Showing papers in "Archiv Der Pharmazie in 2010"
TL;DR: Although, curcumin's poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies.
Abstract: Curcumin (diferuloylmethane), a derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Abundant sources provide interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. The pleiotropic role of this dietary compound includes the inhibition of several cell signaling pathways at multiple levels, such as transcription factors (NF-κB and AP-1), enzymes (COX-2, MMPs), cell cycle arrest (cyclin D1), proliferation (EGFR and Akt), survival pathways (β-catenin and adhesion molecules), and TNF. Curcumin up-regulates caspase family proteins and down-regulates anti-apoptotic genes (Bcl-2 and Bcl-X(L)). In addition, cDNA microarrays analysis adds a new dimension for molecular responses of cancer cells to curcumin at the genomic level. Although, curcumin's poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies. Currently, sufficient data has been shown to advocate phase II and phase III clinical trials of curcumin for a variety of cancer conditions including multiple myeloma, pancreatic, and colon cancer.
461 citations
TL;DR: Amongst the compounds tested, compound 25 exhibited the highest anticancer activity while compounds 14 and 18 exhibited significant antibacterial and antitubercular activities.
Abstract: A series of twenty new 4-substituted-2,6-dimethyl-3,5-bis-N-(heteroaryl)-carbamoyl-1,4-dihydropyridines have been prepared from a three-component one-pot condensation reaction of N-heteroaryl acetoacetamide, an aromatic/heteroaromatic aldehyde, and ammonium acetate under four different experimental conditions. Except for the conventional method, all the experimental conditions were simple, eco-friendly, economical, and the reactions were rapid and high-yielding. The methods employed have been compared in terms of yields, cost, and simplicity. The synthesized compounds were characterized by different spectroscopic techniques and evaluated for their in-vitro anticancer, antibacterial, and antitubercular activities. Amongst the compounds tested, compound 25 exhibited the highest anticancer activity while compounds 14 and 18 exhibited significant antibacterial and antitubercular activities.
78 citations
TL;DR: It is shown how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.
Abstract: The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post-translational modifications, intramolecular contacts, and intermolecular interactions. Ultimately, they all achieve their effect by favoring particular conformations that promote or prevent the kinase domain from catalyzing protein phosphorylation. The central role of kinases in various diseases has encouraged extensive investigations of their biological function and three-dimensional structures, yielding a more detailed understanding of the mechanisms that regulate protein kinase activity by conformational changes. In the present review, we discuss these regulatory mechanisms and show how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations. In addition, we highlight recent developments to monitor ligand-induced structural changes in protein kinases and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.
75 citations
TL;DR: Preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activities and they warrant more consideration as prospective antimicrobials.
Abstract: Benzothiazole and imidazole compounds are extensively studied heterocyclics due to their wide spectrum of bioactivities Among them, the imidazo(2,1-b)-benzothiazole derivatives are pharmacologically important because of their immunostimulant, anti-inflammatory, antifungal, antimicrobial, antitumor, and other activities In the present research work, a novel series of 2,3-diaryl-substituted imidazo(2,1-b)-benzothiazoles 13a-o have been synthesized by reaction of substituted 2-aminobenzothiazoles 1-8 and an appropriately substituted alpha-bromo-1-(4''-substituted)-phenyl-2-(4'-substituted)-phenyl-1-ethanones 9-12 in the presence of anhydrous acetonitrile They were characterized by physicochemical, elemental, and spectral (IR, (1)H-NMR, and Mass) data All the synthesized compounds were screened for their in-vitro antibacterial activity against Gram-positive, Gram-negative bacteria The investigation of antibacterial screening data revealed that most of the compounds tested have demonstrated congruent activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa as compared with the standard ampicillin Among the series, compounds 13d, 13h, and 13m exhibited excellent an antibacterial activity profile as compared with the standard In summary, preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activities and they warrant more consideration as prospective antimicrobials
66 citations
TL;DR: A new series of 4‐aryl‐4H‐chromenes bearing a 2‐arylthiazol‐4‐yl moiety at the 4‐position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF‐7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC50 values less than 5 μM.
Abstract: A new series of 4-aryl-4H-chromenes bearing a 2-arylthiazol-4-yl moiety at the 4-position were prepared as potential cytotoxic agents. The in-vitro cytotoxic activity of the synthesized 4-aryl-4H-chromenes was investigated in comparison with etoposide, a well-known anticancer drug, using MTT colorimetric assay. Among them, the 2-(2-chlorophenyl)thiazol-4-yl analog 4b showed the most potent activity against nasopharyngeal epidermoid carcinoma KB, medulloblastoma DAOY, and astrocytoma 1321N1, and compound 4d bearing a 2-(4-chlorophenyl)thiazol-4-yl moiety at the 4-position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF-7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC(50 )values less than 5 microM. The ability of compound 4b to induce apoptosis was confirmed in a nuclear morphological assay by DAPI staining in the KB and MCF-7 cells.
64 citations
TL;DR: A novel series of fourteen substituted selenadiazoles has been synthesized and the compounds tested for their in vitro antiproliferative and cytotoxic activities revealed that 7 derivatives exhibited good activity against MCF‐7 cells: for instance, 2c and 2f inhibited cell growth with nanomolar GI50 values.
Abstract: A novel series of fourteen substituted selenadiazoles has been synthesized and the compounds tested for their in vitro antiproliferative and cytotoxic activities. The tests were carried out against leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54), and breast (MCF-7) cancer cells. In order to assess the selectivity of the compounds under investigation the assays were also carried out on two non-tumoral lines – one mammary (184B5) and one bronchial epithelium (BEAS-2B) cell line. Assay-based antiproliferative activity studies revealed that seven derivatives (2a, 2c, 2e, 2f, 2g, 3a, and 3b) exhibited good activity against MCF-7 cells: for instance, 2c and 2f inhibited cell growth with nanomolar GI50 values. Compound 2f had a better antitumoral profile than vinorelbine and paclitaxel, two drugs that are used as first-line treatments in advanced, recurrent, and/or metastatic cancer. In the other cell lines the compounds showed moderate activity or were inactive – with the exception of 2a, which was also found to have antiproliferative activity. Modulation of the cell cycle and apoptotic effects of active compounds were further evaluated in MCF-7 cells. Of these, 6-bromo[1,2,5]selenadiazolo[3,4-b]pyridine (2a) was the most active, with an apoptogenic effect 3.9 times higher than that of camptothecin, which was used as a positive control. Compound 2a also provoked cell cycle arrest with a significant decrease in the G0/G1 phase cell population and an increase in S and G2/M cells, thus suggesting mitotic arrest prior to metaphase.
62 citations
TL;DR: The piperidinyl amidrazones 7a–g possessed a significant antiviral activity against herpes simplex viruses (HSV‐1), and compound 7d reduced the number of viral plaques of herpessimplex type‐1 by 67%, with respect to the effect of reference drug Aphidicolin.
Abstract: The reaction of benzoyl hydrazine 1a or benzothiazole-2-carbohydrazide 1b with 2-oxo-N-arylpropanehydrazonoyl chlorides 2a-d yielded (1Z,2E)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-N-(aryl)propanehydrazonoyl chlorides 3a-e. The reaction of 3a-c with sodium benzenesulphinate furnished sulphones 5a-c while the reaction of 5d, e with hydroxyl amine afforded hydroxomoyl derivatives 6a, b. The one-pot sterioselective reaction of N-(aryl)propanehydrazonoyl chlorides 3 with certain aromatic aldehydes in the presence of piperidine resulted in the formation of (1E,2Z,3E)-1-(piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-4-(aryl1)-but-3-enes 7a-g. X-ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperidinyl amidrazones 7a-g possessed a significant antiviral activity against herpes simplex viruses (HSV-1). Compound 7d reduced the number of viral plaques of herpes simplex type-1 (HSV-1) by 67%, with respect to the effect of reference drug Aphidicolin.
49 citations
TL;DR: The results suggested that the prepared compounds possess significant anticancer activity comparable to cisplatin and the antitumor activity of these prepared compounds was accompanied with a reduction in the levels of protein and nucleic acids.
Abstract: A series of new 8-[(2H-tetrazol-5-yl)methoxy]quinoline derivatives, their sugar hydrazones, and their N-glycoside derivatives were synthesized. Furthermore, the 1,2,4-triazole-3-one derivatives 3 and 4 were synthesized from the amidrazone derivative 2. Some of the newly prepared compounds demonstrated inhibitory effects on the growth of MCF-7 human breast cancer cells as compared with the activity of the commonly used anticancer drug, cisplatin. The results of antitumor evaluation revealed that compounds 2-5, 8b, and 12 inhibited the growth of cancer cells through their effect as free-radical regulators by increasing the activity of superoxide dismutase and depletion of intracellular levels of reduced glutathione, catalase and glutathione peroxidase activities, accompanied with a high production of hydrogen peroxide, nitric oxide, and other free radicals causing the killing of tumor cells. The results suggested that the prepared compounds possess significant anticancer activity comparable to cisplatin and the antitumor activity of these prepared compounds was accompanied with a reduction in the levels of protein and nucleic acids.
47 citations
TL;DR: A series of lipophilic molecular combinations obtained by joining (R)‐α‐lipoic acid and ibuprofen via an amide bond might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimer's disease.
Abstract: Current evidences support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimer's disease, and (R)-alpha-lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)-alpha-lipoic acid and ibuprofen via an amide bond. These new entities might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimer's disease. Our study included the synthesis of conjugates 1-3 and the evaluation of their physicochemical and in-vitro antioxidant properties. The new compounds are extremely stable in aqueous buffer solutions (pH = 1.3 and 7.4), and in rat and human plasma they showed a slow bioconversion to ibuprofen and (R)-alpha-lipoic acid. Codrugs 1-3 displayed in vitro free radical scavenging activity and were hydrolyzed more rapidly in brain tissue than in rat serum indicating that these new entities might allow targeted delivery of the parent drugs to neurons. The immunohistochemical analysis of Abeta (1-40) protein showed that Abeta-injected cerebral cortices treated with ibuprofen or compound 1 showed few plaques within capillary vessels and, in particular, Abeta (1-40) protein was less expressed in codrug-1-treated than in ibuprofen-treated cerebral cortex.
46 citations
TL;DR: Three compounds synthesized starting from ethyl 4‐cyano‐1,5‐diphenylpyrazoles attached to different heterocyclic ring systems at position 3 revealed the highest cytotoxic activity and the oral LD50 values revealed that most of the tested compounds are relatively nontoxic.
Abstract: Several 4-cyano-1,5-diphenylpyrazoles attached to different heterocyclic ring systems at position3 were synthesized starting from ethyl 4-cyano-1,5-diphenyl-1H-pyrazole-3-carboxylate 1. Thenewly synthesized compounds were tested in vivo for their anti-estrogenic effects and evaluatedin vitrofor their cytotoxic properties against estrogen-dependent tumors. 3-(5-Mercapto-1,3,4-oxa-diazole-2-yl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile 13 revealed the highest cytotoxic activitywith a GI
45 citations
TL;DR: Some naphthoquinones exhibited inhibition with MIC values of 1.25 μg/mL, similar to that of pharmaceutical concentrations currently used in tuberculosis treatment, justifying further research into the value of these quinones as part of an original treatment for tuberculosis.
Abstract: A series of alpha- and beta-pyran naphthoquinones (lapachones) have been synthesized and evaluated for their in-vitro antibacterial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar-Blue susceptibility test; the activity was expressed as the minimum inhibitory concentration (MIC) in microg/mL. The synthetic methodology consisted of the formation of methylene and aryl o-quinone methides (o-QMs) generated by Knoevenagel condensation of 2-hydroxy-1,4-naphthoquinone with formaldehyde and arylaldehydes. These o-QMs then undergo facile hetero Diels-Alder reactions with dienophiles in aqueous ethanol media. Some naphthoquinones exhibited inhibition with MIC values of 1.25 microg/mL, similar to that of pharmaceutical concentrations currently used in tuberculosis treatment. These results justify further research into the value of these quinones as part of an original treatment for tuberculosis.
TL;DR: A series of novel betulinic acid derivatives 3–11 and betulin derivatives 12–17 were synthesized and compound 15 was found to possess cell growth inhibition even when treated for a short time on anaplastic thyroid cancer cells (SW1736).
Abstract: A series of novel betulinic acid derivatives 3-11 and betulin derivatives 12-17 were synthesized. The compounds were characterized by the means of (1)H- and (13)C-NMR spectroscopy as well as mass spectrometry. The compounds have been tested on ten tumor cell lines of different histogenic origin. The most active derivatives, containing a chloroacetyl group on C-3 in betulinic acid 9 and C-28 in betulin 15, were up to ten times more cytotoxic and many fold more selective towards tumor cells in comparison to normal cells (fibroblasts) than betulinic acid. Furthermore, compound 15 was found to possess cell growth inhibition even when treated for a short time on anaplastic thyroid cancer cells (SW1736).
TL;DR: Docking studies on the DNA‐gyrase enzyme (1KZN) show their role in the antimicrobial activity of the molecules and explain the higher potency of compounds 6a, 6b, 8a, 8b based on ReRanking scores and binding poses of the molecule.
Abstract: Quinazoline derivatives are reported to have anti-inflammatory, analgesic, antibacterial, and anticancer activities. The incorporation of “OCH2CONH2” (oxymethylcarbamide) at 4th position of the quinazoline ring was found to influence the biological activities of the molecules. With this rationale, some new oxadiazolyl methyloxy quinazolines, pyrazolyl acetoxy methyl quinazolines, triazolylmethyloxy quinazolines were synthesized from anthranilic acid through quinazolyl oxyacetylhydrazide intermediates. All the compounds were characterized by IR, 1H-NMR, EI-MS, and C, H, N analyses and evaluated for their antimicrobial activity. Docking studies on the DNA-gyrase enzyme (1KZN) show their role in the antimicrobial activity of the molecules and explain the higher potency of compounds 6a, 6b, 8a, 8b based on ReRanking scores and binding poses of the molecules.
TL;DR: The results suggest that the teratogenic effect of cefazedone and cefazolin sodium on zebrafish embryonic development is associated with the structure of MMTD, which should be recommended as a specified impurity and qualified as serious again.
Abstract: 2-mercapto-5-methyl-1,3,4-thiadiazole (MMTD) is the 3’-side chain of cephalosporin including cefazolin sodium (CFZL) and cefazedone (CFZD). It is not only present in finished products as the residual precursor, but also produced through drug degradation. Performing the zebrafish embryo toxicity test, we evaluated the toxicity effects of cefazolin sodium, cefazedone, their synthetic precursors and intermediates. Our results suggest that the teratogenic effect of cefazedone and cefazolin sodium on zebrafish embryonic development is associated with the structure of MMTD. They mainly interfere with the development of tissues and organs derived from embryonic ectoderm and mesoderm. We further consider the rationality of the quality control limit of MMTD (1.0%) in the specification. As the acceptable daily intakes (ADIs) of cefazolin is 10 mg/kg per day [16] and the minimum teratogenic concentration of MMTD is tenfold lower than that of cefazolin sodium, we recommend that the acceptable daily intakes of MMTD should be 1 mg/(kg day). In general, the therapeutic dose of cefazolin sodium is 2–4 g/day. Based upon the calculation of MMTD quality control limits (1.0%), MMTD intake can be 20–40 mg/day, which will be much more than the acceptable daily intake value of 1 mg/(kg day). Thus, MMTD should be recommended as a specified impurity and qualified as serious again.
TL;DR: The 2,3,4,5tetrahydro-1H-1-benzazepinediones 2 and 5,6,7,8-tetrahedro-4H-thieno[3,2b]azepine-5,8dione (11) were obtained by dealkoxycarbonylation in wet dimethylsulfoxide from fused azepinecarboxylic esters 3 and 10, respectively, 3b and 10 are prepared by Dieckmann reaction with KH in DMF
Abstract: Synthesis of [b]-Fused Azepinediones by Dealkoxycarbonylation
The 2,3,4,5-tetrahydro-1H-1-benzazepinediones 2 and 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-5,8-dione (11) are obtained by dealkoxycarbonylation in wet dimethylsulfoxide from fused azepinecarboxylic esters 3 and 10, respectively, 3b and 10 are prepared by Dieckmann reaction with KH in DMF/toluene from diesters 6 and 9, respectively.
Die 2,3,4,5-Tetrahydro-1H-1-benzazepindione 2 und 5,6,7,8-Tetrahydro-4H-thieno[3,2-b]azepin-5,8-dion (11) werden durch Dealkoxycarbonylierung in wasserhaltigem Dimethylsulfoxid aus den kondensierten Azepincarbonsaureestem 3 bzw. 10 gewonnen. 3b und 10 werden ausgehend von den Diestem 6 bzw. 9 durch Dieckmann-Reaktion mit KH in DMF/Toluen dargestellt.
TL;DR: A series of new 3‐hydroxy‐6‐hydroxymethyl/methyl‐2‐substituted 4H‐pyran‐4‐ones synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds showed no toxicity at all doses.
Abstract: A series of new 3-hydroxy-6-hydroxymethyl/methyl-2-substituted 4H-pyran-4-ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, and ESI-MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)-induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3-hydroxy-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-6-methyl-4H-pyran-4-one (compound 1), 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-3-hydroxy-6-methyl-4H-pyran-4-one (compound 6), 2-[(4-acetyl-4-phenylpiperidin-1-yl)methyl]-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 11), and 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl] methyl}-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 12) were found to have anticonvulsant activity against MES-induced seizures at 4 h. Also, 2-{[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]methyl}-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 8) was determined to be the most active compound against scMet-induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses.
TL;DR: In this paper, a cyclization of the non-isolable adducts 2a-d with α-halogenated electrophilic compounds is described. Butt et al.
Abstract: Facile unequivocal syntheses of the title compounds are reported via “in situ” cyclization of the non-isolable adducts 2a-d with α-halogenated electrophilic compounds. Chemical and spectroscopic evidences for the structures of the new compounds are described.
Heterocyclen-Synthese mit Isothiocyanaten: Synthese einiger neuer polyfunktionell substituierter Thiophene, Δ4-Thiazoline und Thiazolidinone
Einfache eindeutige Synthesen der Titelverbindungen aus α-halogenierten Elektrophilen und den nicht isolierbaren Addukten 2a-d uber eine “in situ” - Cyclisierung werden beschrieben. Chemische und spektroskopische Beweise fur die Strukturen der neuen Verbindungen werden aufgefuhrt.
TL;DR: 7 was found to be the potent inhibitor in vitro for the replication of HIV‐1 (EC50 = 0.20 μg/mL), suggesting a new lead in the development of an antiviral agent.
Abstract: A new series of 2-(naphthalen-2-yloxy)-N-[(aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl] acetamides 5a-f was synthesized from naphthalene-derived glycine derivative 2 via the hydrazinoacetamide analogs 4a-f. Alternatively, treatment of 4a with H(2)SO(4) afforded 2-(naphthalen-2-yloxy)-N-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)methyl) acetamide 6a. Alkylation or sulphonylation of 5a afforded the S-alkylated derivatives 7 and 8, respectively. Interestingly, treatment of 3 with methoxide ion gave the triazine derivative 9. The synthesized compounds have been screened for their inhibitory activity against HIV-1 and HIV-2 in MT-4 cells. However, 7 was found to be the potent inhibitor in vitro for the replication of HIV-1 (EC(50 )= 0.20 microg/mL), suggesting a new lead in the development of an antiviral agent.
TL;DR: The pharmacological screening showed that many of these obtained compounds have good anti‐inflammatory, analgesic, anticonvulsant, and antiparkinsonian activities comparable to diclofenac potassium, Voltarene®, Carbamazepine®, and Benzotropene® as reference drugs.
Abstract: A series of novel thiazolo derivatives 2-15 was synthesized by initial condensation of 2,6-dihydroxyisonicotinohydrazide 1 and 2-chloro-6-hydrazinylisonicotinohydrazide 11 with different organic reagents. The pharmacological screening showed that many of these obtained compounds have good anti-inflammatory, analgesic, anticonvulsant, and antiparkinsonian activities comparable to diclofenac potassium, Voltarene(®), Carbamazepine(®), and Benzotropene(®) as reference drugs. Initially the acute toxicity of the compounds was assayed via the determination of their LD₅₀. The structures of newly synthesized compounds were confirmed by IR, ¹H-NMR, ¹³C-NMR, MS spectral data and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀ and pharmacological activities of the synthesized compounds were reported.
TL;DR: The antimycobacterial and antimicrobial evaluation of newly synthesized 3‐(3‐pyridyl)‐5‐(4‐methoxyphenyl)•4‐(N‐substituted‐1,3‐benzothiazol‐2‐amino)‐4H‐1‐2,4‐triazole 6a–j in good yields shows promising antimicrobial activity whereas compound 6j showed very good antimyCob
Abstract: In this study, we report the antimycobacterial and antimicrobial evaluation of newly synthesized 3-(3-pyridyl)-5-(4-methoxyphenyl)-4-(N-substituted-1,3-benzothiazol-2-amino)-4H-1,2,4-triazole 6a-j in good yields. All the synthesized compounds have been established by elemental analysis, IR, ¹H NMR, ¹³C-NMR and Mass spectral data. In-vitro antimycobacterial activity was carried out against (Mycobacterium tuberculosis) H₃₇Rv strain using Lowenstein-Jensen medium and antimicrobial activity against two Gram positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), two Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and three fungal species (Candida albicans, Aspergillus niger, Aspergillus clavatus) using the broth microdilution method. Compounds 2e, 6a, 6g, 6h, and 6j exhibited promising antimicrobial activity whereas compound 6j showed very good antimycobacterial activity.
TL;DR: A series of new Mannich bases of N‐[(4‐arylpiperazin‐1‐yl]‐3‐(chlorophenyl)‐pyrrolidine‐2,5‐diones 10–23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests.
Abstract: A series of new Mannich bases of N-[(4-arylpiperazin-1-yl)-methyl]-3-(chlorophenyl)-pyrrolidine-2,5-diones 10-23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES-test. In this model of seizures, the most active were N-[{4-(4-chlorophenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 16 and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 17 with ED(50) values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives 10, 14, and 16 were tested in the psychomotor seizure 6-Hz test from which N-[{4-(2-chlorophenyl)-piperazin-1-yl}-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione 10 revealed the highest protection with an ED(50) of 78 mg/kg. Compounds 10, 12, and 17 were also tested in the pilocarpine-induced status PIPS test. Furthermore, 17 was examined in the hippocampal kindling screen after i. p. administration to rats.
TL;DR: In this paper, two guaianolides with a peroxide bridged cyclopentane ring and an α-methylene-γ-butyrolactone structure have been isolated.
Abstract: Aus dem Ether-Extrakt der Blutenkopfchen der Schafgarbe (Achillea millefolium L.) wurden zwei Guaianolide (1,2) mit einer Peroxid-Brucke im Cyclopentan-Ring und einer α-Methylen-γ-butyrolacton-Struktur isoliert. Es werden die Bezeichnungen α-Peroxyachifolid (1) und β-Peroxyisoachifolid (2) vorgeschlagen. 1 ist u.a. verantwortlich fur die Schafgarbendermatitis.
Peroxides as Plant Constituents, VIII1)
Guaianolide-peroxides from Yarrow, Achillea millefolium L., Causing Allergic Contact Dermatitis
From the ether extract of the blossoms of yarrow, Achillea millefolium L., two guaianolides (1, 2) with a peroxide bridged cyclopentane ring and an α-methylene-γ-butyrolactone structure have been isolated. For these compounds the names α-peroxyachifolid (1) and β-peroxyisoachifolid (2) are proposed. 1 is responsible for the allergic contact dermatitis caused by yarrow.
TL;DR: The biological studies revealed a good pharmacological profile for some pyrazolylbenzotriazinones and, in the case of the ethyl 5‐(4‐oxo‐1,2,3‐benzotin‐3(4H)‐yl)‐1‐pyridin‐2‐yl‐1H‐pyrazole‐4‐carboxylate, a good COX‐1/COX‐2 selectivity.
Abstract: Pyrazolylbenzotriazinones are endowed with a structural analogy with the COX-2 selective inhibitor celecoxib. Considering that our research group has long been interested in the 3-pyrazolyl-substituted benzotriazinones as anti-inflammatory agents, six new pyrazolylbenzotriazinone derivatives 16a-c and 18a-c have been prepared by reacting the opportune ethyl 5-(2-aminobenzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate or 5-(2-aminobenzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxyic acid with sodium nitrite in glacial acetic acid. The biological studies revealed a good pharmacological profile for some pyrazolylbenzotriazinones and, in the case of the ethyl 5-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-1-pyridin-2-yl-1H-pyrazole-4-carboxylate, a good COX-1/COX-2 selectivity. Molecular modeling studies confirmed the obtained biological results.
TL;DR: The synthesis and the pharmacological activity of a series of 1‐aroyl derivatives of kynurenic acid methyl ester (4‐oxo‐quinolin‐2‐carboxy methyl (KYNA) esters), structurally related to NSAID indomethacin are described.
Abstract: The synthesis and the pharmacological activity of a series of 1-aroyl derivatives of kynurenic acid methyl ester (4-oxo-quinolin-2-carboxy methyl (KYNA) esters), structurally related to NSAID indomethacin are described. The derivatives were screened in vivo for anti-inflammatory and analgesic activities. Most of the compounds exhibited good anti-inflammatory and analgesic activities. An automatic docking of the synthesized compounds was performed using X-ray structures of COX-1 and COX-2. Docking results are in good accordance with the experimental biological data.
TL;DR: The palladium complexes 12a, b exhibited remarkable antiproliferative activity against MT‐4, CD4+ human acute T‐lymphoblastic leukemia (CCRF‐CEM), human splenic B-lymphoblastoid cells (WIL‐2NS), human acute B‐ lymphoblastics leukemia ( CCRF‐SB), skin melanoma (SK‐MEL‐28), and prostate carcinoma (DU145) cell lines.
Abstract: The palladium complexes [(dppe)Pd(L)(2)PdCl(2)], [(dppe)Pd(L)(2)PtCl(2)], [(dppp)Pd(L)(2)PdCl(2)], [(dppm) Pd(L)(2)NiCl(2)], and [(dppm)Pd(L)(2)SnCl(4)] 15-19 were prepared. The antiproliferative activity of the newly synthesized complexes as well as their previously prepared analogues 3-14 and 20-26 were screened against a large panel of human cancer cell lines derived from haematological CD4(+) human T-cells containing an integrated HTLV-1 genome (MT-4). The complex 12a, b exhibited remarkable antiproliferative activity against MT-4, CD4(+) human acute T-lymphoblastic leukemia (CCRF-CEM), human splenic B-lymphoblastoid cells (WIL-2NS), human acute B-lymphoblastic leukemia (CCRF-SB), skin melanoma (SK-MEL-28), and prostate carcinoma (DU145) cell lines (CC(50 )= 0.5 microM, 0.4 +/- 0.05 microM, 0.6 +/- 0.05 microM, 0.4 +/- 0.1 microM, and 0.8 +/- 0.2 microM, respectively), meanwhile, 9a, b, 14a, b, and 23 showed significant activity against the CCRF-SB cell lines (CC(50) = 0.6 +/- 0.06 microM, 0.7 +/- 0.05 microM, 0.6 +/- 0.05 microM, and 0.8 +/- 0.15 microM, respectively). Further, 19 exhibited activity against the CCRF-CEM cell line (CC(50 )= 0.4 +/- 0.05 microM).
TL;DR: Modification of the phenothiazine structure by a substitution of two benzene rings with pyridine rings to form this new type of azaphenothiazines does not enhance antioxidant activity, although it retains it.
Abstract: A series of 19 derivatives of 2,7-diazaphenothiazine was synthesized and evaluated for their antioxidant activity bearing in mind the structural similarity with "classical" phenothiazines several of which are considered powerful antioxidants. Among the new derivatives that inhibited in vitro Fe(2+)/ascorbate-induced lipid peroxidation of rat liver microsomal membranes, several exhibited significant antioxidant activity with IC(50 )values in the range of 64-125 microM. Although N-substitution led to a variable degree of antioxidant activity, the latter appears to correlate with the lipophilicity (expressed as clogP values) of the substituted derivatives. Reduced lipophilicity may also explain the relatively lower protection offered by these derivatives against lipid peroxidation when compared to their "classical" phenothiazine counterparts. Thus, modification of the phenothiazine structure by a substitution of two benzene rings with pyridine rings to form this new type of azaphenothiazines does not enhance antioxidant activity, although it retains it.
TL;DR: The study showed that the chalcones bearing a 4‐chlorophenyl group 4c or 4‐nitrophenyl group 3b were the most active ones as analgesics and both chalcone 4c and N‐phenyl pyrazole bearing 4‐methoxy phenyl group 5b showed a higher anti‐inflammatory activity than celecoxib but still lower than that of diclofenac sodium.
Abstract: Starting from isatoic anhydrides, several new 2,3-dihydroquinazolin-4(1H)-one derivatives bearing chalcone or pyrazole or thiazole moieties at the third position were synthesized. The analgesic and anti-inflammatory activities for most compounds were studied at a dose level of 50 mg/kg via the acetic-acid-induced writhing-response method and carrageenan-induced edema method, respectively. The study showed that the chalcones bearing a 4-chlorophenyl group 4c or 4-nitrophenyl group 4b were the most active ones as analgesics. Both chalcone 4c and N-phenyl pyrazole bearing 4-methoxy phenyl group 5b showed a higher anti-inflammatory activity than celecoxib but still lower than that of diclofenac sodium. Moreover, the chalcone 4c has nearly the same ulcerogenic index as the selective cyclooxygenase-2 inhibitor celecoxib.
TL;DR: The fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep‐G2 cells with IC50 < 20 μM.
Abstract: Dimethyl acetylenedicarboxylate, ethyl propiolate, and E-dibenzoylethylene react with thienopyrimidines (cyclo-pentyl, -hexyl, and -heptyl) derivatives to form thiazolo[3,2-a]thieno-[2,3-d]pyrimidin-2-ylidene) acetates, thieno[2,3-d]pyrimidin-2-ylthioacrylates, and thieno[2',3':4,5]pyrimido[2,1-b][1,3]thiazin-6-ones, respectively. Reactions proceed via cyclization and thio-addition processes. Some derivatives of thienopyrimidines showed high inhibition of Hep-G2 cell growth compared with the growth of untreated control cells. However, the fused heptyl of thienopyrimidothiazines indicates a promising specific antitumor agent against Hep-G2 cells with IC(50 )< 20 microM.
TL;DR: A series of 2‐phenoxynicotinic acid hydrazides were synthesized and evaluated for their analgesic and anti‐inflammatory activities and several compounds having an unsubstituted phenyl/4‐pyridyl or C‐4 methoxy substituent on the terminal phenyl ring showed moderate to high analgesic or anti-inflammatory activity.
Abstract: A series of 2-phenoxynicotinic acid hydrazides were synthesized and evaluated for their analgesic and anti-inflammatory activities. Several compounds having an unsubstituted phenyl/4-pyridyl or C-4 methoxy substituent on the terminal phenyl ring showed moderate to high analgesic or anti-inflammatory activity in comparison to mefenamic acid as the reference drug. The compounds with highest anti-inflammatory activity were subjected to in vitro COX-1/COX-2 inhibition assays and showed moderate to good COX-1 and weak COX-2 inhibition activities.
TL;DR: New nonclassical acridines, quinolines, and quinazolines were prepared starting from cyclic β‐diketones, namely dimedone, through application of Hantzsch addition, Michael addition, and Mannich reactions, respectively.
Abstract: New nonclassical acridines, quinolines, and quinazolines were prepared starting from cyclic β-diketones, namely dimedone, through application of Hantzsch addition, Michael addition, and Mannich reactions, respectively. The antimicrobial activity revealed that decahydroacridin-1,8-dione 2e bearing a 3-nitrophenyl group and hexahydroquinoline 4e having a 2,4-dichlorophenyl moiety were the most active compounds against both Gram-positive and -negative bacteria based upon using the disc diffusion method. Cytotoxic activity studies for decahydroacridin-1,8-diones 2a-e against liver carcinoma cells (HepG 2 ) using the MTT cell viability assay revealed that decahydroacridin-1,8-dione bearing a 4-methylphenyl moiety 2d showed a higher cytotoxic activity (IC 50 = 4.42 μg/mL) than the other derivatives.