Synthesis of imidazoline and imidazo[2,1-c][1,2,4]triazole aryl derivatives containing the methylthio group as possible antibacterial agents

1-Arylimidazolidine-2-thiones (1a-g) were synthesized by the condensation reaction of N-arylethylenediamines with carbon disulfide in xylene medium. Their further alkylation with methyl iodide led to the formation of some biologically active 1-aryl-2-methylthio-imidazolines (2a-g). The 7-(4-methylphenyl)-3-methylthio-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazole (4b) was obtained by the alkylation of the respective 7-(4-methylphenyl)-2,5,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazol-3(H)-thione (3b) with methyl iodide. Antimicrobial activities of 1-aryl-2-methylthio-imidazolines (2a-g) and the 7-(4-methylphenyl)-3- methylthio-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazole (4b) are presented. All tested compounds showed MIC in the range of 11.0-89.2 microM. Compounds 2a,e were found to be equipotent to chloramphenicol in vitro, whereas 2a,c,e-g and 4b showed superior activity (MIC) to ampicillin.     

An efficient route to novel 4,5-di- and 2,4,5-tri substituted imidazoles from imidazo[1,5-a]-1,3,5-triazine (5,8-diaza-7,9-dideazapurine) derivatives

Two new types of imidazole derivatives: N-(2-R1-5-R2-1H-imidazol-4-yl) thioureas 7a-g and N-(2-R1-5-R2-1H-imidazol-4-yl) formamides 8b,c,g were obtained in high yields by the hydrolytic degradation of 6-R1-8-R2-2-thioxo-2,3-dihydroimidazo[1,5-a]-1,3,5-triazin-4(1H)-ones 5a-g and 6-R1-8-R2-imidazo[1,5-a]-1,3,5-triazin-4(3H)-ones 6b,c,d, respectively. The tautomeric preferences of the new imidazoles were determined.     

Myristoyl esters of lactose

Whereas lactose did not undergo a base-catalyzed transesterification with methyl esters of fatty acids, methyl beta-lactoside reacted under identical conditions to give mono- and di-myristates. This difference in behavior is explained in terms of the formation of an unreactive, internally chelated potassium-lactose complex. Supporting evidence for this hypothesis is the observed change in the anomeric equilibrium of lactose in the presence of potassium carbonate. The monomyristates of methyl beta-lactoside were assigned the structures of 3' and 6' derivatives, and it is concluded that the diesters are the 3',6', and 6,6' derivatives.     

Structure-activity relationship of phosmidosine: importance of the 7,8-dihydro-8-oxoadenosine residue for antitumor activity

To study the structure-activity relationship of phosmidosine, a variety of phosmidosine derivatives 9a-g were synthesized by condensation of N-diisopropyl N'-(N-tritylprolyl)phosphorodiamidite 6 with appropriately protected nucleoside derivatives 7a-g. As the result, replacement of the 7,8-dihydro-8-oxoadenine base by adenine and 6-N-acetyladenine did not affect the antitumor activity. However, phosmidosine derivatives containing uracil, cytosine, and guanine in place of the 7,8-dihydro-8-oxoadenine base did not show significant activity. A plausible explanation for the selective expression of phosmidosine compared with that of phosmidosine analogs having other amino acids in place of proline is also discussed. These results suggest that phosmidosine serves as an inhibitor of prolyl adenosine 5'-phosphate (prolyl-AMP) to inhibit the peptide synthesis in cancer-related cells.     

Synthesis and pharmacological assessment of derivatives of isoxazolo[4,5-d]pyrimidine

A series of new 5-alkyl and 5-arylisoxazolo[4,5-d]pyrimidinones (5a-g, 6-8) were prepared from 4-amino-3-oxo-isoxazolidine-5-carboxylic acid amide. Some of the aryl derivatives of isoxazolo[4,5-d]pyrimidine were tested pharmacologically in comparison with Diazepam. Compounds 5b-d and 7 demonstrated interesting anxiolytic activity.     

Synthesis of the cyclic and acyclic acetal derivatives of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine,a potent antitumor nucleoside. Design of prodrugs to be selectively activated in tumor tissues via the bio-reduction-hydrolysis mechanism

We have designed and synthesized the acetal derivatives of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, 1), the 2',3'-O-nitrobenzylidene derivatives 2 and 3 and the 5'-O-(alkoxy)(nitrophenyl)methyl derivatives 6-10 as potential prodrugs of ECyd. These prodrugs can be selectively activated in tumor tissues via a bio-reduction-hydrolysis mechanism owing to the characteristic properties of tumor tissues, such as hypoxia and lower pH. Although the 2',3'-O-(4-nitrobenzylidene) derivatives 2 and 3 were converted bio-reductively into the corresponding 4-aminobenzylidene derivatives by rat S-9 mix, the reduction products, that is, the corresponding amino congeners 4 and 5, proved to be rather stable in an aqueous solution at pH 6.5 used as a pH model for acidic tumor tissues. In contrast, the 5'-O-(alkoxy)(4-nitropheny)methyl derivatives 6-8 were also reduced by rat S-9 mix to the corresponding amino congeners 11-13, which were hydrolyzed to release ECyd more effectively at pH 6.5 than at pH 7.4. Accordingly, the acyclic acetals 6-8 may be efficient prodrugs of ECyd, that are effectively reduced under physiological conditions releasing ECyd in acidic tumor tissues.     

Design, synthesis and vasorelaxant evaluation of novel coumarin-pyrimidine hybrids

The main objective of the present work depends on the hybridization of coumarin moiety as a vasorelaxant scaffold and pyrimidine ring with known potential cardiovascular activity in order to prepare some new potent antihypertensive candidates. Hence, two groups of pyrimidinyl coumarin derivatives were synthesized and evaluated for their vasorelaxing activity. These compounds were prepared via two routes; either preparation of the guanidinocoumarin 4 followed by a cocktail of cyclization reactions to yield a different array of 6-(substituted pyrimidin-2-yl)aminocoumarins 5-17, or through cyclization of the precursor chalcones 22a-g with guanidine hydrochloride to generate the corresponding final compounds, 8-(6-aryl-2-aminopyrimidin-4-yl)-7-methoxycoumarins 23a-g. The effect of these compounds and the coumarin intermediates 3, 4, 21 and 22a-g on nor-epinephrine induced contracture in thoracic rat aortic rings was investigated using prazocin as reference drug. Several derivatives showed promising activities either equal or even better than that of prazocin (IC(50) 0.487 mM). The most prospective compounds; the pyrimidinylamino coumarin derivatives 8, 17 (IC(50) 0.411, IC(50) 0.421 mM) and the chalcones 22b, 22e (IC(50) 0.371, 0.374 mM) that displayed the highest activity can be a base for lead optimization and simple but efficient design of new compounds. 2D-QSAR analysis was applied to find a correlation between the experimental vasorelaxant activities of the newly synthesized coumarin derivatives and their different physicochemical parameters. The result of this study showed that the increase in aqueous solubility while retaining good hydrophobic character of the overall molecule is the key for maintaining high relaxation activity.     

7-deazainosine derivatives: synthesis and characterization of 7- and 7,8-substituted pyrrolo [2,3-d]pyrimidine ribonucleosides

The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been performed. Tubercidin derivatives were obtained by simple conversion of the amino group of the heterocyclic moiety of the starting 7-deazadenosine compounds, into a hydroxyl group. Preparation of toyocamycin derivatives was accomplished by treatment of the silylated 6-bromo-5-cyanopyrrolo[2,3-d]pyrimidin-4-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose. The glycosylation reaction afforded a mixture of 8-bromo 7-cyano 2',3',5' tri-O-benzoyl 7-deazainosine and 6-bromo-5-cyano-3-(2',3',5'-tri-O-benzoyl-beta-d-ribofuranosyl)pyrrolo[2,3-d]-pyrimidin-4-one isomers: The structures were assigned on the basis of NMR spectroscopy studies. Next deprotection treatment gave the novel 7-deazainosine ribonucleosides.     

A facile regioselective synthesis of novel spiro-thioxanthene and spiro-xanthene-9',2-[1,3,4]thiadiazole derivatives as potential analgesic and anti-inflammatory agents

The 1,3-dipolar cycloaddition of nitrile imines to 9H-thioxanthone-9-thione and 9H-xanthone-9-thione afforded novel spiro-thioxanthene-9',2-[1,3,4]thiadiazoles 6a-g and spiro-xanthene-9',2-[1,3,4]thiadiazoles 7a-g in good yields. Some of the newly synthesized compounds were tested for anti-inflammatory and analgesic activities comparable to ibuprofen. Compounds 6a,d,e and 7a,d,e showed significant activity compared to standard drug. The toxicity studies revealed that neither death nor other behavioral or toxicological changes were observed on rats up to a dose as high as 200 mg/kg.     

Some non-anomerically C-C-linked carbohydrate amino acids related to leucine-synthesis and structure determination

(5'R)-5'-Isobutyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-L-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione was synthesised starting from methyl 2,3-O-isopropylidene-alpha-D-lyxo-pentodialdo-1,4-furanoside via methyl 6-deoxy-6-isopropyl-2,3-O-isopropylidene-alpha-D-lyxo-hexofuranosid-5-ulose applying the Bucherer-Bergs reaction. Its 5'-R configuration was confirmed by X-ray crystallography. Corresponding alpha-amino acid-methyl (5R)-5-amino-5-C-carboxy-5,6-dideoxy-6-isopropyl-alpha-D-lyxo-hexofuranoside (alternative name: 2-[methyl (4R)-beta-L-erythrofuranosid-4-C-yl]-D-leucine) was obtained from the above hydantoin by acid hydrolysis of the isopropylidene group followed by basic hydrolysis of the hydantoin ring. Analogous derivatives with 5S configuration, formed in a minority, were also isolated and characterised.     

Syntheses of phenylpyrazolodiazepin-7-ones as conformationally rigid analogs of aminopyrazole amide scaffold and their antiproliferative effects on cancer cells

Recently, we have reported the syntheses and antiproliferative activities of N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl amide derivatives on melanoma cells. As a continuous work for antiproliferative agents in melanoma, here we report the synthesis of conformationally rigid analogs, phenyl-6,8-dihydropyrazolo[3,4-b][1,4]diazepin-7(1H)-one derivatives 7a-g, 8a-o and their antiproliferative activities against A375P melanoma cell line and U937 hematopoietic cell line. Most compounds showed competitive antiproliferative activities to sorafenib, the reference standard. Among them, N-(3-(1-benzyl-7-oxo-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepin-5-yl)phenyl)-4-chloro-3-(trifluoro methyl)benzamide-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido)-2-methylbenzamide (7b) exhibited potent activities (GI(50)=0.43 μM and 0.06 μM) on both cell lines. It has been further confirmed to be a potent and selective Raf kinases inhibitor and also mild inhibitor of PI3Kα.     

Thiosugars. X. Novel nucleoside analogues derived from 4-thio-L-lyxofuranose

1-O-Acetyl-2,3,5-tri-O-benzyl-4-thio-L-lyxofuranose 1 was transformed into O-benzyl- and O-acetyl-protected 1-(4-thio-L-lyxofuranosyl) nucleoside derivatives by use of the TMSOTf method. Debenzylation with boron tribromide or deacetylation with sodium methoxide yielded the corresponding pyrimidine (7-11, 17, 18, 26 and 27) and purine (29 and 34) nucleoside analogues. The anomeric configurations were determined by NMR spectroscopy and, in the case of the 5-halo- (7-9) and nitrouridine derivative 11 and the 6-methylcytidine derivative 27, by X-ray structural analyses.--The unprotected nucleosides were not anti-virically inhibitory at 250 microM.     

Synthesis and structure determination of some nonanomerically C-C-linked serine glycoconjugates structurally related to mannojirimycin

The Bucherer-Bergs reaction of methyl 2,3-O-isopropylidene-alpha-d-lyxo-hexofuranosid-5-ulose gave (4'S)-4'-carbamoyl-4'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-oxazolidin-2'-one instead of expected hydantoins. A mixture of hydantoins--(5'R)-triphenylmethoxymethyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione and (5'S)-triphenylmethoxymethyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione was obtained from the 5-ulose having protected primary OH group at C-6. The 4'-S configuration of 2 as well as 5'-S configuration of (5'S)-hydroxymethyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione (9) was confirmed by X-ray crystallography. Corresponding alpha-amino acid--methyl (5S)-5-amino-5-C-carboxy-5-deoxy-alpha-d-lyxo-hexofuranoside (alternative name: 2-[methyl (4R)-beta-l-erythrofuranosid-4-C-yl]-l-serine) (11) was obtained from the hydantoin 9 by acid hydrolysis of the isopropylidene and trityl groups followed by basic hydrolysis of the hydantoin ring. Analogous derivatives with 5-R configuration, formed in a minority, were also isolated and characterised.     

5''-Terminal and internal methylated nucleosides in herpes simplex virus type 1 mRNA.

RNA labeled with [methyl-3H]methionine and/or [32P]orthophosphate was isolated from the polyribosomes of herpes simplex virus (HSV) types 1-infected cells and separated into polyadenylylated [poly(A+)]and non-polyadenylylated [poly(A-)] fractions. Virus-specific RNA was obtained by hybridization in liquid to either excess HSV DNA or filters containing immobilized HSV DNA. Analysis in denaturing sucrose gradients indicated that HSV-specific poly(A+) RNA sedimented in a broad peak, with a modal S value of 20. The ratio of [3H]methyl to 32P decreased with increasing size of RNA, suggesting that each RNA chain contains a similar sumber of methyl groups. Further analysis indicated an average of one RNase-resistant structure of the type m7G(5')pppNmpNp or m7G(5')pppNmpNmpNp per 2,780 nucleotides. The following components were identified in the 5'-terminal oligonucleotides of polyribosome-associated HSV-specific poly(A+) and poly(A-) RNA: 7-methylguanosine, N6,2'-O-dimethyladenosine, and the 2'-O-methyl derivatives of guanosine, adenosine, uridine, and denosine, and the 2'-O-methyl derivatives of guanosine, adenosine, uridine, and cytidine. The most common 5'-terminal sequences were m7G(5')pppm6Am and m7G(5')pppGm. An additional modified nucleoside, N6-methyladenosine, was present in an internal position of HSV-specific RNA.     

Antiplasmodial structure-activity relationship of 3-trifluoromethyl-2-arylcarbonylquinoxaline 1,4-di-N-oxide derivatives

Derivatives of 3-trifluoromethyl-2-arylcarbonylquinoxaline 1,4-di-N-oxide (4b-g, 5b-g, 6a-g) were synthesized and evaluated for their capacity to inhibit the growth of chloroquine-resistant Plasmodium falciparum FCB1 strain in culture. Compound 7-chloro-2-(2-furylcarbonyl)-3-trifluoromethyl-1,4-quinoxaline di-N-oxide (5g) was the most active being almost 5 times more active than chloroquine. It was also 50 times more active against P. falciparum than toxic toward MCF7 cells. Structural characteristics for a quinoxaline to be active were defined: bioisosteric modification of phenyl group by 2-thienyl or 2-furyl subunits, R2 position must be free or occupied by a methyl group and R1 position must be free or occupied by Cl, CH3, OCH3 or CF3.     

Immunosuppressive diacetylenes, ceramides and cerebrosides from Hydrocotyle leucocephala

Three C-17 diacetylenic compounds (1-3), one monoterpenoid (4), seven ceramides (leucoceramides A-G, 5a-g), six cerebrosides (leucocerebrosides A-F, 6a-f) and nine known compounds were isolated from the methanolic extract of Hydrocotyle leucocephala. Their structures were established by spectroscopic methods. The isolated compounds 1-3, 5a-g, 6a-f and 7 were shown to be active in the lipopolysaccharide (LPS) induced cytokine production assay for IL-10, IL-12, and TNF-alpha.     

Structural studies of O6-methyldeoxyguanosine and related compounds: a promutagenic DNA lesion by methylating carcinogens.

O6-Methylation of guanine residues in DNA can induce mutations by formation of base mispairing due to the deprotonation of N(1). The electronic, geometric and conformational properties of three N(9)-Substituted O6-methylguanine derivatives, O6-methyldeoxyguanosine (O6mdGuo), O6-methylguanosine (O6mGuo) and O6, 9-dimethylguanine (O6mdGua), were investigated by X-ray and/or NMR studies. O6mdGuo crystallizes in the monoclinic space group P2(1) with cell parameters a = 5.267(1), b = 19.109(2), c = 12.330(2) A, beta = 92.45(1) degrees, V = 1239.8(3) A3, z = 4 (two nucleosides per asymmetric unit), and O6mGua in the monoclinic space group P2(1)/n with cell parameters a = 10.729(2), b = 7.640(1) c = 10.216(1) A, beta = 92.17(2) degrees, V = 836.7(2) A3, z = 4. The geometry and conformation of O6-methylguanine moieties observed in both crystals and are very similar. Furthermore, the molecular dimensions of the O6methylguanine residue resemble more closely those of adenine than those of guanine. The methoxy group is coplanar with the purine ring, the methyl group being cis to N(1). The conformation of O6-methylguanine nucleosides is variable. The glycosidic conformation of O6mdGuo is anti for molecule (a) and high-anti for molecule (b) in the crystal, while that of O6mGuo is syn [Parthasarathy, R & Fridey, S. M. (1986) Carcinogenesis 7, 221-227]. The sugar ring pucker of O6mdGuo is C(2')-endo for molecule (a) and C(1')-exo for molecule (b). The C(4')-C(5') exocyclic bond conformation in O6mdGuo is gauche- for molecule (a) but trans for molecule (b), in contrast with gauche+ for O6mGuo. The hydrogen bonds exhibited by O6-methylguanine derivatives differ from those in guanine derivatives; the amino N(2) and ring N(3) and N(7) atoms of O6-methylguanine residues are involved in hydrogen bonding. 1H-NMR data for O6mdGuo and O6mdGuo reveal the predominance of a C(2')-endo type sugar puckering. In O6mdGuo, however, a contribution of a C(1')-exo sugar puckering is significant. The NOE data also indicate that O6mdGuo molecules exist with nearly equal population for anti (including high anti) and syn glycosidic conformations. These observations and their biological implications are discussed.     

Convenient preparation of L-arabino-hexos-5-ulose derivatives from lactose

2,6-di-O-benzyl- (9), 2-O-benzyl-3,4-O-isopropylidene- (19), and 2-O-benzyl-6-O-m-chlorobenzoyl-L-arabino-hexos-5-ulose (20) have been prepared using 4'-deoxy-4'-eno- and 6'-deoxy-5'-eno lactose dimethyl acetal derivatives 7 and 14 as key intermediates. The synthesis of enol ethers 7 and 14 has been performed with good yields by base-promoted elimination of acetone or p-toluenesulfonic acid from 2',6'-di-O-benzyl-, and 6'-O-p-toluenesulfonyl-2,3:5,6:3',4'-tri-O-isopropylidenelactose dimethyl acetal, respectively. The epoxidation with MCPBA of 7 and 14 in methanol or dichloromethane furnishes C-5'-methoxy and C-5'-m-chlorobenzoyloxy derivatives, easily transformed with good yields into L-arabino 5-ketoaldohexoses 9, 19 and 20.