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Synthesis of novel noscapine triazole tethered derivatives with γ-aminobutyric acid (GABA) linker is reported. Attachment of the linker was done by N-demethylation of noscapine followed by coupling with N-Boc protected GABA. The straightforward synthesis of the target molecules was made by a three-component reaction between GABA-noscapine, p-nitrophenyl azide, and commercially available ketones under metal-free conditions to produce a library with diverse functional groups. Anticancer activity of the synthesized derivatives was evaluated on MCF-7 cancer cell line. The best anticancer activity was demonstrated by a compound with an IC50 value of 57.2 µM, close to that of noscapine (IC50 = 55.2 µM). [ABSTRACT FROM AUTHOR]

In the present study, some new 1,2,3-triazole-tethered analogs of N-northebaine were designed and synthesized. The anti-bacterial properties of novel thebaine derivatives were studied on Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Based on the results, compounds 5b, 5j and 5m showed the best activities against S. aureus (minimum inhibitory concentration (MIC) ~ 25 μM) compared to the parent compound (MIC ~ 321 μM). The most active anti-bacterial derivatives (i.e., 5b, 5j and 5m) and thebaine were considered as potent anti-bacterial wound healing agents. In this regard, fibroblast cell cytotoxicity and proliferation as well as anti-hemolytic activities of the mentioned compounds were studied. The cytotoxicity assay by using 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide (MTT) on human dermal fibroblast cell lines (HDF) revealed that products 5j and 5m didn't show inhibition of cell line growth after 24 h. Based on the investigation results on blood cell disruption for releasing of hemoglobin, compound 5j didn't exhibit any hemolysis activity in different doses. [ABSTRACT FROM AUTHOR]

Noscapine is an isolated compound from the opium poppy, with distinctive chiral structure and chemistry, interacts with other compounds due to having multiple π‐acceptors, hydrogen bond acceptors, and ionic sites. Therefore, it has promising applicability for the enantioselective separation of a wide range of polar, acidic, basic, and neutral compounds. A new noscapine derivative chiral stationary phase (ND‐CSP) has been synthesized by consecutive N‐demethylation, reduction, and N‐propargylation of noscapine followed by attachment of a solid epoxy‐functionalized silica bed through the 1,3‐dipolar Huisgen cycloaddition. The noscapine derivative‐based stationary phase provides a considerable surface coverage, which is greater than some commercial CSPs and can validate better enantioresolution performance. The major advantages inherent to this chiral selector are stability, reproducibility after more than 200 tests, and substantial loading capacity. The characterization by Fourier transform infrared (FTIR) spectroscopy and elemental analysis indicated successful functionalization of the silica surface. Chromatographic method conditions like flow rate and mobile phase composition for enantioseparation of various compounds such as warfarin, propranolol, mandelic acid, and a sulfanilamide derivative were optimized. Comparing the experimental results with docking data revealed a clear correlation between the calculated binding energy of ND‐CSP and each enantiomer with the resolution of enantiomer peaks. [ABSTRACT FROM AUTHOR]

A series of 12 novel triazoles containing derivatives of norsufentanil were put into synthesis having the construction of the alkynyl group on norsufentanil followed by copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. Every single one of the synthesized compounds was evaluated through radioligand binding experiments. The compounds with the best affinities in the in vitro studies were selected to be investigated for their anti-nociceptive activity by way of tail flick test. Compounds 3h and 3i (Ki = 0.55 nM; IC50 = 1.25 nM and, Ki = 0.83 nM; IC50 = 1.87 nM, respectively) displayed the best affinities compared to that of sufentanil's (Ki = 0.70 nM; IC50 = 1.59 nM). 3h put on display the highest potency (ED50 = 4.21 µg/kg) for tail flick test amongst the entire selected compounds. [ABSTRACT FROM AUTHOR]

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Novel 1,2,3-triazole-tethered 9-bromonoscapine derivatives were synthesized by the propargylation of N-nornoscapine followed by Huisgen's 1,3-dipolar cycloaddition of the terminal alkynes with different azides. Cytotoxicity of the products was studied by MTT assay against the MCF-7 breast cancer cell line. Most of the compounds revealed a better cytotoxicity than N-nornoscapine and 9-bromonornoscapine as the parent compounds. Among the synthesized compounds, those with a hydroxylated aliphatic side chain (5p, 5q, and 5r) showed the highest activities (IC50s: 47.2, 37.9, and 32.3 µg/mL, respectively). Molecular docking studies showed that these compounds also had the highest docking scores and effective interactions with binding sites equal to -8.074, -7.425 and -7.820 kcal/mol, respectively. [ABSTRACT FROM AUTHOR]

A series of novel 1,4‐disubstituted 1,2,3‐triazole derivatives of nor‐codeine were synthesized by N‐demethylation of codeine by a new procedure followed by propargylation of nitrogen and alkyne‐azide cycloaddition reaction. Affinities of all compounds to Mu opioid receptors were evaluated by in vitro radioligand binding assay method. Seven compounds out of all eighteen novel products were selected for in vivo analgesic tail flick test. Most of the synthesized compounds showed promising results in which 3‐((1‐(2‐hydroxy‐3‐phenoxypropyl)‐1H‐1,2,3,–triazol‐4‐yl)methyl)‐9‐methoxy‐2,3,4,4a,7,7a hexahydro‐1H‐4,12‐methanobenzofuro[3,2‐e]isoquinolin‐7‐ol (16 e) with an ED50 of 8.68 mg/kg revealed considerable analgesic activity even better than codeine (9.55 mg/kg) as a commercial drug. Also, docking studies were made on Mu opioid receptor (BU72) which showed good agreement with experimental data. The mentioned compound had the highest docking scores of −10.84 and −9.90 kcal/mol for R and S diastereomers, respectively. [ABSTRACT FROM AUTHOR]

The present study has been dedicated to the synthesis of a new and highly stable computed tomography contrast agent based on pegylated deoxycholic acid‐ coated gold nanoparticles (DCA‐PEG‐GNPs) measuring 17 nm in size. To stabilize the gold nanoparticles (GNPs) as well as increasing their vascular retention time, polyethylene glycol, PEG, with a molecular weight of 4 KD, was applied. Besides, for target delivery, deoxycholic acid (DCA) as a biologically active compound and a secondary bile acid, capable of interfering with some cancers, were selected. The bile acid was attached to the nanoparticle's surface with a polyethylene glycol (MW=1 KD) linker via an etherification reaction. Finally, the activity of the prepared compound was studied by means of a clinical CT instrument at various KVp values. The gained results depicted a very high activity of the compound to attenuate X‐rays along with making contrast enhancement, even better than those of Visipaque as a commercial contrast agent. In addition, the DCA‐PEG‐GNPs displayed remarkable stability in a wide range of pHs, i. e. 2.5‐11, and in different temperature conditions, ranging between −78 °C to 48 °C. [ABSTRACT FROM AUTHOR]

Noscapine, a natural alkaloid, has never been used as a parent scaffold in chiral induction. The first examples of noscapinoid compounds as efficient catalysts in asymmetric synthesis are now reported. Three derivatives of noscapine were synthesized from its reaction with different Grignard reagents. Asymmetric addition of diethylzinc to aldehydes was performed in the presence of these catalysts in high yields and good to excellent ees. [ABSTRACT FROM AUTHOR]

Novel substituted amino acid tethered norsufentanil derivatives were synthesized by the four‐component Ugi reaction. Norsufentanil was reacted with succinic anhydride to produce the corresponding carboxylic acid. The resulting carboxylic acid has undergone a multicomponent reaction with different aldehydes, amines, and isocyanides to produce a library of the desired compounds. In all cases, amide bond rotation was observed in the NMR spectra. In vivo analgesic activity of the synthesized compounds was evaluated by a tail flick test. Very encouraging results were obtained for a number of the synthesized products. Some of the synthesized compounds such as 5a, 5b, 5h, 5j, and 5r were found to be more potent than sufentanil, sufentanil citrate, and norsufentanil. Binding modes between the compounds and mu and delta‐opioid receptors were studied by molecular docking method. The relationship between the molecular structural features and the analgesic activity was investigated by a quantitative structure–activity relationship model. The results of the molecular modeling studies and the in vivo analgesic activity suggested that the majority of the synthesized compounds were more potent than sufentanil and norsufentanil. [ABSTRACT FROM AUTHOR]

A new, normal phase high performance liquid chromatography (NP-HPLC) method was developed for separation of Bortezomib (BZB) enantiomers and quantitative determination of (1S,2R)-enantiomer of BZB in active pharmaceutical ingredient (API) samples. The developed method was validated based on International Conference on Harmonisation (ICH) guidelines and it was proved to be accurate, precise and robust. The obtained resolution (RS) between the enantiomers was more than 2. The calibration curve for (1S,2R)-enantiomer was found to be linear in the concentration range of 0.24-5.36mg/L with regression coefficient (R²) of 0.9998. Additionally, the limit of detection (LOD) and limit of quantification (LOQ) were 0.052 and 0.16mg/L, respectively. Also, in this study, a precise, sensitive and robust gradient reversed-phase HPLC (RP-HPLC) method was developed and validated for determination of BZB in API samples. The detector response was linear over the concentration range of 0.26-1110.5mg/L. The values of R², LOD and LOQ were 0.9999, 0.084 and 0.25mg/L, respectively. For both NP-HPLC and RP-HPLC methods, all of the RSD (%) values obtained in the precision study were <1.0%. System suitability parameters in terms of tailing factor (TF), number of theoretical plates (N) and RS were TF < 2.0, N > 2,000 and RS > 2.0. The performance of two common integration methods of valley to valley and drop perpendicular for drawing the baseline between two adjacent peaks were investigated for the determination of diastereomeric impurity (Imp-D) in the BZB-API samples. The results showed that the valley to valley method outperform the drop perpendicular method for calculation of Imp-D peak areas. Therefore, valley to valley method was chosen for peak integration. [ABSTRACT FROM AUTHOR]

In this paper new β-carboline derivatives possessing the 1,2,3-triazole ring at C-1 substituent were synthesized from L-tryptophan by Pictet-Spengler reaction followed by a Huisgen 1,3-dipolar addition. In vitro cytotoxicity and antibacterial activity of synthetic compounds were investigated. Methyl 1-(3 -((1-(3,4-dichlorophenyl)-1 H-1,2,3-triazol-4-yl)methoxy)phenyl)- β-carboline-3-carboxylate ( 7f) showed the highest cytotoxic activity with IC values of 46 and 32 μM against Hela and HepG2 cell lines, respectively. Compounds 7d and 7i (possessing 4-bromophenyl substituent) and 5c showed excellent inhibition activity for Enterococcus faecium with MIC of 8 μg/mL. The results demonstrated that the presence of 1,2,3-triazole rings in β-carboline derivatives improve their biological activities. [ABSTRACT FROM AUTHOR]

New derivatives of 1,2,3-triazolyl 7-carboxamidodesacetoxy cephalosporanic acid were synthesized using alkyne-azide 1,3-dipolar cycloaddition. The synthesized compounds were evaluated for their antibacterial activity against a collection of Gram-positive and Gram-negative bacteria and also in synergy with cefixime and cephalexin. Some compounds inhibited vancomycin-resistant strain of Enterococcus faecium (MIC = 8 µg/mL) and in the synergy experiments compounds 13a, 13f, and 13g decreased the level of MIC against an ESBL strain of Klebsiella pneumonia. A comparative molecular field analysis has been carried out, and the effect of substituents on the antibacterial activities of the synthesized compounds was explained. [ABSTRACT FROM AUTHOR]

A highly efficient of some new spiro-2-aminopyrimidinones via a three-component reaction of cyclic ketones, methylcyanoacetate or malononitrile, and guanidinium carbonate has been developed through a domino Knoevenagel/Michael/cyclization sequence. The hydrogen bonding capacity of these compounds would make these structures especially stable. Furthermore, the antibacterial study reveals that these types of compounds exhibit good . [ABSTRACT FROM AUTHOR]

A series of triazolyl methoxyphenyl 1,8-dioxo-decahydroacridine derivatives has been prepared in a one-pot, pseudo-five-component reaction of aromatic propargylated aldehydes, various azides, dimedone, and a variety of amines in the presence of Cu(OAc)2/sodium ascorbate and 1-methylimidazolium trifluoroacetate ([Hmim]TFA) as the catalyst in good yields. [ABSTRACT FROM AUTHOR]

The combination of the Biginelli reaction with click chemistry has been used for the one-pot synthesis of 1,2,3-triazole linked dihydropyrimidinones from azides, aromatic aldehydes containing a propargyl ether group, urea, and 1,3-dicarbonyl compounds using Cu(OAc)/sodium ascorbate as catalyst in acetic acid under mild reaction conditions. [ABSTRACT FROM AUTHOR]

SBA-15 mesoporous silicas modified with proline and aminopropyl functional groups were employed for synthesis of tetrahydrobenzo[b]pyrane derivatives by simply mixing the precursors with surface-modified catalyst in a mortar. The mesoporous catalysts were characterized by Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), small-angle x-ray diffractometry (SAXS), thermogravimetric/differential thermal analyzer (TG/DTA), Barrett–Joiner–Halenda (BJH) pore size and volume analysis, and Brunauer–Emmett–Teller (BET) surface area measurement methods. The results indicate that SBA-15 mesoporous silica modified with proline and aminopropyl functional groups can be effectively utilized for synthesis of tetrahydrobenzo[b]pyrane derivatives. [ABSTRACT FROM AUTHOR]

The Michael-type addition of a 4-hydroxycoumarin (=4-hydroxy-2 H-1-benzopyran-2-one) 1 to a β-nitrostyrene (=(2-nitroethenyl)benzene) 2 in the presence of AcONH4 leads to substituted (3 E)-3-[amino(aryl)methylidene]chroman-2,4-diones (=(3 E)-3-[amino(aryl)methylene]-2 H-1-benzopyran-2,4(3 H)-diones) 4 ( Table 1). High yields, short reaction time, and easy workup are advantages of this novel one-pot three-component reaction. [ABSTRACT FROM AUTHOR]

The 1-{[(1 H-1,2,3-Triazol-4-yl)methoxy]phenyl}-1 H-pyrazolo[1,2- b]phthalazine-5,10-dione derivatives 5 were synthesized by a simple and efficient method, i.e., by the four-component, one-pot condensation reaction of phthalohydrazide 4, a (propargyloxy)benzaldehyde 1, an active methylene compound 3 (malononitrile or ethyl cyanoacetate), and an azide 2 in the presence of Cu(OAc)2/sodium L-ascorbate as catalyst and 1-methyl-1 H-imidazolium trifluoroacetate ([Hmim](CF3COO)) as an ionic-liquid medium in good to excellent yields ( Scheme 1). [ABSTRACT FROM AUTHOR]

Efficient methods for stereoselective synthesis of polyfunctional ( E)-enaminones and ( Z)-dithiocarbamates via one-pot five- and six-component sequential Ugi/Nucleophilic addition reactions are described. High yields and high bond forming efficiency, and simple operations are the advantages of this method. [ABSTRACT FROM AUTHOR]

Diazabicyclo[2.2.2]octane (DABCO) has been used as a mild and efficient catalyst for synthesis of 2-amino-3-cyano naphthopyran derivatives via a one-pot three-component reaction of aromatic aldehydes, naphthols, and malononitrile at room temperature. The short reaction times, easy workup, good to excellent yields, and mild reaction conditions make this domino Knoevenagel-Michael reaction both practical and attractive. [ABSTRACT FROM AUTHOR]

Diammonium hydrogen phosphate was used as a mild, efficient, neutral, and cheap catalyst for the synthesis of various 4H-benzo[b]pyran derivatives via a one-pot, three-component condensation of aromatic aldehydes, active methylene compounds, and dimedone in aqueous media. [ABSTRACT FROM AUTHOR]

Knoevenagel condensation of various aromatic and heteroaromatic aldehydes with active methylene compounds such as methyl and ethyl cyanoacetate, malononitrile, and cyanoacetamide proceeds smoothly with stirring in water in the presence of 4 mol% of diammonium hydrogen phosphate. The reactions were carried out at room temperature in short periods with a very simple workup procedure and good to high yields. [ABSTRACT FROM AUTHOR]

Knoevenagel condensation of various aromatic and heteroaromatic aldehydes with active methylene compounds like methyl and ethyl cyanoacetate, malononitrile, and cyanoacetamide proceeds smoothly with stirring in water in the presence of 4 mol% of diammonium hydrogen phosphate. The reactions were carried out at room temperature in short periods with very simple workup procedure and good to high yields. [ABSTRACT FROM AUTHOR]

Tetra- n -butylammonium hydroxide (TBAH) has been utilized as a novel and efficient catalyst for the Knoevenagel condensation of aldehydes with acidic methylene compounds such as methyl- and ethylcyanoacetate, malononitrile, and cyanoacetamide to afford substituted olefins. [ABSTRACT FROM AUTHOR]