yukawa-Tsuno, and Swain-Lupton equations), and it was shown that the thiophene ring in the investigated molecules in both the static state and during the formation of H complexes transmits the conjugation effects better than the benzene ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 918–923, July 1974.