Synthesis of some new bioactive 3-amino-2-mercapto-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives

Nine new 2-(substituted phenyl)/alkyl[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-ones, six new 3-amino-2-[(2-oxo-2-(aryl)ethyl)thio]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones, one 2-mercapto[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-one and one 2-chloromethyl[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-one were synthesized from 3-amino-2-mercapto-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one. The newly synthesized compounds were characterized by analytical and spectral data. Compounds were screened for anti-inflammatory, CNS depressant and antimicrobial activities. Some of the compounds exhibited promising biological activities.     

Regioselective synthesis of dispiro[1H-indene-2,3'-pyrrolidine-2',3'-[3H]indole]-1,2'(1'H)-diones of potential anti-tumor properties

1,3-Dipolar cycloaddition reaction of 2-(arylmethylene)-2,3-dihydro-1H-inden-1-ones 1a-g with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a,b and sarcosine (3) afforded dispiro[1H-indene-2,3'-pyrrolidine-2',3'-[3H]indole]-1,2'(1'H)-diones 4a-n and not the isomeric forms dispiro[1H-indene-2,4'-pyrrolidine-2',3'-[3H]indole]-1,2'(1'H)-diones 5 in a highly regioselective manner. Anti-tumor activity screening for the synthesized compounds (4c,d,i-l) at a dose of 10 microM utilizing 56 different human tumor cell lines representing, leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney was carried out. All the tested compounds exhibit promising anti-tumor activity against SK-MEL-2 (melanoma) cell line. Anti-inflammatory activity of the prepared compounds was determined in vivo by the acute carrageenan-induced paw oedema in rats. Many of the prepared compounds exhibit considerable anti-inflammatory properties "at a dose of 50 mg/kg body weight", especially 4a and 4m which reveal remarkable activities relative to indomethacin which was used as a reference standard in this study.     

Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4(3H)-ones and 4, 6- disubstituted- 1, 2, 3, 4-tetrahydroquinazolin-2H-ones

The synthesis of some new 3-substituted quinazolin-4(3H)-ones and 3,4-dihydro-quinazolin-2(1H)-one derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI), disease oriented antitumor screening protocol are investigated. Compounds 2-[2-(4-chlorophenyl)-2-oxo-ethylthio]-3-(4-methoxyphenyl)quinazolin-4(3H)-one (3b), and 3-(4-chlorophenyl)-2-[2-(4-methoxyphenyl)-2-oxo-ethylthio]quinazolin-4(3H)-one (3d), are broad-spectrum antitumors showing effectiveness toward numerous cell lines that belong to different tumor subpanels, Compounds 3b, 3d are the most active members in this study. Those two quinazoline analogues could be considered as useful templates for future development to obtain more potent antitumor agent(s).     

Synthesis, antitrichinnellosis and antiprotozoal activity of some novel thieno[2,3-d]pyrimidin-4(3H)-ones containing benzimidazole ring

Some novel thieno[2,3-d]pyrimidin-4(3H)-ones containing benzimidazol-2-yl-thioethyl- and benzimidazol-2-yl-methanethioethyl moiety in second position of the pyrimidine ring were synthesized in order to determine their antitrichinellosis and antiprotozoal effects. The structures of the compounds were confirmed by IR, (1)H NMR and elemental analysis. The antiparasitic screening showed that the benzimidazole derivatives of thieno[2,3-d]pyrimidin-4(3H)-ones exhibited higher activity against Trichinella spiralis in vitro in comparison albendazole. The most active compound, 2-[2-(5-nitro-1H-benzimidazol-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one 22 revealed 95% activity at a dosage of 5?mg/kg?mw after 24?h, while compounds 8 and 10 applied at the same dose showed efficacy of 90% after 48?h. The compound 2-{2-[(5(6)-nitro-1H-benzimidazol-2-yl)thio]ethyl}-5,6,7,8-tetrahydro[1]-benzothieno[2,3-d]pyrimidin-4(3H)-one 11 exhibited 90% efficacy after 24?h. The pharmaco-therapeutic study in vivo on invaded with Lamblia muris white mice showed 100% effectiveness of the compounds 8, 10, 11, 13-15 and 22, 23 after five-days-treatment course.     

Synthesis and antimicrobial activity of new 1-alkyl/cyclohexyl-3,3-diaryl-1'-methylspiro[azetidine-2,3'-indoline]-2',4-diones

The paper describes the synthesis of new 1-alkyl/cyclohexyl-3,3-diaryl-1'-methylspiro[azetidine-2,3'-indoline]-2',4-diones from the reactions of the 2-diazo-1,2-diarylethanones with 1-methyl-3-(alkyl/cyclohexylimino)indolin-2-ones under thermal condition. The compounds, characterized by satisfactory analytical and spectral (IR, (1)H NMR and (13)C NMR) data, have been screened for their antibacterial and antifungal activities.     

Antimicrobial studies of some novel quinazolinones fused with [1,2,4]-triazole, [1,2,4]-triazine and [1,2,4,5]-tetrazine rings

Three series of novel and new fused heterocyclic systems, viz. triazolo[4,3-a]-quinazolin-7-ones (4), [1,2,4,5]-tetrazino[4,3-a]-quinazolin-8-ones (6) and indolo[2,3-c][1,2,4]-triazino[4,3-a]-quinazolin-8-ones (8) have been synthesized from the key intermediate 3-(substituted-phenyl)-2-hydrazino-quinazolin-4-ones (3). Thus, condensation of (3) with appropriate aromatic acids in the presence of DCC in dichloromethane afforded the fused system (4), while reaction of (3) with isatin in methanol gave the corresponding Schiff base (7) which on cyclodehydration furnished another fused heterocyclic system (8). The intermediate (3) on refluxing with substituted-phenylisothiocyanate gave the substituted-thiosemicarbazide (5), which on oxidative cyclization with bromine in CCl(4) furnished the novel fused system (6). The structures of intermediate and final compounds have been determined by means of IR, (1)H NMR, (13)C NMR, UV and elemental analysis. All the synthesized compounds have been screened for their antibacterial activity against gram-negative bacteria, Escherichia coli, Pseudomonas aeruginosa and gram-positive bacteria, Streptococcus pneumoniae, Bacillus subtilis, as well as demonstrated significant antifungal activity against fungi viz. Candida albicans, Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger.     

Regioselective synthesis and stereochemical structure of anti-tumor active dispiro[3H-indole-3,2'-pyrrolidine-3',3'-piperidine]-2(1H),4'-diones

Reaction of 3,5-bis(arylmethylene)-1-methyl-4-piperidinones 1a-1g with azomethine ylides (generated in situ via decarboxylative condensation of isatins 2a,2b with sarcosine 3) in refluxing ethanol afforded 4'-aryl-5'-(arylmethylene)-dispiro[3H-indole-3,2'-pyrrolidine-3',3'-piperidine]-2(1H),4'-diones 4a-4m as the sole product in a high regioselective manner. Anti-tumor activity screening of 4e,4f,4k,4m, as representative examples of the synthesized compounds, at a dose of 10 microM utilizing 59 different human tumor cell lines representing leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney exhibited that, the tested compounds reflect mild activity against most of the used human tumor cells. Meanwhile, all the tested compounds reveal considerable anti-tumor properties against colon (HCT-116), breast (T-47D), leukemia [HL-60 (TB), MOLT-4, RPMI-8226] and prostate (PC-3) cancers. Anti-inflammatory properties of the prepared compounds (at a dose of 50 mg/kg body weight) using in vivo acute carrageenan-induced paw oedema in rats exhibited that all the tested compounds possess considerable anti-inflammatory activity especially 4a,4k,4l which reveal remarkable activities with potency 125.5, 139.3 and 126.4, respectively, relative to indomethacin which was used as a reference standard (at a dose of 10 mg/kg body weight).     

Synthesis and primary cytotoxicity evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones

New esters (2b and 2c) and hydrazides (3b and 3c) were synthesized from 6-methyl/fluoro-3-phenyl-4(1H, 3H)-quinazolinone-2-thiones (1b and 1c). Subsequent treatment of 3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetic acid hydrazides (3a-e) with 1H-indole-2,3-diones (4a-e) furnished the corresponding 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones (5a-u). The structures of new compounds were determined by analytical and spectral (IR, 1H-NMR, (13)C-NMR, EIMS) methods. Previously reported 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-bromo-1H-2-indolinone 5v and compounds 5b, 5d and 5o chosen as prototypes were evaluated against the full panel of 60 human tumour cell lines at a minimum of five concentrations at tenfold dilutions in the National Cancer Institute in vitro primary cytotoxicity assay. Sulforhodamine B protein assay was used to estimate cell stability or growth. 3-[[(6-Chloro-3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-5-fluoro-1H-2-indolinone 5o showed the most favourable cytotoxicity against a renal cancer cell line UO-31 (log(10)GI(50) value -6.68). Compound 5v was also tested against human immunodeficiency virus 1 (HIV-1). Compound 5v was confirmed moderately active against HIV-1.     

Efficient microwave-assisted synthesis and antitumor activity of novel 4,4'-methylenebis[2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols

Two new series of 4,4'-methylenebis[2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols] 4 and methylenebis-2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-4,1-phenylene diacetates 5 have been efficiently prepared starting from the commercially available salicylaldehyde and where the key step corresponded to the microwave-assisted reaction of intermediates 3,3'-[methylenebis(6-hydroxy-3,1-phenylene)]bis(1-arylprop-2-en-1-ones) 3 with hydrazine hydrate or acetic acid/hydrazine hydrate respectively. Three unacetylated compounds type 4 presented interesting antitumor activities against a wide range of tumor cell lines.     

Synthesis and pharmacological investigation of novel 4-(2-methylphenyl)-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as new class of H(1)-antihistaminic agents

A series of novel 1-substituted-4-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino-3-(2-methylphenyl)-3H-quinazolin-4-one with various one carbon donors. The starting material 2-hydrazino-3-(2-methylphenyl)-3H-quinazolin-4-one was synthesized from 2-methyl aniline by a novel innovative route. The title compounds were tested for their in vivo H(1)-antihistaminic activity on guinea pigs; all the tested compounds protected the animals from histamine-induced bronchospasm significantly. Compound 1-methyl-4-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (72.45%) when compared to the reference standard chlorpheniramine maleate (71%). Compound II showed negligible sedation (11%) when compared to chlorpheniramine maleate (30%). Hence it could serve as the prototype molecule for further development as a new class of H(1)-antihistaminic agents.     

Synthesis, analgesic, anti-inflammatory, ulcerogenic index and antibacterial activities of novel 2-methylthio-3-substituted-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-4(3H)-ones

A variety of novel 2-methylthio-3-substituted-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-4(3H)-ones have been synthesized by reacting (2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)dithiocarbamic acid methyl ester (5) with a variety of amines. The starting material dithiocarbamate (5) was synthesized from 2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo (b) thiophene (1) by a novel innovative route. The title compounds were investigated for analgesic, anti-inflammatory, ulcerogenicity index and antibacterial activities. While the test compounds exhibited significant activity, the compounds 1-methyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A1), 1-dimethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A2), 1-diethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A3) and 1-pyrrolidinyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A4) showed more potent analgesic activity and the compounds 1-dimethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d]pyrimidin-3-yl)thiourea (A2), 1-diethyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno-[2,3-d]pyrimidin-3-yl)thiourea (A3) and 1-pyrrolidinyl-3-(2-methylthio-4-oxo-3H-5,6,7,8-tetrahydrobenzo (b) thieno[2,3-d] pyrimidin-3-yl)thiourea (A4) showed more potent anti-inflammatory activity than the reference standard diclofenac sodium.     

Synthesis of new 2-substituted pyrido[2,3-d]pyrimidin-4(1H)-ones and their antibacterial activity

2-Substituted-5,7-dimethyl pyrido[2,3-d]pyrimidin-4(1H)-ones (8) were synthesized by oxidation of 2-substituted-5,7-dimethyl dihydropyrido[2,3-d]pyrimidin-4(1H)-ones (7) which were in turn prepared from 2-amino-4,6-dimethyl nicotinamide (5) and substituted aryl aldehydes (6). 2-Amino-4,6-dimethyl nicotinamide (5) was prepared from ethyl cyanoacetate (1) via malonamamidine hydrochloride (3). The compounds were characterized by IR, NMR, MS and elemental analyses. Compounds 7 and 8 were screened for antibacterial activity against gram positive and gram negative bacteria. Dehydrogenated compounds (8) showed less antibacterial activity than the compounds 7. Among all the test compounds screened for antibacterial activity 7c (1.25 microg/ml) showed greater activity. All the synthesized compounds were found inactive when screened for antifungal activity at the concentration of 200 microg/ml.     

Synthèse et activité anti-dépressive potentielle de nouvelles triazine-1,2,3 ones-4

A series of 1,2,3-triazin-4-ones was prepared and examined for potential anti-depressive activity by comparison with trazodone 2. Several of them show a potentiation of the central effects of 5-hydroxytryptophan (5-HTP) higher than trazodone, particularly 3-[3-[4-(3-chlorophenyl)piperazin-1-yl]-propyl]-1,2,3-benzotriazin-4(3H)-one 3 and 3-[[3-[4-(3-chlorophenyl)piperazin-1-yl]2-hydroxy]propyl]-1,2,3-benzotriazin-4-(3H)-one 16.     

Synthesis, structure, toxicological and pharmacological investigations of 4-hydroxycoumarin derivatives

Twenty 4-hydroxycoumarin derivatives were synthesized. Five of them are described for the first time. The X-ray crystal structure analysis of 3,3'-(2,3,4-trimethoxyphenylmethylene)bis-(4-hydroxy-2H-1-benzopyran-2-one) (7) and 3,3'-(3,5-dimethoxy-4-hydroxyphenylmethylene)bis-(4-hydroxy-2H-1-benzopyran-2-one) (9) confirmed the structure of these compounds. A comparative pharmacological study of the anticoagulant effect with respect to Warfarin showed that the synthesized compounds have different anticoagulant activities. The most prospective compound is 3,3'-(4-chlorophenylmethylene)bis-(4-hydroxy-2H-1-benzopyran-2-one) (12) with low toxicity, very good index of absorption and dose dependent anticoagulant activity.     

Synthesis and antimicrobial properties of 2-(benzylidene-amino)-benzo[d]isothiazol-3-ones

The in vitro antimicrobial activity of 2-amino-benzo[d]isothiazol-3-one and of several 2-arylideneamino derivatives carrying in the second position a substituted or unsubstituted aromatic ring or an arylalkenylidene moiety was determined by the broth dilution method against several strains selected to define their spectrum and potency. All the compounds demonstrated good antibacterial properties against Bacillus subtilis, streptococci, enterococci and staphylococci including penicillin-resistant clinical isolates. Several compounds showed excellent inhibitory properties against Streptococcus pyogenes, which is the most sensitive microorganism tested. Many benzisothiazolones exhibited good activity against Gram-negative Haemophilus influenzae. As regards antifungal activity, several of the tested compounds inhibited Saccharomyces cerevisiae at concentrations of 3-6 microg ml-1. In all cases the parent 2-amino-benzo[d]isothiazol-3-one was the most effective agent, with minimum inhibitory concentration (MIC) values ranging from 0.07 to 6 microg ml-1. The results obtained indicate that most of these compounds are wide-spectrum antimicrobial substances and promising agents against penicillin-resistant staphylococci.     

Thiazolyl/oxazolyl formazanyl indoles as potent anti-inflammatory agents

A series of 3-(2'-substituted indolidene aminothiazol-4'-yl)-2-(4-chlorophenyl) indoles (3a-3d), 3-(2'-substituted indolidene amino oxazol-4'-yl)-2-(4-chlorophenyl) indoles (3a'-3d') and 3-[2'-(1'-substituted phenyl-3'-substituted indolyl formazan-4'-yl) thiazol-4'-yl]-2-(4-chlorophenyl) indoles (4a-4h), 3-[2'-(1'-substituted phenyl-3'-substituted indolyl formazan-4'-yl) oxazol-4'-yl]-2-(4-chlorophenyl) indoles (4a'-4h') were synthesized and evaluated for their anti-inflammatory activity against carrageenan induced oedema in albino rats at a dose of 50mg/kg p.o. The structure of all these compounds were established on the basis of elemental and spectral (IR, (1)H NMR and mass spectral data) studies. All the compounds of this series show moderate to good activity. The most active compound of this series 3-(2'-methyl indolidene aminothiazol-4'-yl)-2-(4-chlorophenyl) indole (3b) is found to be the most potent and has shown higher percent of inhibition of oedema, lower ulcerogenic liability and acute toxicity than the reference drug phenyl butazone.     

Synthesis of 3-acetoxyazetidin-2-ones and 3-hydroxyazetidin-2-ones with antifungal and antibacterial activity

The synthesis of a series of 3-acetoxyazetidin-2-ones 3a–n and 3-hydroxyazetidin-2-ones 6a–j is reported together with the antibacterial and antifungal evaluation of these compounds. An additional series of 3-acetoxyazetidin-2-ones 11a–h which possess a free carboxylic acid group on the N-1 aryl ring were obtained by treatment of suitably substituted Schiff bases 10a–h with acetoxyacetyl chloride. The novel bicyclic structures 7-acetoxy-6-phenyl-5-thia-1-azabicyclo[4.2.0]octan-8-one 13 and 7-hydroxy-6-phenyl-5-thia-1-azabicyclo[4.2.0]octan-8-one 14 were also obtained. Many of the compounds displayed antifungal activity in vitro when evaluated against the pathogenic fungi Cryptococcus neoformans, Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Trichosporon cutaneum, while 3-acetoxyazetidin-2-ones 11a–h containing a free carboxylic acid group on the N-1 aryl ring displayed antibacterial activity against Staphylococcus aureus, Proteus vulgaris, Pseudomonas aeruginosa, Bacillus subtilis, Klebsiella aerogenes and Escherischia coli.     

In-vitro regeneration of sarin inhibited electric eel acetylcholinesterase by bis-pyridinium oximes bearing xylene linker

A series of bis-pyridinium oximes connected by xylene linker were synthesized and their in-vitro reactivation potential was evaluated against acetylcholinesterase (AChE) inhibited by nerve agent, sarin. Among the synthesized compounds, alpha,alpha'xylene-bis-[3,3'-(hydroxyiminomethyl) pyridinium] dibromide (3b) was found to be most potent reactivator for AChE inhibited by sarin. The oxime 3b exhibits 34% regeneration of inhibited AChE, in comparison to 20 and 15% regeneration by 2-PAM and obidoxime, respectively, at a concentration of 10(-4) M within 10 min.     

Synthesis and anti-inflammatory activity of newer quinazolin-4-one derivatives

2-Methyl-3-aminosubstituted-3H-quinazolin-4-ones (1-2), 2-methyl-3-(substituted-arylidene-amino)-substituted-3H-quinazolin-4-ones (3-10), 2-bromomethyl-3-(substituted-arylidene-amino)-substituted-3H-quinazolin-4-ones (11-18), 2-(5'-pyridin-4-yl-[1,3,4]-oxadiazol-2-yl-sulfanylmethyl)-3-(substituted-arylidene-amino)-substituted-3H-quinazolin-4-ones (19-26), 3-(3-chloro-2-oxo-4-substituted-aryl-azetidin-1-yl)-2-(5-pyridin-4-yl-[1,3,4]-oxadiazol-2-yl-sulfanylmethyl)-substituted-3H-quinazolin-4-ones (27-34) and 3-(4-oxo-2-substituted-aryl-thiazolidin-3-yl)-2-(5-pyridin-4-yl-[1,3,4]-oxadiazol-2-yl-sulfanylmethyl)-substituted-3H-quinazolin-4-ones (35-42) were synthesized in present study. All the compounds exhibited anti-inflammatory activity at the dose 50 mg/kg p.o. varying degree from 16.3 to 36.3% inhibition of oedema. Compound 40 showed same activity at 25, 50 and 100 mg/kg p.o. like standard drugs. The structure of all these newly synthesized compounds was confirmed by their analytical (C, H, N) and spectral (IR and (1)H NMR) data.