Synthesis of 2-substituted-6-(4<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazol-4-yl)benzo[<Emphasis Type="Italic">d</Emphasis>]oxazoles as potential anticonvulsant agents

A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles were synthesized. The anticonvulsant effect and neurotoxicity of the compounds (intraperitoneally) were evaluated with the maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests in mice. 2-Phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3g) was the most active and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED₅₀) of 29.5 mg/kg, a median toxicity dose (TD₅₀) of 285 mg/kg, and a protective index (PI) of 9.7, which is greater than the reference drug, carbamazepine, which has a PI of 6.4.     

Synthesis and antimicrobial activity of 1<Emphasis Type="Italic">H</Emphasis>,10<Emphasis Type="Italic">H</Emphasis>-benzo[<Emphasis Type="Italic">e</Emphasis>]pyrrolo[3,2-g]indole derivatives

We have synthesized a series of new phenylazo derivatives of 1H,10H-benzo[e]pyrrolo[3, 2-g]indole containing 3-(p-bromophenylazo) (II), 3-(p-iodophenylazo) (III), 3-(p-sulfamidophenylazo) (IV), 3-formyl (V), 3,8-diformyl (VI), 3-phenylazo (VII), 3-(p-chlorophenylazo) (VIII), 3-(p-nitrophenylazo) (IX), 2,9-di(adamantylaminocarbonyl) (X), 2,9-di(p-benzenesulfamidoaminocarbonyl) (XI), 2,9-di(isonicotinoylhydrazidecarbonyl) (XII), and 2,9-di(carbohydrazide) (XIII) substituents. The antimicrobial, antifungal, and antituberculosis activity was investigated in vitro with respect to various microorganisms including conditionally pathogenic mycobacteria and pathogenic fungi. It is established that the tested compounds possess high antimicrobial activity. The synthesized compounds are of great interest for further, more thorough investigations and experiments on animals with the corresponding infectious diseases. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 2, pp. 23–25, February, 2009.     

Synthesis and <Emphasis Type="Italic">in Vitro</Emphasis> cytotoxic activities of 2-alkyl-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-2,6-diazacyclopenta[<Emphasis Type="Italic">b</Emphasis>]anthracene-5,10-diones

A series of 2-alkyl-2,3-dihydro-1H-2,6-diazacyclopenta[b]anthracene-5,10-diones (4a–f) was synthesized and their in vitro cytotoxic activities were evaluated against six human cancer cell lines (HCT15, SK-OV-3, SNB19, A549, MCF7 and MCF7/ADR). They all appeared to be less potent than doxorubicin against all doxorubicin sensitive human cancer cell lines tested. However, these compounds retained considerable cytotoxic activity against the doxorubicin-resistant cell line MCF7/ADR, implying their therapeutic potential to treat doxorubicin-resistant tumors. The most active compound 4c was equipotent with doxorubicin against HCT15 cell line.     

Synthesis and cytotoxic activities of 2-alkyl-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-2,6,9-triazacyclopenta[<Emphasis Type="Italic">b</Emphasis>]anthracene-5,10-diones

A series of 2-alkyl-2,3-dihydro-1H-2,6,9-triazacyclopenta[b]anthracene-5,10-diones (4a-f) were synthesized and their in vitro cytotoxic activities were evaluated against six human cancer cell lines (HCT15, SK-OV-3, A549, SNB19, MCF7 and MCF7/ADR). A number of compounds including 4c and 4d showed 2-180 times more potent cytotoxic activity than doxorubicin against all human cancer cell lines tested. Furthermore, these compounds retained considerable cytotoxic activity against the doxorubicin-resistant cell line MCF7/ADR, implying their therapeutic potential to treat doxorubicin-resistant tumors.     

Synthesis and analgesic activity of 4-aroyl-1<Emphasis Type="Italic">H</Emphasis>-benzo[<Emphasis Type="Italic">c</Emphasis>]oxepin-3-ones

A series of 4-aroyl-1H-benzo[c]oxepin-4-ones have been prepared by heating ethyl 2-aroyl-3-(2-bromophenyl)propenoates. The synthesized compounds possess higher analgesic activity than the reference drug (analgin) and exhibit low toxicity.     

Synthesis and biological testing of (5<Emphasis Type="Italic">Z</Emphasis>)-2-aryl-5-arylmethylidene-3,5-dihydro-4<Emphasis Type="Italic">H</Emphasis>-imidazol-4-ones as antimitotic agents

Compounds interacting with cell protein tubulin and microtubules represent an important type of antimitotic agents. A series of tubulin-targeted 2-aryl-4-benzoyl-imidazoles were reported to possess high cytotoxicity, and so, we prepared a series of structural isomers of these to be evaluated as antimitotic agents. The synthesis of the novel (Z)-2-aryl-5-arylmethylidene-3,5-dihydro-4H-imidazol-4-ones involved coupling of substituted hippuric acids with aromatic aldehydes. Subsequent conversion of the resulting oxazolones to the corresponding imidazolones was carried out under microwave irradiation in the presence of urea and ammonium acetate. The cytotoxicity of the majority of the compounds to human epithelial carcinoma cancer cell line A549 was in the sub-micromolar range and was found to be more sensitive to the substituents on the 5-arylmethylidene fragment than on the 2-aryl ring in general. The cytotoxicities of the synthesized compounds were lower than those of the previously reported isomeric 2-aryl-4-benzoyl-imidazoles, and the basic structure–activity relationships in the isomeric pairs were different. Synthesized (5Z)-5-[(4-bromophenyl)methylidene]-2-(4-methylphenyl)-3,5-dihydro-4H-imidazol-4-one, which had the highest cytotoxicity (IC₅₀ ~ 440 nM) in the series of novel compounds, had a definite cytostatic effect on the A549 cells, but its antiproliferative properties were not linked to action on the microtubules. This would be an interesting lead compound for additional investigation into the mechanism of cytostatic action, and further structural optimization.     

Synthesis and biological activity of substituted 6-alkyl(6<Emphasis Type="Italic">H</Emphasis>)-3-phenyl-1,2,4-triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]-1,3,4-thiadiazines

A series of substituted 6-alkyl(6H)-3-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines have been synthesized by reaction of 3-alkyl-4-amino-5-thio-1,2,4-triazoles with substituted phenacylbromides in the presence of an equimolar amount of KOH. Mass spectra for the dissociative ionization by electron impact, antibacterial activity, and antitumor properties of the synthesized compounds have been studied. It was established that some compounds at doses of 50 – 100 mg/kg decrease the growth of sarcomas 45 and 37 by 35 – 47%.     

<Emphasis Type="Italic">In Vitro</Emphasis> antioxidant and anti-inflammatory activities of Jaceosidin from <Emphasis Type="Italic">Artemisia princeps</Emphasis> Pampanini <Emphasis Type="Italic">cv.</Emphasis> Sajabal

Oxidized low-density lipoprotein (oxLDL) plays a key role in the inflammatory processes of atherosclerosis. Jaceosidin isolated from the methanolic extracts of the aerial parts of Artemisia princeps Pampanini cv. Sajabal was tested for antioxidant and anti-inflammatory activities. Jaceosidin inhibited the Cu²⁺-mediated LDL oxidation with IC₅₀ values of 10.2 μM in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation. The antioxidant activities of jaceosidin were exhibited in the conjugated diene production, relative electrophoretic mobility, and apoB-100 fragmentation on copper-mediated LDL oxidation. Jaceosidin also inhibited the generation of reactive oxygen species (ROS) concerning in regulation of NF-κB signaling. And jaceosidin inhibited nuclear factor-kappa B (NF-κB) activity, nitric oxide (NO) production, and suppressed expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.     

Synthesis and biological evaluation of some functionalized 1<Emphasis Type="Italic">H</Emphasis>-1,2,3-triazole tethered pyrazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]pyridin-6(7<Emphasis Type="Italic">H</Emphasis>)-ones as antimicrobial and apoptosis inducing agents

A series of novel molecular hybrids containing pyrazole, pyridinone and 1,2,3-triazoles have been synthesized by one-pot four-component reaction of Meldrum’s acid, substituted aryl azides, 4-(prop-2-yn-1-yloxy)aryl aldehyde and 3-methyl-1-phenyl-1H-pyrazol-5-amine using L-proline as a basic organocatalyst besides CuSO₄.5H₂O and sodium ascorbate as catalysts for click chemistry in PEG-400 as a highly efficient and green media. Apoptosis studies have been carried out on ovarian follicles of goat (Capra hircus) and in vitro antibacterial activity has been done against six strains namely Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa and antifungal activity against two yeast strains namely, Candida albicans and Saccharomyces cerevisiae.     

Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1<Emphasis Type="Italic">H</Emphasis>-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug

The antitubercular drug; para-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1H-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. The obtained derivatives were screened against Mycobacterium tuberculosis H37Rv revealing good to high activity for the active compounds (MIC values of 0.39–1.5 μg/mL) compared to the marketed drugs isoniazid, rifampicin and ethambutol. Moreover, the most active analogue N-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxy-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzohydrazide (20) was found to be ten-fold more potent than PAS and equipotent to rifampicin (MIC 0.39 µg/mL), while exhibiting low cytotoxicity with a selectivity index of >128. In addition, this compound was shown to be active against persistent forms of mycobacteria comparable to standard drugs in nutrient starvation model. Accordingly, we introduce compound 20 as a valuable lead for further development. A 3D-QSAR study was also conducted to help in explaining the observed activity and to serve as a tool for further development.     

Synthesis and antimicrobial screening of <Emphasis Type="Italic">N</Emphasis>-(1-methyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-4-carbonyl)-thiourea derivatives

In the search of bioactive molecules in the class of functionally 4-substituted pyrazolic compounds, a series of N-(1-methyl-1H-pyrazole-4-carbonyl)-thiourea derivatives were prepared by addition of various substituted anilines to 1-methyl-1H-pyrazole-4-carbonyl isothiocyanate. The new thioureides and the intermediary compounds were characterized by spectroscopic data and elemental analyses and were evaluated for antibacterial and antifungal activities.     

Synthesis and antitumor evaluation of some 1,3,4-oxadiazole-2(3<Emphasis Type="Italic">H</Emphasis>)-thione and 1,2,4-triazole-5(1<Emphasis Type="Italic">H</Emphasis>)-thione derivatives

A series of 1,3,4-oxadiazole-2-thione and 1,2,4-triazole-5-thione derivatives have been successfully synthesized and studied for their antitumor activity. These compounds were prepared from carboxylic acids and chiral aminoacid esters. The prepared compounds were evaluated for their cytotoxicity against cancer in vitro using hydroxyurea (HU) as positive control. A fair number of compounds were found to have significant antitumor activity. To study the molecular basis of interaction and affinity of binding of the target molecules, all the compounds were docked into the ATPase domain of TP-II and tubulin using Schrödinger.     

Microwave-assisted synthesis,molecular docking and antimicrobial activity of novel 2-(3-aryl,1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)-8<Emphasis Type="Italic">H</Emphasis>-pyrano[2,3-f]chromen-4-ones

An efficient synthetic protocol of microwave-assisted synthesis of some novel 2-(3-aryl,1-phenyl-1H-pyrazol-4-yl)-8H-pyrano[2,3-f]chromen-4-ones 6a–j in excellent yields starting from 3-(3-aryl,1-phenyl-1H-pyrazol-4-yl)-1-(5-hydroxy-2H-chromen-6-yl)-propenones 5a–j was described. This approach offers the advantages of short reaction time (3–5 min), mild reaction conditions, high yields (80–88 %) and convenient operation. All the synthesized compounds were tested in vitro for their antimicrobial activity. The compounds 5h (Ar = 3-ethoxyphenyl), 6c (Ar = 4-chlorophenyl), 6e (Ar = 4-hydroxyphenyl) and 6i (Ar = 3,4-methoxyphenyl) were found to be potent against tested bacterial strains, and compounds 5g (Ar = 4-ethoxyphenyl), 6c (Ar = 4-chlorophenyl) and 6i (Ar = 3,4-methoxyphenyl) were found to be potent against tested fungal strains. The final compounds were subjected to molecular docking studies for the inhibition of enzyme DNA gyrase. The in silico molecular docking results are matching with the in vitro antimicrobial studies, and they may be considered as good inhibitor of DNA gyrase.     

<Emphasis Type="Italic">ent</Emphasis>-Abietane diterpenoids from <Emphasis Type="Italic">Isodon xerophilus</Emphasis>

Three new ent-abietanoids, named xerophilusins XIV–XVI, and four known analogues, as well as four known chemical constituents were isolated from the leaves of Isodon xerophilus. Their structures were elucidated by extensive spectroscopic studies, and comparison with literature data. In addition, the cytotoxic activity of the ent-abietanoids against chronic myelogenous leukemia (K562), stomach adenocarcinoma (MKN45), and hepatocellular carcinoma (HepG2) human cell lines was investigated and no activities were observed.     

Identification of medicinal <Emphasis Type="Italic">Dendrobium</Emphasis> species by phylogenetic analyses using <Emphasis Type="Italic">matK</Emphasis> and <Emphasis Type="Italic">rbcL</Emphasis> sequences

Species identification of five Dendrobium plants was conducted using phylogenetic analysis and the validity of the method was verified. Some Dendrobium plants (Orchidaceae) have been used as herbal medicines but the difficulty in identifying their botanical origin by traditional methods prevented their full modern utilization. Based on the emerging field of molecular systematics as a powerful classification tool, a phylogenetic analysis was conducted using sequences of two plastid genes, the maturase-coding gene (matK) and the large subunit of ribulose 1,5-bisphosphate carboxylase-coding gene (rbcL), as DNA barcodes for species identification of Dendrobium plants. We investigated five medicinal Dendrobium species, Dendrobium fimbriatum, D. moniliforme, D. nobile, D. pulchellum, and D. tosaense. The phylogenetic trees constructed from matK data successfully distinguished each species from each other. On the other hand, rbcL, as a single-locus barcode, offered less species discriminating power than matK, possibly due to its being present with little variation. When results using matK sequences of D. officinale that was deposited in the DNA database were combined, D. officinale and D. tosaense showed a close genetic relationship, which brought us closer to resolving the question of their taxonomic identity. Identification of the plant source as well as the uniformity of the chemical components is critical for the quality control of herbal medicines and it is important that the processed materials be validated. The methods presented here could be applied to the analysis of processed Dendrobium plants and be a promising tool for the identification of botanical origins of crude drugs.     

Synthesis and antimicrobial activity of novel 5-amino-4-cyano-<Emphasis Type="Italic">1H</Emphasis>-pyrazole and quinazolin-4(<Emphasis Type="Italic">3H</Emphasis>)-one derivatives

New substituted aroylhydrazones (4a-f) were synthesized from the acid hydrazide (3) and the corresponding aldehyde or aldose. 5-Amino-4-cyano-1H-pyrazole derivatives (6a-f) were prepared by the reaction of the aroylhydrazones (4a-f) with malononitrile. The synthesized compounds were tested for antimicrobial activity against various bacteria and fungi and showed moderate to high inhibition activities. Compounds incorporating a sugar moiety as well as a pyrazolyl ring in their structure displayed the highest antimicrobial activity.