Oualid Talhi

Novel benzofuran–chromone and –coumarin derivatives: synthesis and biological activity in K562 human leukemia cells

Not widely distributed in nature, aurones, (Z)-2-benzylidene-benzofuran-3(2H)-ones, are one of the less common and lesser-known representatives of a flavonoid subclass. Nevertheless, they exhibit a strong and broad variety of biological activities. We have combined the benzofuranone part of a classical aurone with either a chromone or a coumarin scaffold which proved to feature interesting biological activities including antimicrobial, antiviral, anticancer, anti-inflammatory and antioxidant properties. Herein we present a series of 26 novel benzofuran derivatives with the first biological results in K562 human leukemia cells showing that compounds 21b, 29b and 29c are able to induce around 24% apoptosis.

The Antiinflammatory Potential of Flavonoids: Mechanistic Aspects

Abstract Flavonoids are a subclass of phenolic compounds that occur ubiquitously in food plants and vegetables. This class of compounds shares a common 15-carbon structure represented by a benzene ring (A) condensed with a heterocyclic six-membered pyran or pyranone ring (C) that carries a phenyl ring (B) in the 2-, 3-, or 4-position. These compounds are known to modulate important cellular signaling processes including those associated with inflammatory diseases, hence rendering them a clinical potential in this area. In general, the antiinflammatory properties of flavonoids involve the inhibition of the activity of several proinflammatory biochemical mediators (cytokines, adhesion molecules, NO ) and enzymes (COX-2, LOX, iNOS). In addition, these compounds may also interact with important transcription factors and signaling pathways, including nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) thus regulating the proinflammatory genes’ expression. Importantly, the capacity of flavonoids to interact with these cellular markers is dependent on specific structural features. In general, the hydroxyl substitutions at the 3′-, 4′-, 5-, and 7-positions, the unsaturated C2 C3 function and the 4-keto group of the C-ring are the main structural requirements to provide efficient inhibition of signaling molecules. This manuscript revises relevant studies focusing the structure–affinity relationship between flavonoids and key inflammatory markers, underlying the specific structural features involved in these interactions, as well as an approach to some synthetic strategies aiming the enhancement of flavonoids antiinflammatory properties.Flavonoids are a subclass of phenolic compounds that occur ubiquitously in food plants and vegetables. This class of compounds shares a common 15-carbon structure represented by a benzene ring (A) condensed with a heterocyclic six-membered pyran or pyranone ring (C) that carries a phenyl ring (B) in the 2-, 3-, or 4-position. These compounds are known to modulate important cellular signaling processes including those associated with inflammatory diseases, hence rendering them a clinical potential in this area. In general, the antiinflammatory properties of flavonoids involve the inhibition of the activity of several proinflammatory biochemical mediators (cytokines, adhesion molecules, NO) and enzymes (COX-2, LOX, iNOS). In addition, these compounds may also interact with important transcription factors and signaling pathways, including nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) thus regulating the proinflammatory genes’ expression. Importantly, the capacity of flavonoids to interact with these cellular markers is dependent on specific structural features. In general, the hydroxyl substitutions at the 3′-, 4′-, 5-, and 7-positions, the unsaturated C2C3 function and the 4-keto group of the C-ring are the main structural requirements to provide efficient inhibition of signaling molecules. This manuscript revises relevant studies focusing the structure–affinity relationship between flavonoids and key inflammatory markers, underlying the specific structural features involved in these interactions, as well as an approach to some synthetic strategies aiming the enhancement of flavonoids antiinflammatory properties.

Advances in spirocyclic hybrids: chemistry and medicinal actions

The present review deals with the progress in medicinal chemistry of spirocyclic compounds, a wider class of natural and synthetic organic molecules, defined as a hybrid of two molecular entities covalently linked via a unique tetrahedral carbon. This spiro central carbon confers to the molecules a tridimensional structurally oriented framework, which is found in many medicinally relevant compounds, a well-known example is the antihypertensive spironolactone. Various bioactive natural products possess the privileged spiro linkage and different chemo-types thereof become synthetically accessible since the 20th century. Actually, there has been a growing interest in the synthesis of heterocyclic hybrids gathered via a spiro carbon. Most of these combinations are two moieties in one scaffold being able to interfere with biological systems through sequential mechanisms. Spirocyclic hybrids containing indole or oxindole units are compounds exhibiting higher interaction with biological receptors by protein inhibition or enzymatic pathways and their recognition as promising anticancer agents in targeted chemotherapy is foreseen. These specific, low-weight and noncomplex spirocyclic hybrids are potent inhibitors of SIRT1, Mdm2-p53 and PLK4, showing affinity for anaplastic lymphoma kinase (ALK) receptor. They are also known as excellent DNA binders, acting on cellular division by arresting the cell cycle at different phases and inducing apoptotic cell death. A structural diversity of spirocyclic hybrids has proved neuroprotective effects, anti-HIV, antiviral and antibacterial activities. Hundred of papers are mentioned in this review underlying chemical issues and pharmacological potencies of spiro compounds, which render them impressive synthetic hits for innovative drug conception.

Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release

We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinskis rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation in vitro and Bcr-Abl+ patient blast xenograft growth in zebrafish. Furthermore, OT-55 synergized with omacetaxine in imatinib-resistant KBM-5 R cells to inhibit the expression of Mcl-1, triggering apoptosis. In imatinib-resistant K562 R cells, OT-55 triggered necrosis and blocked tumor formation in zebrafish in combination with omacetaxine.

Anticancer Activity Study of Chromone and Coumarin Hybrids using Electrical Impedance Spectroscopy

AIMS Oncology treatments aim at selective toxicity for tumor (compared to normal) cells, and chromone- coumarin hybrids have shown such activity. METHODS In this study, we test a novel series of synthetic chromone and coumarin derivatives (1-9) for cytotoxic activity against a panel of tumor cell lines (MCF-7, A549, HepG2, HTC-116, B16 and Caco-2) opposed to non-tumor cells (HEK-293t). Electrical impedance spectroscopy was used to monitor cell viability in real time. RESULTS Compound 8 showed the most potent activity, and it significantly diminished cancer cell proliferation and viability in different cell lines. It induced apoptosis in a dose-dependent manner, as shown by Western blot and flow cytometry. CONCLUSION Electrical impedance spectroscopy appears to be a convenient tool for in vitro cytotoxicity analysis, which could be useful for identifying drug effects and side effects during early phases of drug discovery and development.

Organobase catalysed one-pot exo-selective synthesis of meso-spiro[cyclohexanone-pyrandione] derivatives

An exo-selective one-pot synthesis of novel spiro[cyclohexanone-pyrandione] derivatives through two sequential organobase-catalysed 1,4-conjugate additions of pyran-2,4-dione precursors on diarylideneacetone derivatives is described. The resulting 7,11-diaryl-2-oxaspiro[5.5]undec-3-ene-1,5,9-triones were obtained as a 2 : 1 mixture of exo- and endo-diastereomers and adopt a meso-form due to the bilateral symmetry existing in the scaffold. Chiral-HPLC, NMR and single-crystal X-ray diffraction (including synchrotron data) have been used to elucidate the spiro[cyclohexanone-pyrandione] structure, showing therefore the exo/endo-diastereomers obtained in a meso-form, the cis-7,11-diaryl configuration (equatorial position) and different conformational changes in the cyclohexanone skeleton both in liquid and solid states. DFT studies proved the exo-stereoselectivity of the reaction by determining the exo/cis equatorial–equatorial configuration as the most thermodynamically stable form of our spiro[cyclohexanone-pyrandione] skeleton, while the structural substitution has no effect.

Cholinesterase Inhibitory Activity of Some semi-Rigid Spiro Heterocycles: POM Analyses and Crystalline Structure of Pharmacophore Site

BACKGROUND Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in patients of Alzheimers disease (AD), cholinesterase inhibitors are currently the most prescribed drugs for the treatment of AD. OBJECTIVE our aim in this article was to investigate the inhibitory potential of five known compounds (2-6) with spiro skeleton against AChE and BChE using ELISA microplate assays. In addition to their ChE inhibitory effect, their physico-chemical properties were also calculated. Moreover, the present work aims at investigating the charge/geometrical effect of a hypothetical pharmacophore or bidentate site in a bioactive group, on the inhibition efficiency of spiro compounds 2-6 by using Petra/Osiris/ molinspiration (POM) and X-ray analyses. METHOD In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested in vitro for their inhibitory potential against AChE and BChE using ELISA microtiter plate assays at 25 µg/mL. RESULTS Results revealed that three of the spiro compounds tested exert more than 50% inhibition against one of cholinesterases. Compound 5 displayed 68.73 ± 4.73% of inhibition toward AChE, whereas compound 6 showed 56.17 ± 0.83% of inhibition toward BChE; these two previously synthesized compounds have been the most active hits. CONCLUSIONS Our data obtained from screening of compounds 2-6 against the two cholinesterases indicate that three of these show good potential to selectively inhibit AChE or BChE. Spiro compounds 2, 5, and 6 exhibited the most potent activity of the series against AChE or BChE with inhibition values in the range 55-70%.

The French Paradox at Tea Time: From Antioxidant Flavonoids and Stilbenes Toward Bio-inspired Synthetic Derivatives

Natural and synthetic xanthone derivatives are well known for their ability to act as antioxidants and/or enzyme inhibitors. This paper aims to present a successful synthetic methodology toward xanthenedione derivatives and the study of their aromatization to xanthones. Additionally their ability to reduce Fe(III), to scavenge DPPH radicals, and to inhibit AChE was evaluated. The results demonstrated that xanthenedione derivative 5e, bearing a catechol unit, showed higher reduction capacity than BHT and, similar to quercetin, strong DPPH scavenging activity (EC50 = 3.79 ± 0.06 µM) and it was also shown to be a potent AChEI (IC50 = 31.0 ± 0.09 µM) compared to galantamine (IC50 = 211.8 ± 9.5 µM).

1,3-Dicyclo-hexyl-imidazolidine-2,4,5-trione: a second polymorph.

The title compound, C15H22N2O3, was obtained as a by-product of oxidative cleavage of 1,3-dicyclohexyl-(3-oxo-2,3-dihydrobenzofuran-2-yl)imidazolidine-2,4-dione. Herein, we report the crystal structure of a second polymorph, which was obtained by crystallization from an ethanol solution at 253 K, instead of slow evaporation of the same solvent at room temperature. While the first polymorph [Talhi et al. (2011). Acta Cryst. E67, o3243] crystallized in the non-centrosymmetric space group P212121, this second polymorph crystallizes in the centrosymmetric space group P21/n. Compared to the first polymorph, in the crystal no C=O⋯C=O interactions were found (C⋯O intermolecular distance longer than 3.15 Å) and instead, close packing of individual molecular units is mediated by C—H⋯π and weak C—H⋯O interactions.

1,3-Dicyclo­hexyl­imidazolidine-2,4,5-trione

The title compound, C15H22N2O3, has been isolated as a by-product of an oxidative cleavage of the C—C bond linking two five-membered rings of 1,3-dicyclohexyl-5-(3-oxo-2,3-dihydrobenzofuran-2-yl)imidazolidine-2,4-dione. Individual molecular units are engaged in weak C=O⋯C=O interactions [O⋯C = 2.814 (10) and 2.871 (11) Å], leading to the formation of supramolecular chains which close pack, mediated by van der Waals contacts, in the bc plane.