Synthesis and biological activity of condensed derivatives of thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]thiazolo(thiazino,thiazepino)[3,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidines

Methods for the synthesis of new heterosystems including condensed pyrano[4′,3′:4,5]pyrido[2,3-b]-thieno[3,2-d]thiazolo(thiazino, thiazepino)[3,2-a]pyrimidines, thiazolo(thiazino, thiazepino)[3″,2″:1′,2′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolines, and cyclopenta[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d]thiazolo(thiazino)[3,2-a]pyrimidines are developed. The synthesis is carried out on the basis of 1-amino-2-ethoxycarbonylpyrano[4,3-d]thieno[2,3-b]pyridines and -thieno[2,3-b]isoquinolines. Antitumor and anticonvulsant properties of the synthesized products have been evaluated. Compounds possessing low toxicity and moderate biological activity are found. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 3, pp. 17–21, March, 2009.     

Synthesis and structure-activity relationship studies of 2,3-dihydroimidazo[2,1-a]isoquinoline analogs as antitumor agents

5-Aryl-2,3-dihydroimidazo[2,1-a]isoquinolines were reported to have strong antitumor activity and one of the derivatives such as 5-[4′-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a] isoquinoline (1, SDZ 62–434) was found to be more effective than the clinical cytostatic agent edelfosine (2) inin vitro andin vivo assays. Currently SDZ 62–434 is in clinical trials in Europe. The structure-activity relationship studies of SDZ 62–434 showed that compounds with substitution on ring A were less active than the lead compound. Ring B in SDZ 62–434 was essential for the activity because compounds without B ring had no antitumor activity. Among the 3-arylisoquinolin-1-one derivatives, 3-[4′-(piperidonomethyl)phenyl] substituted analog had no antitumor activity but simple phenyl substituted compound, such as4, showed the most potent antitumor activity in various human tumor cell lines.     

Binding of [H]MSX-2 (3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargylxanthine) to rat striatal membranes — a new, selective antagonist radioligand for A2A adenosine receptors

The present study describes the preparation and binding properties of a new, potent, and selective A_2A adenosine receptor (AR) antagonist radioligand, [³H]3-(3-hydroxypropyl)-7-methyl-8-(m-methoxystyryl)-1-propargylxanthine ([³H]MSX-2). [³H]MSX-2 binding to rat striatal membranes was saturable and reversible. Saturation experiments showed that [³H]MSX-2 labeled a single class of binding sites with high affinity (K_d=8.0 nM) and limited capacity (B_max=1.16 fmol·mg⁻¹ of protein). The presence of 100 μM GTP, or 10 mM magnesium chloride, respectively, had no effect on [³H]MSX-2 binding. AR agonists competed with the binding of 1 nM [³H]MSX-2 with the following order of potency: 5′-N-ethylcarboxamidoadenosine (NECA)>2-[4-(carboxyethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine (CGS-21680)>2-chloroadenosine (2-CADO)>N⁶-cyclopentyladenosine (CPA). AR antagonists showed the following order of potency: 8-(m-bromostyryl)-3,7-dimethyl-1-propargylxanthine (BS-DMPX)>1,3-dipropyl-8-cyclopentylxanthine (DPCPX)>(R)-5,6-dimethyl-7-(1-phenylethyl)-2-(4-pyridyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (SH-128)>3,7-dimethyl-1-propargylxanthine (DMPX)>caffeine. The K_i values for antagonists were in accordance with data from binding studies with the agonist radioligand [³H]CGS21680, while agonist affinities were 3–7-fold lower. [³H]MSX-2 is a highly selective A_2A AR antagonist radioligand exhibiting a selectivity of at least two orders of magnitude versus all other AR subtypes. The new radioligand shows high specific radioactivity (85 Ci/mmol, 3150 GBq/mmol) and acceptable nonspecific binding at rat striatal membranes of 20–30%, at 1 nM.     

Synthesis,Anti-Inflammatory,and Ulcerogenicity Studies of Novel Substituted and Fused Pyrazolo[3,4-d]pyrimidin-4-ones

In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7–12) as well as fused pyrazolo[3′,4′:4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14–16) and 7,8,9,10-tetrahydropyrazolo[3′,4′:4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a–f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.     

Heterocyclen via Mannichbasen, 7. Mitt. Synthese von Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-onen

Heterocycles via Mannich Bases, VII: Synthesis of Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-ones The title compounds 4 are synthesised from 5-amino-3-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one (2) and ketone Mannich bases or dehydro Mannich bases.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Design and synthesis of 3-[3-(substituted phenyl)-4-piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5-dihydro-isoxazol-5-yl]-1H-indoles as potent anti-inflammatory agents

The synthesis of new indole derivatives bearing isoxazoline moiety (3a–d and 4a–d) has been described. IR, ¹H NMR, and mass spectral data supported the structures of synthesized compounds. The compounds were tested in vivo for their anti-inflammatory activity by carrageenin-induced rat paw edema method. The compounds that showed good anti-inflammatory activity were screened for their ulcerogenic and lipid peroxidation activities. The most active compound of this series is 3-[3-(4-methoxyphenyl)- 4-morpholin-4-ylmethyl)-4,5-dihydro-isoxazol-5yl]-1H-indole 4d.     

Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents

Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA.     

Potential anti-inflammatory activity and ulcerogenicity study of some novel pyrimido[4′,5′:4,5]pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>]azepine derivatives

A series of novel tricyclic pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives were synthesized using the starting compound 3-amino-1-oxo-2-phenyl-5-(pyrrolidin-1-yl)-1,2,4a,5,6,7,8,9-octahydropyrimido[1,6-a]azepine-4-carbonitrile 4. This series includes the 3-aryl derivatives 6a, b, the 3-cycloaminoalkyl derivatives 8a–f, the 3-mercaptomethyl derivatives 10 and 11a, b, the 2-cycloaminomethyl derivatives 13a–c, the 1-cycloamino derivatives 15a–c and the 1-amino derivative 16. The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw oedema test in rats using diclofenac sodium as the reference drug. Ulcer indices for the most active compounds were calculated. The 3-mercaptomethylacetic acid derivative 10 was the most active compound, showing activity comparable to diclofenac sodium with minimal ulcerogenic effect while the rest of the tested compound exhibited moderate anti-inflammatory activity.     

Synthesis and antimicrobial activity of [6′-methyl-4′-methoxy-2-oxo-2H-[1]-benzopyran)-2″,4″-dihydro-[1″, 2″, 4″]-triazol-3″-one and 3″-phenyl-thiazolidin-4″-one-phenoxymethyl derivatives of dipyranoquinoline

A series of bioactive 3H,7H,8H,11H-9-[(5″-(6′-methyl-2-oxo-2H-[1]-4′-benzopyranoxy)-2″,4″-dihydro-[1″,2″,4″]-triazol-3″-one)methyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (4) and 3H,7H,8H,11H-9-[(2′-(3″-phenyl-thiazolidin-4″-one)-phenoxymethyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (7) analogs of 3H,7H,8H,11H-9-bromomethyl-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (1) have been synthesized and evaluated for their antibacterial activity against Gram-positive bacteria (S. aureus) and Gram-negative bacteria (S. typhi and E. coli). Pyranoquinolines with triazole and thiazolidine moieties exhibited promising antibacterial activity. The structures of all synthesised compounds were confirmed on the basis of analytical and spectral data.     

New isoflavone glycosides from <Emphasis Type="Italic">Iris spuria</Emphasis> L. (Calizona) cultivated in Egypt

Two new isoflavone glycosides, tectorigenin 7-O-β-d-glucopyranoside-4′-O-[β-d-glucopyranosyl-(1″″ → 6′′′)-β-d-glucopyranoside] (1) and iristectorigenin B 4′-O-[β-d-glucopyranosyl-(1′′′ → 6″)-β-d-glucopyranoside] (2), together with 11 known compounds, including six isoflavones, tectorigenin 7-O-β-d-glucopyranoside-4′-O-β-d-glucopyranoside (3), tectorigenin 4′-O-[β-d-glucopyranosyl-(1′′′ → 6″)-β-d-glucopyranoside] (4), tectorigenin 7-O-β-d-glucopyranoside (5), genistein 7-O-β-d-glucopyranoside (6), tectorigenin 4′-O-β-d-glucopyranoside (7), and tectorigenin (8); two phenolic acid glycosides, vanillic acid 4-O-β-d-glucopyranoside (9) and glucosyringic acid (10); a phenylpropanoid glycoside, E-coniferin (11); an auronol derivative, maesopsin 6-O-β-d-glucopyranoside (12); and a pyrrole derivative, 4-(2-formyl-5-hydroxymethylpyrrol-1-yl) butyric acid (13), were isolated from fresh Iris spuria (Calizona) rhizomes. The structures of these compounds were established on the basis of spectroscopic and chemical evidence. Inhibitory effects on the activation of Epstein–Barr virus early antigen were examined for compounds 1–8 and 12.     

Design, synthesis and in vitro antibacterial and antifungal activities of some novel spiro[azetidine-2,3��-indole]-2,4(1��H)-dione

The present study deals with the synthesis of novel spiro[azetidine-2,3′-indole]-2′,4(1′H)-dione derivative from the reactions of 3-(phenylimino)-1,3-dihydro-2H-indol-2-one derivatives with chloracetyl chloride in the presence of triethylamine (TEA). All the compounds were characterized using IR, ¹H-NMR, MS, and elemental analysis. They were screened for their antibacterial and antifungal activities. The bacterial strains used were Gram-positive Staphylococcus aureus (MTCC-96) and Gram-negative Escherichia coli (MTCC-521) and Pseudomonas aeruginosa (MTCC-647). The antifungal screening was done on Candida albicans (MTCC-183) and Asperigillus niger (MTCC-343) fungal strains. Results revealed that, compounds (7a), (7b), (7c), (7d), and (7e) showed very good activity with MIC value of 6.25–12.5 μg/ml against three evaluated bacterial strains and the remaining compounds showed good to moderate activity comparable to standard drugs as antibacterial agents. Compounds (7c) and (7h) displayed equipotent antifungal activity in comparison to standard drugs. Amoxicillin, gentamycin, and streptomycin were used as standard drugs for antibacterial activity while fluconazole and itraconazole were used as standard drugs for antifungal activity. Structure–activity relationship study of the compounds showed that the presence of electron withdrawing group substitution at 5′ and 7′ positions of indoline ring and on ortho or para position of phenyl ring increases both antibacterial and antifungal activity of the compound. Henceforth, our findings will have a good impact on chemists and biochemists for further investigations in search of spiro-fused antimicrobial agents.     

Synthesis and antitumor screening of new 1,7-diphenyl-3-(1,3-disubstituted-1H-pyrazole-4-carbonyl)-[1,2,4]triazolo[4,3-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-5(1H)-ones

A new series of 3-(1,3-disubstituted-1H-pyrazole-4-carbonyl)-1,7-diphenyl-[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones 4 was prepared by reaction of the enaminone 2 with hydrazonoyl halides 3. The preliminary screening for antitumor activity of the synthesized compounds was carried out against Ehrlich Ascites Carcinoma tumor cells. The results revealed that the studied compounds 4 have low or no antitumor activity towards EAC tumor cells.     

Synthesis and anti-HIV evaluation of the novel 2-(m-chlorobenzyl)-4-substituted-7-methyl-1, 1, 3-trioxo-pyrazolo[4, 5-e] [1, 2, 4]thiadiazines

A novel series of 2-(m-Chlorobenzyl)-4-substituted-1, 1, 3-trioxo-2H,4H-pyrazolo[4, 5-e][1, 2, 4] thiadiazines (7a-k) were synthesized, and evaluated for their anti-HIV replication in MT-4 cell cultures. Compound (7a) showed activity against HIV-1-induced cytopathicity, with an EC₅₀ value of 45.6 μM, but none of the compounds exhibited inhibitory activity against HIV-2.     

Synthesis and Biological Activity of New [1,3]Thiazolo[4,5-d]pyridazin-4(5H)-ones

A series of novel 2-(N-pyrrolidino, N-piperidino or N-morpholino)-7-phenyl(α-furoyl or α-thienyl)-[1,3]thiazolo[4,5-d]pyridazinones 10a–c, 14–16a,b was synthesized in 78–87% yields via the reaction of methyl 5-benzoyl(α-furoyl or α-thienyl)-2-aminosubstituted-thiazol-4-carboxylates 9a–c, 13a–e with hydrazine. These new compounds have been tested for their in vivo analgesic and anti-inflammatory activities. All compounds have been characterized by ¹H-NMR, ¹³C-NMR spectroscopy, and liquid chromatography–mass spectrometry.     

Untersuchungen an 1,3-Dicarbonylverbindungen, 25. Mitt. Pyrano[3,2-b]indol-4(5H)-on und 9-Chlor-1-oxo-1H-pyrrolo[1,2-a]indol-2-carbaldehyd

1,3-Dicarbonyl Compounds, XXV: Pyrano[3,2-b]indole-4(5H)-one and 9-Chloro-1-oxo-1H-pyrrolo[1,2-a]indole-2-carbaldehyde On treatment with POCl₃DMF the BF₂ chelate 2 , obtained from the 1,3-dicarbonyl compound 1 , yields the title substances 5 and 9 . Compound 5 is characterized by way of the thione 6 and the oxonol 7 , compound 9 by way of the 1,4-dihydropyridines 10 .     

Enantioselective synthesis of (R)- and (S)-2-methyl-[3,3,2-2H3] alanines

The synthesis of optically pure (R)- and (S)-2-methyl-[3,3,3-²H₃] alanines of biological interest is described. The stereochemistry of the reaction of the lithio derivative of (R)-(©)-2,5-dimethoxy-3-benzyl-3-methyl-3, 6-dihydropyrazine with alkyl and deuterated alkyl iodides is discussed. The configuration of the newly formed center of chirality in (R)- and (S)-2-methyl-[3,3,3-²H₃] alanines is derived from ¹ H NMR.     

Synthesis of novel 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one derivatives with antioxidant activity

A series of 3-chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one derivatives (2a–k) bearing different amino acids were synthesized by base condensation reaction. 3-Chloro-1-(5H-dibenz[b,f]azepine-5yl)propan-1-one(2) was obtained by N-acylation of 5H-dibenz[b,f]azepine (1). All the synthesized compounds were evaluated for their potential over antioxidant activities against inhibition of lipid peroxidation by β-carotene and linoleic acid assay and inhibition of human low-density lipoprotein (LDL) oxidation assay. Typically, compound 2 showed weak antioxidant activity, whereas coupling of different amino acids enhances the antioxidant activities based on the presence of different functional groups. Among the derivatives, compound 2d showed significant antioxidant activities followed by 2h, 2i, 2j and 2k.     

Synthesis and antibacterial activity of 3,4-dihyhdropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones

A series of 3,4-dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-ones were synthesized by the reaction of ethyl 3-alkyl(aryl)carboxamidothieno[2,3-b]pyridine-2-carboxylates with aliphatic amines. The starting carboxamides were obtained via the reaction of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate with acid chlorides. It is established that the synthesized pyridothienopyrimidinones possess antistaphylococcal activity. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 9, pp. 37–39, September, 2008.     

Evaluation of the anti-inflammatory activity of some pyrrolo[2,3-d]pyrimidine derivatives

A series of novel pyrrolo[2,3-d]pyrimidine and fused pyrrolo[2,3-d]pyrimidine derivatives were synthesized and their structures were characterized by elemental analysis, ¹H NMR, IR, and mass spectroscopy. Their in vivo anti-inflammatory activities were evaluated, and the results indicated that some of the title compounds compounds showed significant activities. These compounds are 2b ((7-(4-Methoxyphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine), 7b (4-(2-(Benzyl)hydrazinyl)-7-(4-methoxyphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d] pyrimidine), 7d (4-(2-(Benzyl)hydrazinyl)-7-(4-methoxyphenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine), and 9b (4-(3,5-Dimethyl-4H-pyrazol-1-yl)-7-(4-Methoxyphenyl)-5,6-diphenyl-4,7dihydro-3H-pyrrolo[2,3-d]pyrimidine).