Synthesis andin vitro evaluation of some novel benzofuran derivatives as potential anti-HIV-1, anticancer, and antimicrobial agents

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and 6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2(1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound 5c was determined by X-ray crystallography. The compounds prepared were evaluated for their in vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds 5c and 9a produced a significant reduction [symbols, see text] the viral cytopathic effect (93.19% and 59.55%) at concentrations > 2.0 x 10(-4) M and 2.5 x 10(-5) M respectively. Compound 9a was confirmed to have moderate anti-HIV activity. Compounds 2a, 2d, and 5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.     

Design and synthesis of some oxadiazolyl, thiadiazolyl, thiazolidinyl, and thiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents

Four series of 1H-pyrazole derivatives have been synthesized. The first series was prepared by cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazole-4-carbaldehyde aroyl-hydrazone 4a-c with acetic anhydride to afford the corresponding oxadiazoline derivatives 5a-c. The other series were prepared by the cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-4-substituted thiocarbamoylhydrazonomethyl-1H-pyrazole 6a-c with acetic anhydride, ethyl bromoacetate or phenacyl bromide giving rise to 3-(5-bromo-2-thienyl)-1-phenyl-4-[3-acetyl-5-(N-substituted acetamido)-2,3-dihydro-1,3,4-thiadiazol-2-yl]-1H-pyrazoles 7a-c, 3-(5-bromo-2-thienyl)-1-phenyl-4-(3-substituted- 4-oxothiazolidin-2-ylidenehydrazonomethyl)-1H-pyrazoles 8a-c, or 3-(5-bromo-2-thienyl)-1-phenyl-4-(3-substituted-4- phenyl-2,3-dihydrothiazol-2-ylidenehydrazonomethyl)-1H-pyraz oles 9a-c respectively. Some of these compounds showed anti-inflammatory, antibacterial or antifungal activities comparable to that of Proquazone, Ampicillin, or Clotrimazole respectively.     

Synthesis and biological evaluation of new thiazolopyrimidines

In this study, a series of 4-amino-5-cyano-3-substituted-2,3-dihydrothiazol-2-thiones (1a-c), as well as their triazolo and triazinopyrimidine derivatives such as 8-substituted-3-benzyl-5-methylthiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2-thiones (4-6, 10) and 3-benzyl-5-methyl thiazolo[5,4-e]pyrimidino[3,4-b][1,2,4]triazin-2-thiones (7a-b) were prepared as potential antimicrobial and antitumor agents. Some of the tested compounds showed promising antimicrobial activity and non of them showed any appreciable antitumor activity.     

Synthesis of pyrido[2,1-c][1,2,4]triazine,1,2,4 triazolo[4,3-a] pyridine and 2-(substituted-pyrazolyl)nicotinonitrile and their effect on Biomphalaria alexandrina snail enzymes

The reaction of 2-hydrazino-4-(4-methoxyphenyl)-6-pheny-nicotinonitrile 3 with halo compounds yielded 4a-c,5,6. Heating 3 with carbon disulphide gave 7-(4-methoxyphenyl)-5-phenyl-3-thioxo-2,3-dihydro [1,2,4-] triazolo [4,3-a] pyridine-8-carboxylic amide 7. The behaviour of 3 towards some alpha,beta-unsaturated nitriles ,ethoxymethylene and ketene dithioacetal derivatives has been investigated, affording 9a-c,11a-c,13a-c,16a,b respectively. The activity of compounds 4a,5,6 and 7 have been investigated as molluscicidal.     

Synthesis and antimicrobial testing of some new S-substituted-thiopyridines,thienopyridines, pyridothienopyrimidines and pyridothienotriazines

The reaction of 5-acetyl-4-aryl-3-cyano-6-methylpyridine-2(1H)-thiones (1a, b) with 4-methylphenacyl bromide, chloro-N-arylacetamides or chloroacetonitrile gave the corresponding S-substituted thiopyridines 2a-c, 4a-f and 6a-c, respectively. The latter compounds underwent intramolecular Thorpe-Ziegler cyclization to give 2-substituted 5-acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridines 3a-c, 5a-f and 7a-c. Compounds 5a-f and 7b, c are key intermediates in the synthesis of the target compounds. Some compounds showed remarkable antimicrobial activity.     

Synthesis and Biological Investigations of Some New Thiazolylbenzimidazoles and Benzimidazolylthiazolo[3,2-a]pyridines

2-[(4-Oxo-4,5-dihydrothiazol-2-yl)methyl]-1H-benzimidazole ( 2 ) was prepared through the reaction of 2-cyanomethyl-1H-benzimidazole ( 1 ) with thioglycolic acid. The syntheses of its arylidene 3 and diazo-coupled compounds 5 and the cyclization of the aforementioned thiazolylbenzimidazole to benzimidazolylthiazolo[3,2-a]pyridines 8 were also performed. The prepared compounds were screened for their in-vitro antibacterial, antifungal, anti-HIV, and anticancer activities: they show promising antifungal activity.     

Synthesis and Biological Screening of 5-{[(4,6-Disubstituted pyrimidine-2-yl)thio]methyl}-N-phenyl-1,3,4-thiadiazol-2-amines

A number of substituted-α,β-unsaturated carbonyl compounds (1a-i) were prepared by Claisen-Schmidt condensation of substituted acetophenone with selected araldehydes, which on cycloaddition with thiourea furnished 4,6-disubstituted pyrimidine-2-thiols (2a-i). Reaction of (2a-i) with ethyl chloroacetate followed by condensation with hydrazine hydrate yielded 2-[(4,6-disubstituted pyrimidine-2-yl) thio] acetohydrazides (4a-c). Condensation of compounds (4a-c) with phenyl isothiocyanate gave 2-{[(4,6-disubstituted pyrimidine-2-yl) thio] acetyl}-N-phenylhydrazinecarbothioamides (5a-c) which on treatment with concentrated sulphuric acid afforded titled compounds 5-{(4,6-disubstituted pyrimidine-2-yl) thio] methyl}-N-phenyl-1,3,4-thiadiazole-2-amines (6a-c). These compounds have been characterized on the basis of elemental analysis, IR, (1)H NMR and MS. Compounds have been evaluated for their anticancer and antioxidant activities. Compounds 2b, 2c and 6b exhibited significant antitumor activity against human breast cancer MCF 7 cell line. However, moderate antioxidant activity was observed with compounds 2c, 2d, 2g and 6b.     

Synthesis and antimicrobial activity of some benzofuran derivatives

The Friedel-Craft's acylation of 2,3-diphenyl-5-methylbenzofuran 1a with succinic anhydride gives beta-(2,3-diphenyl-5-methylbenzofuranoyl)propionic acid 1b. Acid 1b reacts with hydrazines yielding the corresponding tetrahydropyridazinones 2. 4,5-Dihydro-1,2-oxazin-6H-6-one 6 is formed by reaction of 1b with hydroxylamine hydrochloride. The reaction of the pyridazinone 2a with dialkyl sulfates, ethyl chloroacetate, Grignard reagents, amines in presence of formaldehyde (Mannich reaction), o-amino-phenol and thiourea has been investigated. The antimicrobial activities of compounds 1a-c, 2a-c, e, f, 4a, b and 5a, b as well as 7b are studied.     

Synthesis of some novel substituted purine derivatives as potential anticancer, anti-HIV-1 and antimicrobial agents

In search of novel purine antimetabolites, a series of 8-substituted methylxanthine derivatives was prepared in order to explore their in vitro anticancer, anti-HIV-1 and antimicrobial activities. The target compounds include: 8-[(3-substituted-4-oxo-thiazolidin-2-ylidene)hydrazino]-1,3-dimethyl (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 5a-e, 8-[(3,4-disubstituted 2,3-dihydrothiazol-2-ylidene)hydrazino]-1,3,7-trimethyl-3,7-dihydropurine-2,6-diones 6a-d and 8-(5-amino-3-arylpyrazol-1-yl)-1,3-dimethyl- (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 7a-g. The in vitro anticancer results revealed that compound 5d exhibited a super sensitivity profile towards leukemia K-562 with a GI(50) value of <0.01 microM. Compound 7c showed significant activity against colon cancer HCT-15 and renal cancer CAKI-1 (GI(50) values of 0.47 and 0.78 microM, respectively). Compound 7a displayed high activity against colon cancer HCT-15 (GI(50 )= 0.8 microM). The anti-HIV-1 results indicated that compound 6b displayed a good reduction of viral cytopathic effect (56.69%). The antimicrobial results showed that compound 5a was four times more active than ampicillin against P. aerugenosa (MIC =or< 25 microg/mL), compound 5b had twice the activity of ampicillin, while compounds 5d, 7c and 7f were equipotent to ampicillin. On the other hand, compound 7a was equipotent to ampicillin against P. vulgaris (MIC = 50 microg/mL).     

Synthesis of 5-(2-,3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity

New S-alkylated 5-(2-,3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiols (5a-c, 6a-c) and 5-(2-,3- and 4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols (7a-c, 8a-c, 9a-c) were synthesized by the alkylation of 3-(2-,3- and 4-methoxyphenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones (3a-c) or 3-(2-,3- and 4-methoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones (4a-c) with 1-iodobutane or 1-(1,3-benzodioxol-5-yl)-2-bromo-1-ethanone, 2-bromo-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone and 2-bromo-1-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1-ethanone. Compounds 3a-c and 4a-c were synthesized by the acylation of thiosemicarbazide or 4-phenyl-3-thiosemicarbazide with 2-, 3- and 4-methoxybenzoyl chlorides and further cyclization of the obtained acylderivatives 1a-c and 2a-c. The synthesized compounds 4a-c, 5a, 6a-c, 7a-c, 8a-c, 9b,c exhibit anti-inflammatory activity.     

Novel substituted benzothiophene and thienothiophene carboxanilides and quinolones: synthesis, photochemical synthesis, DNA-binding properties, antitumor evaluation and 3D-derived QSAR analysis

A series of new N,N-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo[b]thienyl- and thieno[2,3-b]thienylcarboxanilides and benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones were prepared. Quinolones were prepared by the reaction of photochemical dehydrohalogenation of corresponding anilides. Carboxanilides and quinolones were tested for the antiproliferative activity. 2-Imidazolinyl-substituted derivatives showed very prominent activity. By use of the experimentally obtained antitumor measurements, 3D-derived QSAR analysis was performed for the set of compounds. Highly predictive 3D-derived QSAR models were obtained, and molecular properties that have the highest impact on antitumor activity were identified. Carboxanilides 6a-c and quinolones 9a-c and 11a were evaluated for DNA binding propensities and topoisomerases I and II inhibition as part of their mechanism of action assessment. The evaluated differences in the mode of action nicely correlate with the results of the 3D-QSAR analysis. Taken together, the results indicate which modifications of the compounds from the series should further improve their anticancer properties.     

Synthesis and anticonvulsant activity of novel and potent 2,3-benzodiazepine AMPA/kainate receptor antagonists.

We have previously shown that 1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (3) possess marked anticonvulsant properties and antagonize seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) in analogy to the structurally related 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA/kainate receptor antagonist. We now report the synthesis of 3-(N-alkylcarbamoyl)-1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (4a-h) and 1-aryl-3, 5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepine-4-thiones (5a-c). The activity of all compounds, intraperitoneally (ip) injected, was evaluated against audiogenic seizures in DBA/2 mice and against seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in Swiss mice. Some of the new compounds 4 and 5 showed remarkable anticonvulsant activity, and their toxicity, as evidenced by the rotarod test, is lower than that of 1. The time course of anticonvulsant activity of derivatives 4b and 5b,c was studied and compared to that of 1 and 3b,c. Compounds 4a,b and 5a-c antagonize seizures induced by AMPA and kainate (KA) and their anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 3c, 4b, and 5c to antagonize KA-evoked currents in primary cultures of granule neurons was tested and compared with that of the parent compounds 1 and 1-(4-aminophenyl)-3, 4-dihydro-4-methyl-3-methylcarbamoyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine (2, GYKI 53655).     

Antitumor and antimicrobial activities of some hetero aromatic benzofurans derived from naturally occurring visnagin

Bromination of visnaginone (1) yielded the dibromo derivative (2), which upon methylation with methyl iodide gave 1-(2,7-dibromo-4,6-dimethoxybenzofuran-5-yl) ethanone (3). Compound (3) reacted with dimethylformamide dimethylacetal to give (4). The reaction of (3) with aromatic aldehydes namely (vanillin, benzaldehyde and 3-anisaldehyde) in ammonium acetate, malononitrile and/or butyric cyanoanhydride gave the 2-amino substituted nicotinonitriles (5a-c) and the 2-hydroxyl substituted nicotinonitriles (7a-c), respectively, while in piperidine gave (E)-1-(2,7-dibromo-4,6-dimethoxybenzofuran-5-yl)-3-(substituted)prop-2-en-l-one (11a-c). (5a) was hydrolyzed with sulfuric acid on cold to give the nicotinic acid derivative (6a). When compound (3) reacted with hydrazines and aromatic amines, it gave the Schiff bases (8a,b) and (10a,b), respectively. (8b) reacted with thioglycolic acid to give the thiazolidin-4-one (9b). When (11a-c) reacted with thiourea, it gave the pyrimidine derivatives (12a-c). (11a,b) also reacted with butyric cyanoanhydride and hydroxylamine hydrochloride to give (13a,b) and (15a,b), respectively. When the carboxylate (13a) was treated with 2,4-dinitroaniline, it gave the carboxamide (14a). Compounds (11b,c) reacted with hydrazine derivatives (hydrazine hydrate and phenylhydrazine) yielding the substituted pyrazole derivatives (16b,c) and (17b,c), respectively. All the structures of the synthesized compounds were elucidated by elemental analyses and spectral data. The newly synthesized benzofuran compounds showed a strong to moderate cytotoxicity against liver HEPG2 cancer cell line compared to 5-fluorouracil and doxorubicin (the anticancer agents). Compounds (2, 6a, 13a, 14a, 16c and 17b) were the most active compounds in descending order. The synthesized compounds were also tested for their antimicrobial activity. Compound (10b) showed the highest activity against all the tested strains followed by 6, 10a, 5a, 8b and 7a in descending order.     

Synthesis of novel biologically active heterocyclic compounds from 2-oxo-2H-benzopyran-6-yl-imidazolidine

6-Aminocoumarin on treatment with oxalyl chloride gives coumarinyl-6-isocynate (1a-c) which on treatment with glycine gives 1H-3-[2'-oxo-2'H-benzopyran-6'-yl]-5-imidazolidine-2, 4-dione (2a-c). (2a-c) when refluxed with o-chlorobenzaldehyde, m-hydroxybenzaldehyde, 3,4-dimethoxybenzaldehyde and 3-nitrobenzaldehyde separately gives 1H-5-(2"-chlorobenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (3a-c), 1H-5-(3"-hydroxybenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (4a-c), 1H-5-(3",4"-dimethoxybenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (5a-c) and 1H-5-(3"-nitrobenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (6a-c), respectively. 3-(2"-Chlorophenyl)-3a,4-dihydro-6-(2'-oxo-2'H-benzopyran-6'-yl) imidazo[4,5-c]isoxazol-5-one 7a-c is obtained from (3a-c) and hydroxylamine hydrochloride while 2,3a,4-trihydro-3-(3"-hydroxyphenyl)-6-(2'-oxo-2'H-benzopyran-6'-yl) imidazo[4,5-c]pyrazol-5-one (8a-c) obtained by reaction of (4a-c) with hydrazine hydrate. Compound (5a-c) on treatment with urea gives 5,7-dihydro-2-hydroxy-6-(3",4"-dimethoxyphenyl)-9-(2'-oxo-2'H-benzopyran-6'-yl) purin-8-one (9a-c) and compound (6a-c) on treatment with thiourea gives 5,7-dihydro-2-mercapto-6-(3"-nitrophenyl)-9-(2'-oxo-2'H-benzopyran-6'-yl)purin-8-one (10a-c). The structures of the compounds have been established on the basis of spectral analytical data. All the compounds have been screened for their antimicrobial activities against three bacterial strains S. aureus, S. typhi and E. coli. Compounds 2b, 3b, 4b, 5b, 6b, 7b, 8b, 9b and 10b with the presence of methyl groups at C7' and C8' of coumarin moiety were found to be more active than others.     

Synthesis, cytotoxicity, and antiviral activity of some acyclic analogues of the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics tubercidin, toyocamycin, and sangivamycin

A number of 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3d-d]pyrimidine derivatives that are structurally related to toyocamycin and sangivamycin and the seco nucleosides of tubercidin, toyocamycin, and sangivamycin were prepared and tested for their biological activity. Treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]-pyrimidine with 1,3-bis(benzyloxy)-2-propoxymethyl chloride afforded compound 3, which without isolation was debrominated to obtain 4-amino-5-cyano-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine. Although catalytic hydrogenolysis failed, the benzyl ether functionalities of 4 were successfully cleaved by boron trichloride to afford 4-amino-5-cyano-7-[(1,3-dihydroxy-2- propoxy)methyl]pyrrolo[2,3-d]pyrimidine. Conventional functional group transformation of the cyano group of 6 provided a number of novel 5-substituted derivatives. Tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were treated separately with sodium metaperiodate and then with sodium borohydride to afford the 2',3'-seco derivatives 9a-c, respectively. The acyclic nucleoside 4-chloro-2-(methylthio)-7-[[1,3-bis(benzyloxy)-2- propoxy]methyl]pyrrolo[2,3-d]pyrimidine was aminated, desulfurized with Raney Ni, and then debenzylated to provide the tubercidin analogue 11. Cytotoxicity evaluation against L1210 murine leukemic cells in vitro showed that although the parent compounds tubercidin (8a), toyocamycin (8b), and sangivamycin (8c) were very potent growth inhibitors, the acyclic derivatives 6, 7a-c, and 9a-c had only slight growth-inhibitory activity. Evaluation of compounds 6, 7a, 7b, 7c, 9a, 9b, 9c, 11 for cytoxicity and activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) revealed that only the carboxamide (7a) and the thioamide (7c) were active. Compound 7c was the more potent of the two, inhibiting HCMV but not HSV-1 at concentrations producing little cytotoxicity.     

Syntheses and in vitro antimicrobial evaluation of some benzimidazol-2-ylmethylthioureas, benzimidazol-2-ylacetylthiosemicarbazides and products of their condensation with monochloroacetic acid

N-Benzimidazol-2-ylacetyl-N'-[alkyl- and arylthio (carbamoyl)]hydrazines and N-benzimidazol-2-ylmethyl-N'-alkyl- and -arylthioureas were subjected to condensation with monochloroacetic acid to afford N-benzimidazol-2-ylacetyl-N'-2,3, 4,5-tetrahydro-4-oxo-3-alkyl- and -arylthiazol-2-ylidenehydrazines and 3-benzimidazol-2-ylmethyl-2-alkyl- and arylimino-2,3-dihydrothiazol-4-(5H)ones, respectively. In preliminary antimicrobial testing, some compounds turned out to have significant activity against Staphylococcus aureus.     

Novel synthesis and antifungal activity of pyrrole and pyrrolo[2,3-d]pyrimidine derivatives containing sulfonamido moieties

Several sulfonamides containing pyrroles (2a-c, 6a-d, 8a-d), pyrrolo[2,3-d] pyrimidines (3a-c), acetanilides (11a-c) and tetrahydrobenzothiophenes (13a-c) were synthesized starting from N4-chloroacetylsulfanilamides (1a-d). The structures of synthesized compounds were elucidated by elemental analyses and spectral data. Compounds 2b, 3b, 6b, 8b and 8d exhibited a remarkable antifungal activity compared with the standard fungicide mycostatine.     

Synthesis of beta-hydroxypropanoic acid derivatives as potential anti-inflammatory, analgesic and antimicrobial agents

A series of new 3-(substituted) 3-hydroxy-propanoic acid ethyl esters 1a-c, hydrazides 2a-c, thiosemicarbazides 3a-f, and semicarbazides 3g, 3h has been synthesized. Cyclization of compounds 3a-d in basic medium yielded 1,2,4-triazole-5-thiones 4a-d. On the other hand, reaction of hydrazides 2a-c with CS(2 )in basic medium afforded 1,3,4-oxadiazole-5-thiones 5a-c. All the synthesized compounds were characterized by their physical and spectral analyses data. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic, and antimicrobial activities. Compounds 1c, 3g, 4a, 4b, 4c, and 5c exhibited comparable anti-inflammatory activity to that of indomethacin and compounds 1c, 4c, and 5c were more analgesics than acetyl salicylic acid. Compounds 4b, 4c, and 5c showed superior GI safety profile (33.3%, 33.3% and 50.0% ulceration) than that of indomethacin (100% ulceration) at 100 mg/kg oral dose. Compounds 4b, 4c, and 5c were also non-toxic with a median lethal dose (LD(50)) up to 200 mg/kg. The antibacterial and antifungal screenings identified compounds 3c, 4b, 4d, 5a, and 5b as the most effective against a variety of tested microorganisms.     

Synthesis and cytotoxicity of 4-amino-5-oxopyrido[2,3-d]pyrimidine nucleosides

A number of nucleoside analogues have been either used clinically as anticancer drugs or evaluated in clinical studies, while new nucleoside analogues continue to show promise. In this article, we report synthesis and cytotoxicity of a series of new pyrido[2, 3-d]pyrimidine nucleosides. 2-Amino-3-cyano-4-methoxypyridine was converted, in two steps, to 4-amino-5-oxopyrido[2,3-d]pyrimidine. A variety of 1-O-acetylated pentose sugar derivatives were condensed with silylated 4-amino-5-oxopyrido[2,3-d]pyrimidine, followed by protection, to afford a series of 4-amino-5-oxopyrido[2, 3-d]pyrimidine nucleosides. Further derivatizations provided an additional group of pyrido[2,3-d]pyrimidine nucleosides. These nucleosides were evaluated for in vitro cytotoxicity to human prostate cancer (HTB-81) and mouse melanoma (B16) cells as well as normal human fibroblasts (NHF). A number of compounds (1a,b, 2a-c,f, 3f+4d) showed significant cytotoxicity to cancer cells, with 4-amino-5-oxo-8-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (1b) being the most potent proliferation inhibitor (EC(50): 0.06-0.08 microM) to all types of cells tested. However, a selective inhibition to the cancer cells was observed for 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine (2b), which is a potent inhibitor of HTB-81 (EC(50): 0.73 microM) and has a favorable in vitro selectivity index (28).     

Novel synthesis, cytotoxic evaluation, and structure-activity relationship studies of a series of alpha-alkylidene-gamma-lactones and lactams

5-Alkyl- and 5-arylalkyl-3-methylenedihydrofuran-2-ones 13a-e, 3-alkylidenedihydrofuran-2-ones 18a-c, and 3-methylenepyrrolidin-2-ones 16a-e were synthesized utilizing ethyl 2-diethoxyphosphoryl-4-nitroalkanoates 9a-e as common intermediates. All obtained compounds were tested against L-1210, HL-60, and NALM-6 leukemia cells. The highest cytotoxic activity was observed for 3-methylenefuranones 13d,e bearing benzyl or 3,4-dimethoxyphenylmethyl substituents at position 5, with IC(50) values of 5.4 and 6.0 microM, respectively. Contrary to the literature reports, no enhancement in activity due to the presence of a hydroxy group was found when the cytotoxicity of furanones 13a,b,d and 5-(1'-hydroxyalkyl)-3-methylenedihydrofuran-2-ones 6a,b,d was compared. The anticancer activity of pyrrolidinones 16a-e and 3-alkylidenefuranones 18a-c was much weaker than that of furanones 13a-e.