Synthesis and biological activity of new heterocyclic structures: [1,3]thiazino[2,3-i]purine, thiazolo[3,2-c] [1,2,3]triazolo[4,5-e]pyrimidine and [1,2,3]triazolo [4', 5': 4,5] pyrimido[6,1-b][1,3]thiazine.

Some derivatives of thiazolo[3,2-c]pyrimidine, pyrimido[6,1-b][1,3]thiazine, thiazolo[2,3-i]purine, [1,3]thiazino[2,3-i]purine, thiazolo[3,2-c][1,2,3]triazolo[4,5-e]pyrimidine and [1,2,3]triazolo[4',5':4,5]pyrimido[6,1-b][1,3]thiazine were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely, Escherichia coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, Aspergillus sp., and for antiviral activity on Herpes simplex virus, Type 1 (HSV-1), Vesicular stomatitis virus (VSV) and Coxsackievirus B5 (CoxB5). The compounds proved to be devoid of activity against viruses, mycetes and gram-negative bacteria, while some of them exhibited a modest activity against gram-positive bacterial strains.     

Potential antitumor agents. 37. Synthesis and antitumor activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline

This paper reports synthesis and antitumor activity of new guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline. The compounds were tested as potential antitumor agents at the National Cancer Institute. The effect of the guanylhydrazone of 2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde (41) was investigated, and it was found to be an inhibitor of Complex III of the mitochondrial respiratory chain and is able to induce apoptosis in the cell lines HT29 and HL60.     

Fluorine-containing heterocycles: synthesis and some reactions of new 3-amino-2-functionalized-6-(2'-thienyl)-4-trifluoromethylthieno [2,3-b]pyridines

3-Cyano-6-(2'-thienyl)-4-trifluoromethylpyridine-2(1H)-thione (2) was prepared and reacted with chloroacetone or phenacyl bromide to yield the 2-acetyl or benzoyl-3-amino-6-(2'-thienyl)-4-trifluoromethylthieno[2,3-b]pyridines (3a, b). In contrast, the reaction of 2 with chloroacetamide or its N-aryl derivatives gave the corresponding 2-carbamoylmethyl thiopyridines 4a-c. Upon treatment of these educts with K2CO3 or C2H5ONa in ethanol, they underwent intramolecular Thorpe-Ziegler cyclization to afford 3-amino-2-carbamoyl-6-(2'-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridine (5a) and its N-aryl analogs 5b, c. Compounds 5a-c underwent some reactions to yield new pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and pyrido[3',2':4,5]thieno[3,2-d][1,2,3] triazines.     

Synthesis of new pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines and a 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno [2,3-d]-pyrimidine ring system

A series of substituted pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 4-6, 8, pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 11-13 and 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno[2,3-d] pyrimidines 16-19 have been synthesized from 3, 10 and 15 through the reaction with orthoesters and carbon disulphide, respectively.     

Synthesis and biological evaluation of some pyrimidine, pyrimido[2,1-b][1,3]thiazine and thiazolo[3,2-a]pyrimidine derivatives

4,6-Diamino-1H-pyrimidine-2-thione (1) was used for the preparation of pyrimidine derivatives 2-5. Compound 5 was cyclized to produce pyrimido[2,1-b][1,3]thiazine derivative 6 which was condensed with p-chlorobenzaldehyde to give compound 7. The latter compound was reacted with hydroxylamine to give isoxazolo[4,5-d]thiazino[2,3-a]pyrimidine 8. Compound 8b was treated with 2-chloroethyl methyl ether to afford compound 9. Similarly, compound 3 reacted with chloroacetic acid to give thiazolo[3,2-a]pyrimidine 10, which was condensed with p-chlorobenzaldehyde to give compound 11. Compound 11 was condensed with hydroxylamine to give isoxazolo[4,5-d]thiazolo[2,3-a]pyrimidine 12. Compound 12b was treated with 2-chloroethyl methyl ether to afford compound 13. Biological evaluation of some prepared products showed that many of them revealed promising antimicrobial activity.     

Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents

The key intermediate octahydroquinazoline (1) was obtained in one pot synthesis by a modification of the Biginelli reaction. Compound 1 was allowed to react with phenacyl bromide and bromomalononitrile to furnish thiazolo[2,3-b]quinazoline 3 and 12, respectively. Interaction of compound 12 with formamide, formic acid and phenyl isothiocyanate yielded the corresponding pyrimidino[4',5':4.5]thiazolo[2,3-b] quinazolines 13, 14 and 17, respectively. The structure of the synthesized compounds were elucidated by elemental analyses and spectroscopic analyses. Some of the prepared compounds were tested for their antifungal activity in comparison with tioconazole as a reference fungicide.     

5-HT and benzodiazepine receptor ligands. III. Synthesis and receptor affinities of 1,2,4-triazolo[4',3':1,6]pyridazino[4,5-b]quinoline and 2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one derivatives

The syntheses as well as 5-HT and Benzodiazepine receptor binding studies of some 1,2,4-Triazolo[4',3':1,6]piridazino[4,5-b]quinoline and 2,3-Dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one derivatives are reported. While the triazole-containing heterocycles are devoid of any biological activity, 2-benzyl-2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinoline-1-one shows some affinity for the central type of benzodiazepine receptors.     

Synthesis of novel thieno[2,3-d]pyrimidine, thieno[2,3-b]pyridine and thiazolo[3,2-a]thieno[2,3-d]pyrimidine derivatives and their effect on the production of mycotoxins.

The thiophene derivative 1 reacts with the active methylene reagents 2a-c to afford the thieno[2,3-d]pyrimidine derivatives 6a,b and 8, respectively. 1 reacts with phenacyl bromide 2d to afford the N-alkylation product 9 and reacts with phenacyl thiocyanate 2e to afford the N-(thiazol-2-yl) derivative 10, which was further cyclized into thiazolo[3,2-a]thieno[2,3-d]pyrimidine derivative 12. Compound 1 reacts also with the cinnamonitriles 3a,b to afford the thieno[2,3-b]pyridines 15a,b, respectively. 1 undergoes either acetylation or hydrolysis to afford the thieno[2,3-b]pyridine derivative 19 and the thiophene derivative 22, respectively. Some of the new compounds show inhibitory effect to the production of mycotoxins and to fungal growth.     

Reactions of 4-oxo-4H-pyrido(3',2':4,5)thieno(3,2-d)-1,3-oxazines with amines]

The reaction of the title compounds with amines gave in dependence of the reaction conditions and the structure of the title compounds and the amine 3-acylamino-thieno[2,3-b]pyridine-2-carbonamides (B), 4-oxo-4 H-pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (D),N-(2-carboxy-thieno[2,3-b]pyridine-3-yl)amidines (C) and N-(thieno[2,3-b]pyridin-3-yl)amidines (E). Substances of structure C and E seem to be of biological interest, especially for their antianaphylactic reactions.     

Synthesis of 6,7-dialkoxy-2-arylmethylidene-2,3- dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol-3-ones exhibiting anti-inflammatory activity

New 6,7-dialkoxy-2-arylmethylidene-2,3- dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol-3-ones (3a-h, 4b, c, e, g) were synthesized from 2-(5,6-dialkoxy-1H-benzo[d]imidazol-2-ylsulfanyl)acetic acids (1, 2) and corresponding aromatic aldehydes in acetic anhydride. The compounds 3e, f and 4b, g were also synthesized from corresponding aromatic aldehydes and 6,7-dialkoxy-2,3-dihydrobenzo[4,5]imidazo[2,1-b][1,3]thiazol -3-ones (5, 6) obtained by the cyclization of the acids 1 and 2 in acetic anhydride. The synthesized compounds 3a-h and 4b, c, e, g exhibit anti-inflammatory activity.     

Synthesis of N-(2-carboxy-thieno(2,3-b)pyridin-3-yl)-amidines by the reaction with 4-oxo-4H-pyrido(3',2':4,5)-thieno(3,2-d)-1,3-oxazines with secondary cycloaliphatic amines]

4-Oxo-4H-pyrido[3',2':4,5]thieno[3,2-d]1,3-oxazines react with secondary cycloaliphatic amines to give besides the expected bisamides the amine salts of N-(2-carboxy-thieno[2,3-b]pyridine-3-yl)amidines. These compounds showed inhibitory activity against different lipoxygenases, but a small chemical stability.     

Sterically controlled regiospecific heterocyclization of 3-hydrazino-5-methyl-1,2,4-triazino[5,6-b]indole to 10-methyl-1,2,4-triazolo[4',3':2,3[1,2,4-triazino[5,6-b]indoles

3-Hydrazino-5-methyl-1,2,4-triazino[5,6-b]indole underwent sterically controlled regiospecific heterocyclizations with a variety of one-carbon cyclizing agents to give the sterically more favored linearly annulated 10-methyl-1,2,4-triazolo[4',3':2,3[1,2,4-triazino[5,6-b]indoles rather than the sterically less favored angularly annulated 10-methyl-1,2,4-triazolo[3',4':3,4]1,2,4-triazino[5,6-b]indoles. The assigned structures were corroborated by comparison with unequivocally synthesized authentics, chemical and spectral data. The antimicrobial activity of some of the prepared compounds was investigated.     

Bisbenzothieno[3,2-b: 2',3'-e]pyridines

Heating potassium 3-aminobenzo[b]thiophene-2-carboxylate (1) with ethyl propiolate or ethyl 3-ethoxyacrylate in acetic acid yielded the ethyl 2-(6,12-Dihydro-bis[1]benzothieno[3,2-b:2',3'-e]pyridin-6-yl)acetate (3) as main product and 1,4-dihydro-[1]benzothieno[3,2-b]-4-pyridone (2) as by-product. The dihydropyridine (DHP) 3 was dehydrogenated with ammonium cerium nitrate (CAN) to give the pyridine (Py) 4. The half wave potential E(1/2) = 1.64 V showed that 3 was much more stable against oxidizing agents than the reference compound nifedipine with E(1/2) = 1.15 V. Alkaline saponification of the acetic acid ester 4 did not yield the corresponding acetic acid, because decarboxylation took place to form the methylpyridine 5.     

Synthesis and pharmacological properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines

The synthesis and properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines (7a--g) were described. New compounds were studied in rats and in mice in the tests used for preclinical assessment of antidepressant or anxiolytic activity. Compound 7c showed weak antagonism towards the reserpine-induced hypothermia and shortened immobility time in the despair test. None of the tested compounds had an anxiety-relieving action.     

Synthesis and some reactions of 1-methyl-1H-2-cyanomethyl-imidazo[4,5-b]pyridine. Tuberculostatic activity of obtained compounds

1-Methyl-1H-2-cyanomethyl-imidazo[4,5-b]pyridine was synthesized and the reactivity of its CN and --CH2--groups was investigated. 5 H-Dipyrido[1,2-a: 3',2'd]imidazole derivatives were also prepared. Some of the obtained compounds were screened for their tuberculostatic activity.     

Bisbenzofuro[3,2-b: 2',3'-e]pyridines

Heating the potassium 3-enaminobenzo[b]furan-2-carboxylate 3 in acetic acid on 110 degrees C yielded the pentacyclic acetate 6. The acetic acid 7, formed by hydrolysis of the ester 6, decarboxylated easily giving 6-methyl-bis[1]benzofuro[3,2-b: 2',3'-e]pyridine (8).     

The genotoxicity of DNA intercalating drug 8-methoxy pyrimido [4',5':4,5]thieno(2,3-b)quinoline-4(3H)-one

8-methoxypyrimido[4',5':4,5]thieno(2,3-b)quinoline-4(3H)-one (MPTQ) is known to have antitumor and cytotoxic activities on various types of tumors. This compound showed a strong clastogenic effect on bone marrow cells of Swiss albino mice treated in vivo (17.5-35 mg/kg body weight). MPTQ induced micronuclei formation (MN) at doses of 17.5, 23.3, and 35 mg/kg. Dose and time-yield effect of MPTQ was studied in the case of chromosome aberration assay. MPTQ induced a statistically significant increase in the frequency of chromosome aberrations and micronuclei induction. The drug induced significant abnormal sperms even in the sperm shape abnormality assay. Based on the data reported in the literature, we have tried to establish the relationship between the clastogenic effect observed and process of MPTQ intercalation into DNA and the formation of protein-associated DNA-strand breaks probably promoted by topoisomerase enzymes.     

1,3-Bis(pyridin-2-ylthio)propan-2-one,Bis(thieno[2,3-b]pyridin-2-yl)-ketone und 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-one

1,3-Bis(pyridin-2-ylthio)propan-2-ones, Bis(thieno[2,3-b]pyridin-2-yl)ketones and 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-ones Reaction of 1a-d with 1,3-dichloroacetone gives the bissulphides 2a-d . Base catalyzed cyclization of 2a-d affords heterocyclically substituted ketones 3a-e . Treatment of 3a and 3b in conc. H₃PO₄ leads to the bispyridothienopyridines 5a and 5b .     

Antimitotic agents: synthesis of imidazo[4,5-c]pyridin-6-ylcarbamates and imidazo[4,5-b]pyridin-5-ylcarbamates

Cyclization of ethyl 5,6-diamino-4-hydrazinopyridin-2-ylcarbamate (10) with a mixture of CS2 and Et3N in dimethylacetamide gave mainly ethyl 1,4-diamino-2(3H)-thioxoimidazo[4,5-c]pyridin-6-ylcarbamate (15), whereas, in the absence of dimethylacetamide, a double cyclization gave mainly ethyl 5-amino-2(1H)-4-dithioxodiimidazo-[4,5-b:5,4-c]pyridin-7-ylcarb amate (16). Cyclization of the benzylidenehydrazino derivative (6) of 10 with either CS2-Et3N or (EtO)3CH-HCl gave 1-(benzylideneamino)imidazo[4,5-c]pyridines 11 and 7 as major products and 7-(benzylidenehydrazino)imidazo[4,5-b]pyridines 12 and 8 as minor products. Dethiolation of 11 to give 7 and of 12 to give 8 was effected with excess Raney nickel in refluxing ethanol. The benzylidene group of 11 was removed with hydrazine in ethanolic HCl to give 15. This key compound was condensed with benzaldehydes to give 1-benzylideneamino derivatives (20, 21) and alkylated with benzyl halides to give 2-benzylthio derivatives (24-26). In addition, cyclization of ethyl 5,6-diamino-4-(benzylidene-1-methylhydrazino)pyridin-2-ylcarbam ate (30) with (EtO)3CH provided a method for the synthesis of an imidazo[4,5-c]- and -[4,5-b]pyridines gave compounds that inhibited proliferation of growth and caused mitotic arrest against lymphoid leukemia L1210 at micromolar concentrations. However, the more active in vitro compounds (7, 8, 24-26) gave only borderline activity in mice against lymphocytic leukemia P388.     

Synthesis of certain pyrimido[2,1-b]benzothiazole and benzothiazolo[2,3-b]quinazoline derivatives for in vitro antitumor and antiviral activities

Some new pyrimido[2,1-b]benzothiazole and benzothiazolo[2,3-b]quinazoline derivatives have been synthesized and tested for their antitumor and antiviral activities. Among therm, compounds 5c and 8d exhibited a broad spectrum antitumor activity with full panel (MG-MID) median growth inhibition (GI50) of 11.0 and 11.9 mumol/l, respectively. On the other hand, compounds 5c and 5d showed potential activity against Herpes simplex type-1(HSV-1) with 61 and 50% reduction in the viral plaques, respectively. The detailed synthesis, spectroscopic and biological data are reported.