Synthesis, characterization and in vitro antibacterial activity of new steroidal thiazolo quinoxalines

Herein, we report the synthesis of different steroidal thiazolo quinoxaline derivatives as antibacterial agents against Escherichia coli. Steroidal ketone thiosemicarbazones (4-6) were obtained from corresponding ketones (1-3) by refluxing with thiosemicarbazide. The thiosemicarbazones on reaction with 2,3-dichloroquinoxalines at 80 degrees C gives 3beta-acetoxy-5alpha-cholestan-6-[thiazolo(4,5-b)quinoxaline-2-yl-hydrazone] (7), 3beta-chloro-cholestan-6-[thiazolo(4,5-b)quinoxaline-2-yl-hydrazone] (8), and 5alpha-cholestan-6-[thiazolo(4,5-b)quinoxaline-2-yl-hydrazone] (9). The structures of the compounds were evident by elemental, IR, (1)H NMR and FAB mass spectral analyses. The antibacterial activities of these compounds were evaluated by disk diffusion method against the culture of E. coli and the results were compared with the standard drug amoxicillin. The results reveal that the compounds are better antibacterial agents as compared to amoxicillin. Among all the three compounds (7-9), compound 8 showed better zone of inhibition.     

Design and synthesis of azolopyrimidoquinolines, pyrimidoquinazolines as anti-oxidant, anti-inflammatory and analgesic activities

The 5,10-dihydro-2-thioxo-pyrimido[4,5-b]quinolines (2a-c) and its oxidized form 3 were prepared and used as key intermediates for the synthesis of thiazolo[3',2':1,2]pyrimido[4,5-b]-quinolines (5a-c), isoxazolo[5',4':4',5']thiazolo[3',2':1,2]pyrimido[4,5-b]quinolines (6a-c), 4-chloro-2-methylthio-pyrimido[4,5-b]quinoline, its amino derivatives (19-21) and 10,11,12,13-tetrahydro-5H-quino[2',3':4,5]pyrimido[6,1-b]quinazoline (22). The newly synthesized compounds were characterized by IR, NMR (1H, 13C) and mass spectral studies. Representative of the synthesized compounds was tested and evaluated for anti-oxidant, anti-inflammatory and analgesic activities. Compounds 2a-c showed the highest inhibitory anti-oxidant activity either using erythrocyte hemolysis or ABTS methods. Compounds 2a, 10b, 16, and 17a manifested the best protective effect against DNA damage induced by bleomycin. Compounds 2c, 5a, 20a, 2a, and 2b exhibited a potent anti-inflammatory activity using carrageenan-induced paw edema test in rats.     

Antineoplastic activity of the thiazolo[5,4-b]quinoline derivative D3CLP in K-562 cells is mediated through effector caspases activation

Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalates to DNA and inhibits topoisomerase II in vitro inducing cell death. The clinical use of m-Amsa and other neoplastic drugs is limited due to side effects and drug resistance. In the present study we evaluated one thiazolo[5,4-b]quinoline derivate, 9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinoline (D3CLP), considered isosteric with 9-anilinoacridines, in order to determine its relative cytotoxic activity in tumoral versus non-tumoral cells, as well as the cell death mechanism induced by D3CLP on K-562 human leukemia cells. D3CLP was found to be four times more cytotoxic to tumor cells than Peripheral Blood Monocyte Cells (PBMCs). On the other hand, D3CLP induces cell death without previous cell cycle arrest at any phase, as shown by flow cytometry after 12 h of exposure to this compound. Interestingly, we detected a subdiploid peak 24 h after treatment. Signs of apoptosis were evident, as detected by TUNEL positive cells, chromatin condensation and nuclear fragmentation. Effector caspases activation were assessed with peak activity at 24 h after treatment (as detected by fluorometry assays), at which time a subdiploid peak was found in flow cytometry histograms. All data are consistent with the induction of apoptotic cell death in K-562 cells via effector caspases activation. In conclusion, the significant cytotoxicity of D3CLP together with the cell death type it produces, justifies further experimental and preclinical evaluation of this compound in the effort to find new and highly specific anti-tumor agents against leukemia cells.     

Synthesis and antimicrobial evaluation of some new thiazole, thiazolidinone and thiazoline derivatives starting from 1-chloro-3,4-dihydronaphthalene-2-carboxaldehyde

The thiosemicarbazones (3 and 6) and N-arylidene cyanoacetohydrazide (12) were prepared and used as key intermediates for the synthesis of 4-thiazolidinones (4, 5, 7-9), thiazoles (10a,b and 11a-d) and thiazoline (13) derivatives. Treatment of 13 with a mixture of triethylorthoformate and acetic anhydride afforded thiazolo[5,4-d]pyrimidinone derivative (14). The newly synthesized compounds were characterized by IR, (1)H NMR and mass spectral studies. Representative compounds of the synthesized products were tested and evaluated as antimicrobial agents.     

Synthesis and antimalarial activity of pyrazolo and pyrimido benzothiazine dioxide derivatives

A series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Compounds 3-amino-7-chloro-9-(2'-methylphenyl)-1,9-dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2b and 2,4-diamino-8-chloro-10H-phenyl-pyrimido-[5,4-b]benzothiazine 5,5-dioxide 3a were the most promising as inhibitors of hemoglobin hydrolysis, however, their effect as inhibitors of beta-hematin formation was marginal, except for compound 3-amino-7-chloro-9-(3'-chlorophenyl)-1,9dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2g. The most active compound to emerge from the in vitro and in vivo murine studies was 2b, suggesting an antimalarial activity via inhibition of hemoglobin hydrolysis, however, not as efficient as chloroquine.     

New acyclic nucleosides analogues as potential analgesic, anti-inflammatory, anti-oxidant and anti-microbial derived from pyrimido[4,5-b]quinolines

Synthesis of 2-thioxopyrimido[4,5-b]quinoline 3a-c by microwave oven was used as a base to synthesis acyclic nucleosides analogue of types, 3-(penta-O-acetyl-glycosyl)-6-(4-chlorophenyl)-10-(4-chlorophenylmethylene)-7,8,9,10-tetrahydro[1,2,4]triazolo[4',3':1,2]-pyrimido[4,5-b]quinolin-4-ones (7a-c), 2-tetra-O-acetyl-glycosylhydrazon-N3-acetyl-5-(4-chlorophenyl)-9-(4-chlorophenylmethylene)-6,7,8,9-pentahydro-1H-pyrimido[4,5-b]-quinolin-4-ones (10a-c) and 3-(glycosyl)-6-(4-chlorophenyl)-10-(4-chlorophenylmethylene)-7,8,9,10-tetrahydro[1,2,4]triazolo[4',3':1,2]pyrimido[4,5-b]quinolin-4-ones (8a-c), (12a-c). The title compounds were investigated for analgesic, anti-inflammatory, anti-oxidant and anti-microbial activities. Compounds 8a,b and 12a,b exhibited highly significant activity towards gram-negative and gram-positive bacteria, showed more potent anti-inflammatory and analgesic activities than the acetylated glycoside derivatives 7a,b and 10a,b and exhibited high anti-oxidant activity when compared to the ascorbic acid.     

Synthesis and anticancer evaluation of certain 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro[3,2-c]quinoline derivatives

Certain linear 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCI's 60 cancer cell lines. For the linear 4-anilinofuro[2,3-b]quinoline derivatives, 1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (5a) is the most cytotoxic with a mean GI50 value of 0.025 microM. Substitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b) or 4-anilino moiety (3-7) led to a decrease of cytotoxicity. For the angular 4-anilinofuro[3,2-c]quinoline derivatives, (E)-1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (14a) exhibited potent inhibitory activities on UO-31, UACC-257, and UACC-62, with GI50 values of 0.03,<0.01, and<0.01 microM respectively. The same cytotoxicity profile was observed for its methyl counterpart, 14b, in which the GI50 values against UO-31, UACC-257, and UACC-62 was<0.01, 0.04 and<0.01 microM respectively. These results deserve full attention especially because 14a and 14b are relatively non-cytotoxic with the mean GI50 value of 7.73 and 8.91 microM respectively.     

Synthesis of a new series of heterocyclic scaffolds for medicinal purposes

A new series of substituted 8-fluro-4H-pyrimido[2,1-b] [1,3]benzothiazole-4-ones () substituted 7-methyl-4H-isoxazolo[2,3-a]pyrimidin-4-ones, and substituted 2-methyl-5,6,7,8-tetrahydro-9H-isoxazolo[2,3-a]pyridopyrimidin-9-ones, compounds I-VII, have been prepared via condensation of beta-keto esters with 2-aminopyridine derivatives, in the presence of polyphosphoric acid. The same technique has also been used to prepare diazepine compounds, VIII-X, by condensation of a gamma-keto ester with 2-aminopyridine derivatives. Details of synthetic procedures are shown. The new compounds have been characterized by elemental analysis, GC-MS, FT-IR and NMR spectrometry. Antibacterial, antifungal and anticancer (cytotoxic) activities, for three of these compounds, have been investigated and are presented.     

New 5-substituted thiazolo[3,2-b][1,2,4]triazol-6-ones: synthesis and anticancer evaluation

Following [2+3]-cyclocondensation reaction of 1,2,4-triazole-3(5)-thiol with N-arylmaleimides or with monochloroacetic acid and oxocompounds, N-(R-phenyl)-(6-oxo-5,6-dihydro[1,3]thiazol[3,2-b][1,2,4]triazol-5-yl)acetamides (1-5) and 5-ylidene-[1,3]thiazolo[3,2-b][1,2,4]triazol-6-ones (6-11) were synthesized as possible anticancer agents. Anticancer activity evaluation on the full panel of nearly 60 human cancer cell lines showed that synthesized compounds displayed this kind of activity on renal cancer, leukemia, colon cancer, breast cancer and melanoma cell lines. It was shown that 5-ylidene-[1,3]thiazolo[3,2-b][1,2,4]triazol-6-ones are characterized with more potent anticancer activity than respective amides. The structures of the compounds were determined by (1)H NMR, (13)C NMR and X-ray analysis.     

Synthesis and pharmacological evaluation of new 4-2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethylbenzoic acids as LTD(4)-antagonists

A group of new 4-[2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethyl]benzoic acids have been synthesized and pharmacologically evaluated as LTD(4)-antagonists. Thiazole derivatives, especially 4-[2-[7-(4-cyclobutylthiazole-2-ylmethoxyl)naphthalen- 2-ylmetho-xy]et hyl]benzoic acid, present considerable activity and improved pharmacokinetic profiles in comparison with our quinoline containing lead molecule confirming the interest of our compounds as potentially oral antiasthmatics and that the 4-alkylthiazole system can be considered as bioisosteric of the quinoline ring at least in our series of compounds.     

Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists

In search for a new lead of non-imidazole histamine H3-receptor antagonists, a series of 1[(2-thiazolopyridine)-4-n-propyl]piperazines, the analogous 1-[(2-oxazolopyridine)-4-npropyl]piperazines, 1-[(2-benzothiazole)-4-n-propyl]piperazine and 1-[(2-benzooxazole)4-n-propyl]piperazine were prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs the thiazolo derivatives have slightly higher activity than their oxazolo analogues. The most potent compound of these series is the 1-(2-thiazolo[4,5-c]pyridine)-4-n-propylpiperazine (3c) with pA2 = 7.25 (its oxazole analogue (4g) showed pA2 = 6.9). The structure-activity relationships for compounds with various positions of the nitrogen in the benzene ring for the thiazoles compared with oxazoles are discussed.     

Syntheses and evaluation of 3-(3-bromo phenyl)-5-phenyl-1-(thiazolo [4,5-b] quinoxaline-2-yl)-2-pyrazoline derivatives

A variety of 3-(3-bromo phenyl)-5-phenyl-1-(thiazolo [4,5-b] quinoxaline-2-yl)-2-pyrazoline were obtained by the refluxing of 1-N-thiocarbamoyl 3,5-diphenyl-2-pyrazoline with 2,3-dichloroquinoxaline. The chemical structures of the compounds were elucidated by UV, IR, (1)H NMR, and (13)C NMR spectroscopy. The purity of the compounds was confirmed by their elemental analysis. The antiamoebic activity of these compounds was evaluated by microdilution method against HMI:IMSS strain of Entamoeba histolytica and the IC(50) values were compared with the standard drug metronidazole. Some of the quinoxaline derivatives showed less IC(50) values than metronidazole. To elucidate the toxic effect, MTT assay was performed using kidney epithelial cell line. The results showed that all the compounds are non-toxic.     

Synthesis and antitubercular activity of imidazo[2,1-b]thiazoles.

A number of selected imidazo[2,1-b]thiazoles entered the screening at the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) and one of these compounds, 2-chloro-6-phenylimidazo[2,1-b]thiazole, showed antitubercular activity. On this basis we planned the synthesis of new analogues bearing a substituted ring at the 6 position. For one compound only (2-chloro-6-p-chlorophenylimidazo[2,1-b]thiazole) the 5-nitroso derivative was also prepared. The antitubercular activity of these compounds was compared with the known analogues lacking the chlorine at the 2 position. 5-Nitroso-6-p-chlorophenylimidazo[2,1-b]thiazole showed potent antitubercular activity.     

Novel 5,7-disubstituted 6-amino-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitriles, the promising protein kinase inhibitors with antiproliferative activity

New derivatives of pyrrolo[2,3-b]pyrazine were synthesized and tested on a panel of cultured human tumor cell lines. It was found that 6-amino-5-(3-chlorophenylamino)-7-(1-methyl-1H-benzo[d]imidazol-2-yl)-5H-pyrrolo[3,2-b]pyrazine-2,3-dicarbonitrile (4j) exhibited a significant antiproliferative activity: GI50 for cell lines RXF 393 (renal cancer) and BT-549 (breast cancer) were 14 and 82 nM, respectively. To identify possible molecular targets, docking of the most active compounds into the active sites of cyclin-dependent kinases was performed. Molecular modeling of the inhibitor-enzyme complexes showed the differences in the binding poses of new pyrrolo[2,3-b]pyrazine derivatives in the kinase ATP-binding site compared with known pyrrolo[2,3-b]pyrazine inhibitors called aloisines. The patterns of drug kinase interactions correlated well with antiproliferative activities of novel derivatives. Key interactions and binding mode of docked compounds are discussed.     

Synthesis and antioxidant activity evaluation of new hexahydropyrimido[5,4-c]quinoline-2,5-diones and 2-thioxohexahydropyrimido[5,4-c]quinoline-5-ones obtained by Biginelli reaction in two steps

New hexahydropyrimido[5,4-c]quinoline-2,5-diones and 2-thioxohexahydropyrimido[5,4-c]quinoline-5-ones were prepared in two steps from ethyl 4-phenyl-6-methyl-2-oxo tetrahydropyrimidine-5-carboxylates or 4-phenyl-6-methyl-2-thioxotetrahydropyrimidine-5-carboxylates, previously prepared by Biginelli reaction using appropriate aldehyde, urea derivatives and ethyl acetoacetate. Their antioxidant properties were evaluated by two methods: scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and scavenging effect on hydroxyl radicals. The results show that the compounds containing thiourea moiety have better activity.     

Synthesis of new 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1,3-thiazolino[5,4-b]quinoxaline derivatives and evaluation of their antiamoebic activity

In an effort to develop potent antiamoebic agents, we have synthesized chalcones (1-8), amino-5-substituted-(3-phenyl(2-pyrazolinyl))methane-1-thione derivatives (1a-8a) and 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1,3-thiazolino[5,4-b]quinoxaline derivatives (1b-8b) and evaluated for their in vitro antiamoebic activity against HM1:IMSS strain of E. histolytica. All the compounds were characterized by electronic, IR, (1)H NMR and mass spectroscopic data. It was observed that the antiamoebic activity enhances on modifying the structure of chalcones to the pyrazolines and further to quinoxalines. The MTT assay was performed on human kidney epithelial cell line to check the cytotoxicity of the compounds and the results were compared with metronidazole. Compound 6b showed better antiamoebic activity and less toxicity than metronidazole.     

Synthesis of new substituted azetidinoyl and thiazolidinoyl-1,3,4-thiadiazino (6,5-b) indoles as promising anti-inflammatory agents

Various N-({5-[(arylmethylene)amino]-1,3,4-thiadiazol-2-yl}methyl) [1,3,4] thiadiazino[6,5-b]indol-3-amine (6a-6h), 2-aryl-3-{5-[([1,3,4] thiadiazino[6,5-b]indol-3-ylamino)methyl]-1,3,4-thiadiazol-2-yl}-1,3-thiazolidin-4-one (7a-7h), and 3-chloro-4-aryl-1-{5-[{[1,3,4]thiadiazino[6,5-b]indol-3-ylamino]methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-one (8a-8h) have been synthesized in the present study. The structure of these newly synthesized compounds were confirmed by their analytical and spectral data. These compounds were also evaluated for their anti-inflammatory, ulcerogenic and analgesic activities. Compound 8g has shown most active anti-inflammatory and analgesic activities with better ulcerogenic activity than phenylbutazone, while this compound was found to be associated with lesser degree of anti-inflammatory and analgesic activities as compared to indomethacin.     

Synthesis and biological activity of new 2-amino-8-chloro-5,5-dioxo[1,2,4]triazolo[2,3-b][1,4,2]benzodithiazines

Two series of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)-4-arylsemicarbazides 6-17 and 2-arylamino-8-chloro-5,5-dioxo[1,2,4]triazolo[2,3-b][1,4,2]benzodithiazines 18-26 were prepared in order to evaluate their biological activity. Compounds 6 and 18-26 were tested for their in vitro cytotoxic potency against 12 human cancer cell lines. The compounds 6 and 19 were inactive, whereas triazolobenzodithiazines 18, 20-26 possess tumor growth inhibitory properties. The prominent methyl 8-chloro-2-(4-chlorophenylamino)-5,5-dioxo[1,2,4]triazolo[2,3-b][1,4,2]benzodithiazine-7-carboxylate (21) exhibited potency higher or comparable to cisplatin. Moreover, compounds 6, 9, 19 and 23-25 with structure similar to other chemotherapeutic agents were tested for their antibacterial activity and exhibited MIC and MBC against Staphylococcus aureus (3.9-31.5 microg ml).