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In consideration of green and efficient organic chemical methodology, we reported here a green, an efficient and convenient procedure for synthesis of 3-aryl-2,3-dihydro-1,3,4-thiadiazoles based on benzofuran as well as chromone moieties, using the grinding technique. Condensation of 1-(4,7-dimethoxybenzofuran-5-yl)ethan-1-ones 2, 3; 7-hydroxy-5-methoxy-2-methyl-4-oxo-4H-chromene-6-carbaldehyde (4); and 4-oxo-4H-chromene-3-carbaldehydes 10a–c with alkyl hydrazine carbodithioates followed with some hydrazonoyl halides 7a–g under grinding and solvent-free condition led to the formation of the targeted 3-aryl-2,3-dihydro-1,3,4-thiadiazoles 8a–g, 9a,b, and 12a–f, correspondingly. Structures of the synthesized compounds were clarified based on their elemental analyses and spectral data. Eleven of the entire target compounds were selected for anticancer activity against 60 human cancer cell lines at a single dose (10‾5 M) by the National Cancer Institute (NCI, Bethesda, USA).

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Simple and rapid route for Meerwein arylation reaction using iron powder or a mixture of tin/tin chloride has been developed. In the presence of iron powder, different aryl diazonium salts ...

A simple and convenient rout for the synthesis of linear 2-imino-2H,6H-pyrano[3,2-g] chromen-6-ones and 2H,6H-pyrano[3,2-g]chromene-2,6-diones has been described starting from natural occurring fur...

The popular use of Pterocarpus erinaceus as antimicrobial prompted us to study the antifungal properties of its bark, leaves and roots against Candida albicans, Aspergillus fumigatus, and Aspergillus niger. Thus, the broth microdilution method was used to perform the test and only the root extract showed significant antifungal activity against A. fumigatus with value at MIC 16 μg/mL. This root extract was further partitioned by immiscible liquid-liquid extraction into five fractions. Successive chromatographic columns were used for the purification of the organic fractions which led to the isolation and the identification of five compounds including two new (3 and 5) and three known (1, 2, and 4). Their structures were established as muningin 1, the mixture of formononetin and pseudobaptigenin 2, boutotone 3, isoliquiritigenin 4, and boutomycone 5, by the mean of spectroscopic data compared to those reported in the literature. Compounds 1-5 were also tested on A. fumigatus against which 1, 2, and 5 showed antifungal effects with MIC values at 853.3, 28.7, and 452.3 μM, respectively. The obtained results indicated that the traditional use of this plant as antimicrobial could be related to its roots.

International audience; Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.

Indole alkaloids constitute a large class of natural products and their diverse and complex structures have been attributed to potent biological activities such as anticancer, anti-inflammatory, antimicrobial, antimalarial, antiplasmodial and protein kinase inhibition. The isolation of bioactive compounds from natural sources is difficult, costly and an extremely time-consuming process, therefore synthetic pathways are more convenient than natural separation to deliver such compounds in considerable amounts. In this respect, this review provides comprehensive information on the structures and the synthesis of bioactive indole alkaloids utilizing 1H-indole-3-carboxaldehyde and its derivatives as starting compounds. 1 Overview2 Phytoalexins2.1 Brassinin, Cyclobrassinin and Brassitin2.2 1-Methoxybrassinin, 1-Methoxyspirobrassinol and 1-Methoxyspirobrassinin2.3 4-Methoxybrassinin and 4-Methoxycyclobrassinin2.4 Cyclobrassinone2.5 Brassilexin2.6 (S)-(–)-Spirobrassinin2.7 Camalexin3 Bis(indole) Alkaloids: Rhopaladines A–D4 Coscinamides A and B5 α-Cyclopiazonic Acid6 Dipodazine7 Isocryptolepine8 Apparicine9 Carbazole Alkaloids: Mukonine and Clausine E10 Indolmycin11 Conclusion

Introduction Medicinal applications of Genista species throughout the Mediterranean area are widespread. More specifically, Genista ferox Poirret., endemic to North Africa, holds important diuretic, anti-gout and –rheumatism actions. It is also employed for the treatment of scrofulous tumors. The aim of the present study was to evaluate the antioxidant and anti-proliferative effects of the ethanolic extract and isolated fractions of aerial parts of G. ferox. Identification by UPLC and NMR analyses of constituents of the most active fraction was equally carried out. Methods Genista ferox extract and fractions were examined for their total flavonoid content, scavenging activities against DPPH, ABTS and OH· radicals, H2O2 elimination, Fe++ chelating capacity. Anti-proliferative activity using breast carcinoma cells (MCF-7) and CDC25 phosphatase was also assessed. Results Significant levels of flavonoids were recorded in FIII fraction which exhibited the highest inhibition percentages against DPPH (95.79 ± 1.37), ABTS (83.17 ± 4.30) (p Conclusion Data from the present study suggest that Genista ferox is a rich source for value-added molecules as potential antioxidants and anti-proliferative agents for optimal human health.

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedlander condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.

The investigation of natural products used in Traditional Medicine in Africa is complicated as modern analytical and screening methods are often not available. Computer aided product identification from traditional usage records (CAPITURE) may provide an interesting alternative and has been evaluated in the context of an ethnobotanical survey on fungal diseases and their traditional treatment in Tchamba District (Togo). 53 traditional healers were interviewed and their knowledge recorded. Several indicators, the Use Value (UV), Plant Part Value (PPV), Specific Use (SU) Value, Intraspecific Use Value (IUV) and Informant Consensus Factor (ICF), were applied to the data. Those indices, in addition to a bibliographic review, were then fed into a computer-aided approach which predicted two interesting plants out of the 43 species survey-recorded and their specific activities: Pterocarpus erinaceus sap against ringworm, Daniellia oliveri sap against intertrigo and respectively their roots and trunk barks against candidiasis. Subsequent laboratory-based studies have confirmed the predicted antimicrobial activities with MIC (128 μg/mL to 30 mg/mL) and without any notable toxicity on a normal human cell (MRC-5 cells). Although such a method may not be flawless, it is able to provide first leads, and in the face of limited resources, is an attractive alternative worth considering.

The synthesis of 2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones was revisited and a catalyst-free method was established, by exploring the reactivity of 3-[(2-aminoaryl)amino]dimedones towards carbonylated electrophiles. 2D NMR and single-crystal X-ray diffraction studies were used to characterize the structures unequivocally and to review the mechanism leading to the formation of supposed positional isomers. The action of 3-[(2-aminoaryl)amino]dimedones on chromene-3-carboxylic acid, fumaryl, and oxalyl chloride has led to dibenzo[b,e][1,4]diazepin-1-one ring opening to produce novel Z-configured enaminone and linear diamides.

Formylated chlorothieno[2,3-b]pyridine derivatives were synthesized by reaction between N-protected 3-acetyl-2-aminothiophenes and Vilsmeier–Haack reagent under classical conditions. These products were not accessible without N-protection of the starting materials or by reaction between the reagent and 4-chlorothieno[2,3-b]pyridine under any conditions. The conditions of the reaction could be altered to produce unformylated derivatives in better yields than reaction with unprotected aminothiophene.

Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2&bull, &minus, ). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association between the over-expression of the Folate Receptor Alpha (FRA) in TNBC and other cancer cells, has led to the possibility that TNBCs might be treated by targeting the FRA with redox selenium covalent Folic Acid conjugates. The present study reports the synthesis of the redox active vitamer, Selenofolate, generating superoxide. Superoxide (O2&bull, ) catalytic generation by Selenofolate was assessed by an in vitro chemiluminescence (CL) assay and by a Dihydroethidium (DHE) in vivo assay. Cytotoxicity of Selenofolate was assessed against the TNBC cell line MDA-MB-468 and an immortalized, mammary epithelial cell line, HME50-5E. Cytotoxicity of Selenofolate was compared to Folic Acid and sodium selenite, in a time and dose dependent manner. Selenofolate and selenite treatments resulted in greater inhibition of MDA-MB-468 cell proliferation than HME50-5E as evaluated by Trypan Blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay and Annexin V apoptosis assays. Folate receptor alpha (FRA) protein expression was assessed by Western blotting, with the experimental results showing that redox active Selenofolate and selenite, but not Folic Acid, was cytotoxic to MDA-MB-468 cells in vitro, suggesting a possible clinical option for treating TNBC and other cancers over-expressing FRA.

Arylsulfatase A (ARSA) plays a crucial role in the reproduction of mammals due to its involvement in the specific gamete interaction preceding sperm and egg fusion leading to fertilization. Recently, it has been shown that zona pellucida (ZP) sperm binding and in vivo fertilization in mice are markedly hampered by using a specific anti-ARSA antibody. Herein, the design and discovery of the first ARSA small molecule inhibitor based on a coumarin-containing polycyde are presented. Through a structure-based approach applied on our in-house library, compound 1r was identified as an ARSA reversible inhibitor (ARSAi); then its activity was validated through both surface plasmon resonance and biochemical inhibition experiments, the first providing a K-D value of 21 mu M and the latter an IC50 value of 13.2 mu M. Further investigations highlighted that compound 1r induced 20% sperm death at 25 mu M and also impaired sperm motility; nevertheless both the effects were mediated by ROS production, since they were rescued by the cotreatment of 1r and N-acetyl cysteine (NAC). Interestingly, while 1r was not able to hamper the ZP/sperm binding, it markedly decreased the in vitro oocyte fertilization by mouse sperm up to 60%. Notably, this effect was not hampered by 1r/NAC coadministration, hence allowing the ruling out of an ROS-dependent mechanism. In conclusion, herein is reported the first ever hit of ARSAi as a chemical tool that will enable better exploration of ARSA's biological role in fertilization as well as provide a starting point for developing 1r structure optimization aimed at increasing enzyme inhibition potency but also providing a deeper understanding of the involvement of ARSA in the fertilization pathway mechanism.

Two novel compounds were isolated for the first time from Calycotome spinosa (L.) Link, an alkaloid 5-Hydroxy-1H-indole (4) and a cyclitol D-pinitol (5), together with the three well-known flavonoids; Chrysin-7-O-(β-D-glucopyranoside) (1), Chrysin-7-O-β-D-(6″-acetyl)glycopyranoside (2) and Apigenin-7-O-β-D-glycopyranoside (3). The chemical structures of the isolated compounds were elucidated by spectroscopic data and mass spectrometric analyses; including a fresh approach 1D-NMR, 2D-NMR with LC-ESI-MS/MS. In this study, the new compound (4) that has been obtained from the leaves MeOH extract presented the best radical scavenging activity (DPPH) (IC

A new series of thermally stable linked bis-merocyanine dyes were synthesized from thiazolium salt derivatives and bis-rhodanines in good yields. The synthesized compounds were fully characterized by FT-IR, UV/Vis, NMR and mass spectrometry and their thermal properties were determined by TGA and DSC. The shape of the absorption spectra of bis-merocyanine dyes is affected both by the nature of the spacer and the polarity of the solvent. Absorption and fluorescence spectra of compound B1T6 were measured at room temperature (298 K), in various solvents to investigate their solvatochromic behaviour. The ground and excited state dipole moments of B1T6 compound were estimated experimentally by solvatochromic shift method using Bilot-Kawski, Lippert-Mataga, Bakhshiev, Kawski-Chamma-Viallet and Reidchardt's microscopic solvent polarity functions. It was observed that the excited-state dipole moment was found to be higher than the corresponding ground-state dipole moments, due to a substantial redistribution of electron densities and charges in a more polar excited-state. The geometry of this compound was optimized; HOMO-LUMO energy values and the ground state dipole moment μg were also evaluated theoretically by quantum chemical calculations using the DFT method by adopting B3LYP/G-31 G (d, p) of theory (Gaussian 09).

An efficient and high yielding protocol is reported for the synthesis of new class of 4-anilinoquinolino-quinazoline hybrids. The target compounds were prepared first by the reaction of 2-aminobenzamide with 2-chloroquinoline-3-carbaldehydes. After oxidation and chlorination, the key 2-quinolyl-4-chloroquinazolines were converted to the corresponding 2-(2-arylaminoquinolyl)-4-arylaminoquinazolines and N-heteroaryl-2-(2-(heteroarylamino)quinolin-3-yl)quinazolin-4-amines.

A variety of novel 2-hydroxy-1,4-benzoxazines were synthesised through the Petasis multicomponent reaction of 2-[(arylmethyl)amino] phenols with arylboronic acids and glyoxal catalysed by pyridinium toluene- p-sulphonate. A plausible reaction mechanism has also been proposed.

An efficient synthesis of novel 2-[aryl(arylamino)methyl]-6-methyl-4H-furo[3,2-c]pyran-3,4(2H)-diones is described by using a three-component reaction of α-bromodehydroaceticacid (α-Br-DHA) with anilines and benzaldehydes. Ammonium acetate is a suitable base to catalyse the diastereoselective tautomerism of the furo[3,2-c]pyran-3,4-diones into (Z)-3-[3-aryl-3-(arylamino)acryloyl]-4-hydroxy-6-methyl-2H-pyran-2-ones by opening the furan ring. These latter compounds were also obtained by a three-component reaction (α-Br-DHA, anilines, benzaldehydes) catalysed by ammonium acetate.

Eight heterocycles have been prepared in a one-pot reaction manner based on the Hantzsch dihydropyridine synthesis. The synthesis afforded seven dihydropyridines (DHP) and one unexpected 1,3-oxazin-6-one. Their structures were confirmed based on NMR spectroscopy and mass spectrometry. The obtained products have been evaluated for their cytotoxicity against eight cancer cell lines and one normal cell line. Two halogenated DHPs (7 and 8) displayed cytotoxicity toward all the nine tested cancer cell lines with IC50 values from 4.10 to 58.90 μm, while others showed selective activities. DHPs (7 and 8) bearing a Me group at C(2) and C(6) as well as a halogenated substituent at C(4′) were more antiproliferative than the others.

A mild and simple oximation reaction of 4-chloro-3-formylcoumarin with hydroxylamine hydrochloride in basic medium gave unexpected three components via oxime.Those compounds were separatedin good yields by preparative TLC and by chemical means using differentreaction conditions. IR, 1H NMR, 13C NMR and mass spectral data confirmed the structure of the separated compounds.

Despite the discovery of tyrosine kinase inhibitors (TKIs) for the treatment of breakpoint cluster region-Abelson (BCR-ABL)+ cancer types, patients with chronic myeloid leukemia (CML) treated with TKIs develop resistance and severe adverse effects. Combination treatment, especially with a histone deacetylase (HDAC) 6 inhibitor (HDAC6i), appears to be an attractive option to prevent TKI resistance, considering the potential capacity of an HDAC6i to diminish BCR-ABL expression. We first validated the in vivo anti-cancer potential of the compound 7b by significantly reducing the tumor burden of BALB/c mice xenografted with K-562 cells, without notable organ toxicity. Here, we hypothesize that the HDAC6i compound 7b can lead to BCR-ABL downregulation in CML cells and sensitize them to TKI treatment. The results showed that combination treatment with imatinib and 7b resulted in strong synergistic caspase-dependent apoptotic cell death and drastically reduced the proportion of leukemia stem cells, whereas this treatment only moderately affected healthy cells. Ultimately, the combination significantly decreased colony formation in a semisolid methylcellulose medium and tumor mass in xenografted zebrafish compared to each compound alone. Mechanistically, the combination induced BCR-ABL ubiquitination and downregulation followed by disturbance of key proteins in downstream pathways involved in CML proliferation and survival. Taken together, our results suggest that an HDAC6i potentiates the effect of imatinib and could overcome TKI resistance in CML cells.

To search for effective and selective inhibitors of cholinesterases (AChE and BuChE), a series of poly-functionalized Tacrine-derived compounds specifically 2-(alkylthio)-4-aryl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-5-amines were designed an synthesized via Friedlander reaction. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data (1H NMR, 13C NMR) and elemental analyses (CHNS). Compounds 3a-h were evaluated for their abilities to inhibit AChE and BChE. The obtained biological results revealed that some synthesized compounds displayed higher anti-cholinesterase activity in comparison to Galantamine. Among them, compound 3d bearing S-ethyl and 4-chlorophenyl moieties showed the most potent activity against AChE/BuChE with IC50s values of 4,32 and 15,10 μM, respectively. The anti-AChE activity of 3d was 5-fold more than that of reference drug Galantamine. Moreover, molecular docking studies were performed for the most active derivatives, 3d and 3c, in which binding mode between these compounds and the receptors were determined. Density functional theory (DFT) method at B3LYP/6–311++G (d,p) level of theory was employed to gain insights into the molecular structure of the target compounds. Molecular electrostatic potential (MEP) mapping, reactivity indices such as electronegativity, electrophilic index, softness and hardness as well as frontier molecular orbitals HOMO-LUMO have been investigated for 3a-3c as representative compounds. In addition, their antiradical activity has been predicted by computing bond dissociation enthalpies (BDEs).

A variety of novel 2-alkylthiopyrimidines were synthesized through simple condensation of arylidenemalononitriles with different 2-alkylthiouronium halide derivatives catalyzed by anhydrous potassium carbonate (K2CO3). The reactions have been carried out under mild conditions in i-PrOH, and the products were obtained in moderate to good yields with a simple work-up method. Subsequently, some examples of these compounds have been converted into Tacrine analogs by applying the Friedländer reaction.

International audience; Two novel compounds were isolated for the first time from Calycotome spinosa (L.) Link, an alkaloid 5-Hydroxy-1H-indole (4) and a cyclitol D-pinitol (5), together with the three well-known flavonoids; Chrysin-7-O-(β-D-glucopyranoside) (1), Chrysin-7-O-β-D-(6″-acetyl)glycopyranoside (2) and Apigenin-7-O-β-D-glycopyranoside (3). The chemical structures of the isolated compounds were elucidated by spectroscopic data and mass spectrometric analyses; including a fresh approach 1D-NMR, 2D-NMR with LC-ESI-MS/MS. In this study, the new compound (4) that has been obtained from the leaves MeOH extract presented the best radical scavenging activity (DPPH) (IC50 < 10 µg/mL) compared to the standard butylated hydroxytoluene (BHT, IC50 = 34.73 ± 0.23 μg/mL) and showed the highest total antioxidant capacity (TAC = 985.54 ± 0.13 mg AAE/g extract) in contrast to ascorbic acid (TAC = 905.95 ± 0.07 mg AAE/g extract). Furthermore, the strongest reducing power (EC50 = 344.82 ± 0.02 µg/mL), as well as the remarkable scavenging potential by ABTS assay (IC50 = 7.8 ± 0.43 µg/mL), were exhibited by the same composite (4). Followed by the methanol crude extract and the compound (3) that also showed a potent antioxidant (DPPH; IC50 = 41.04 ± 0.15 and 47.36 ± 0.21 µg/mL, TAC; 671.02 ± 0.21 and 608.67 ± 0.34 mg AAE/g extract, FRAP; EC50 = 763.73 ± 0.32 and 814.61 ± 0.31 µg/mL, ABTS; IC50 = 19.18 ± 0.06 and 63.72 ± 0.64 µg/mL, respectively), but less than the previous samples. On the opposite side, compound (5) had the lowest activity, in which its values were less interesting to determine. Moreover, compound (4) has equally exerted an attractive antibacterial activity against Staphylococcus aureus (ATTC-25923), Pseudomonas aeruginosa (ATTC- 27853) and Salmonella abony (NCTC 6017), as measured by the disc diffusion assay, with inhibition zones of 16 ± 0.5, 9.83 ± 0.29 and 8 ± 0.28 mm, in that order. To the best of our knowledge, 5-Hydroxy-1H-indole was isolated from plants for the second time in our current work. Thus, the obtained results from this investigation propose that the leaves of C. spinosa are a rich natural source for value molecules as potential antioxidants and antimicrobial agents for best human health.

DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line. © 2014 American Chemical Society.