Design and Synthesis of Novel N-Benzylidene Derivatives of 3-Amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine under Microwave, In Silico ADME Predictions, In Vitro Antitumoral Activities and In Vivo Toxicity.

The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using 1H and 13C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski's rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC50 < 0.3 µM) and no toxicity on fibroblasts (IC50 > 25 µM). A dose-dependent inhibition of Store-Operated Ca+2 Entry (SOCE) was observed in the HEK293 cell line with 10h. In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 µM at 72 hpf.

Highly Flexible Poly(1,12-dodecylene 5,5'-isopropylidene-bis(ethyl 2-furoate)): A Promising Biobased Polyester Derived from a Renewable Cost-Effective Bisfuranic Precursor and a Long-Chain Aliphatic Spacer.

The continuous search for novel biobased polymers with high-performance properties has highlighted the role of monofuranic-based polyesters as some of the most promising for future plastic industry but has neglected the huge potential for the polymers' innovation, relatively low cost, and synthesis easiness of 5,5'-isopropylidene bis-(ethyl 2-furoate) (DEbF), obtained from the platform chemical, worldwide-produced furfural. In this vein, poly(1,12-dodecylene 5,5'-isopropylidene -bis(ethyl 2-furoate)) (PDDbF) was introduced, for the first time, as a biobased bisfuranic long-chain aliphatic polyester with an extreme flexibility function, competing with fossil-based polyethylene. This new polyester in-depth characterization confirmed its expected structure (FTIR, 1H, and 13C NMR) and relevant thermal features (DSC, TGA, and DMTA), notably, an essentially amorphous character with a glass transition temperature of -6 °C and main maximum decomposition temperature of 340 °C. Furthermore, PDDbF displayed an elongation at break as high as 732%, around five times higher than that of the 2,5-furandicarboxylic acid counterpart, stressing the unique features of the bisfuranic class of polymers compared to monofuranic ones. The enhanced ductility combined with the relevant thermal properties makes PDDbF a highly promising material for flexible packaging.

A novel synthetised sulphonylhydrazone coumarin (E)-4-methyl-N'-(1-(3-oxo-3H-benzo[f]chromen-2- yl)ethylidene)benzenesulphonohydrazide protect against isoproterenol-induced myocardial infarction in rats by attenuating oxidative damage, biological changes and electrocardiogram.

Coumarins and their derivatives are becoming a potential source for new drug discovery due to their vast array of biological activities. The present study was designed to investigate the cardioprotective effects of a newly synthesised coumarin, symbolised as 5,6-PhSHC, against cardiac remodelling process in isoproterenol (ISO) induced myocardial infarction (MI) in male Wistar rats by evaluating haematological, biochemical and cardiac biomarkers. Rats were pre/co-treated with 5,6-PhSHC or clopidogrel (150 µg/kg body weight) daily for a period of 7 days and then MI was induced by injecting ISO (85 mg/kg body weight), at an interval of 24 hours for 2 consecutive days, on the sixth and seventh days. The in vivo exploration indicated that the injection of 5,6-PhSHC improved the electrocardiographic (ECG) pattern and prevented severe heart damage by reducing leakage of the cardiac injury markers, such as troponin-T (cTn-T), lactate dehydrogenase (LDH), and creatine kinase-MB. The cellular architecture of cardiac sections, altered in the myocardium of infracted rats, was reversed by 5,6-PhSHC treatment. Results showed that injection of 5,6-PhSHC elicited significant cardioprotective effects by prevention of myocardium cell necrosis and inflammatory cells infiltration, along with marked decrease in plasma levels of fibrinogen. In addition, the total cholesterol, triglyceride, LDL-c, and HDL profiles underwent remarkable beneficial changes. It was also interesting to note that 5,6-PhSHC enhanced the antioxidative defence mechanisms by increasing myocardial glutathione (GSH) level, superoxide dismutase (SOD), and catalase (CAT) activities, together with reducing the levels of thiobarbituric-acid-reactive substances (TBARS), when compared with ISO-induced rats. Taken together, these findings suggested a beneficial role for 5,6-PhSHC against ISO-induced MI in rats. Furthermore, in silico analysis showed that 5,6-PhSHC possess high computational affinities (E-value >-9.0 kcal/mol) against cyclooxygenase-2 (PDB-ID: 1CX2), vitamin K epoxide reductase (PDB-ID: 3KP9), glycoprotein-IIb/IIIa (PDB-ID: 2VDM) and catalase (PDB-ID: 1DGF). Therefore, the present study provided promising data that the newly synthesised coumarin can be useful in the design and synthesis of novel drug against myocardial infarction.

Cardiopreventive capacity of a novel (E)-N'-(1-(7-methoxy-2-oxo-2H-chromen-3-yl) ethylidene)-4-methylbenzenesulfonohydrazide against isoproterenol-induced myocardial infarction by moderating biochemical, oxidative stress, and histological parameters.

This study is carried out to assess the cardiopreventive effect of (E)-N'-(1-(7-methoxy-2-oxo-2H-chromen-3-yl) ethylidene)-4-methylbenzenesulfonohydrazide or SHC, a novel synthesized coumarin, against myocardial infarction induced by isoproterenol (ISO). The SHC compound was identified and characterized by spectral methods (infrared, 1 H NMR [nuclear magnetic resonance], 13 C NMR, Nuclear Overhauser Effect Spectroscopy, and high-resolution mass spectroscopy). Male Wistar rats were divided into four groups: Control, ISO (rats were injected subcutaneously by 85 mg/kg body weight [BW] of isoproterenol at Days 6 and 7 of the experience), ISO + SHC (150 µg/kg BW, orally for 7 days) and ISO + acenocoumarol (150 µg/kg BW, orally for 7 days). Results showed that ISO induced a remarkable alteration of electrocardiogram (ECG) pattern and increases of plasma cardiac troponin T, creatine kinase-MB, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, lactate dehydrogenase, aspartate transaminase, and malondialdehyde. In addition, ISO reduced the high-density lipoprotein-cholesterol content and the activities of superoxide dismutase and glutathione peroxidase, with the induction of myocardial necrosis. However, SHC administration revealed a significant decrease in cardiac dysfunction markers, restored normal ECG pattern, as well as improving lipids parameters. Moreover, SHC treatment remarkably alleviated the cardiac oxidative stress and the myocardial remodeling process. Overall, the SHC offers good protection from acute myocardial infarction through the antioxidant capacity.

A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA in Mycobacterium tuberculosis.

A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.

Potential effect of new (E)-4-hydroxy -N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide against acute myocardial infarction: Haemodynamic, biochemical and histological studies.

This study aimed to explore the cardioprotective effect of new synthesized coumarin (E)-4-hydroxy-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide denoted (Hyd.Cou) against myocardial infarction disorders. Male Wistar rats were divided into four groups; Control, isoproterenol (ISO), ISO + Acenocoumarol (Ac) and ISO + Hyd.Cou. Results showed that the ISO group exhibited serious alteration in EGC pattern, significant heart hypertrophy (+33%), haemodynamic disturbance and increase in plasma rate of CK-MB, LDH and troponin-T by 44, 53, and 170%, respectively, as compared to Control. Moreover, isoproterenol induced a rise in plasma angiotensin-converting enzyme activity (ACE) by 49%, dyslipidaemia, and increased thiobarbituric acid-reactive substances (TBARS) by 117% associated with decrease in the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) by 46% and 58%, respectively in myocardium. Interestingly, the molecular docking calculation demonstrated strong interactions of Hyd.Cou with the receptors of the protein disulphide isomerase (PDI) which could highlight the antithrombotic effect. Moreover, Hyd.Cou improved plasma cardiac dysfunction biomarkers, mitigated the ventricle remodelling process and alleviated heart oxidative stress damage. Overall, Hyd.Cou prevented the heart from the remodelling process through inhibition of ACE activity and oxidative stress improvement.

Anti-embolic and anti-oxidative effects of a novel (E)-4-amino-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide against isoproterenol and vitamin-K induced ischemic stroke.

This study aimed to evaluate the cerebroprotective potential of a novel synthetic coumarin, (E)-4-amino-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene) benzohydrazide noted (HC) against a pharmaceutically induced ischemic stroke in experimental male Wistar rats. Animals were randomly allocated into four groups: control, Stroke, Stroke + Ace (acenocoumarol) and Stroke + HC-treated group for 7 days. Our results showed that stroke group evidenced atrial flutter, significant cardiac hypertrophy (+23%) and increase in plasma level of troponin-T, with disturbance in plasma ionic levels and rise in fibrinogen rate and oxidative damages in heart and brain. Moreover, the histological findings revealed myocardium necrosis, cardiac cavity thrombi and brain injury as compared to normal rats. However, HC-treatment significantly prevents the embolic process, improves cerebral damages and mitigates the oxidative stress markers in stroke rats. Overall, HC is endowed with a thrombolytic potential against MI and stroke in such severe conditions through an anti-vit K (AVK) mechanism.

(E)-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide protecting rat heart tissues from isoproterenol toxicity: Evidence from in vitro and in vivo tests.

The current study was aimed to assess the protective effect of a new molecule (E)-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide, denoted 1c, against cardiac remodeling process in isoproterenol (Isop) induced myocardial infarction (MI) in rats. Male Wistar rats were randomly divided into four groups, control, Isop (85 mg/kg body weight was injected subcutaneously into rats at an interval of 24 h for 2 days (6th and 7th day) to induce MI and pretreated animals with acenocoumarol (Ace) (150 µg/kg bw) and 1c (150 µg/kg bw) by oral administration during 7 days and injected with isoproterenol (Isop + Ace) and (Isop + 1c) groups. Results in vitro showed that 1c is endowed with potent inhibition of angiotensin-converting enzyme (ACE) with an IC50 39.12 µg/ml. The in vivo exploration evidenced alteration in the ECG pattern, notable cardiac hypertrophy and increase in plasma level of fibrinogen, troponin-T, CK-MB and LDH, AST and ALT by 171%, 300%, 50%, 64% and 75% respectively with histological myocardium necrosis and cells inflammatory infiltration. However, pre-treatment with 1c improved the ECG pattern reduced significantly the cardiac dysfunction markers and ameliorated the thrombolytic process by decreasing fibrinogen level as compared to untreated infracted rats. Overall, (E)-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide 1c could be used as anticoagulant agent to prevent thrombosis in acute myocardial infarction.

(E)-N'-(1-(7-Hydroxy-2-Oxo-2H-Chromen-3-Yl) Ethylidene) Benzohydrazide, a Novel Synthesized Coumarin, Ameliorates Isoproterenol-Induced Myocardial Infarction in Rats through Attenuating Oxidative Stress, Inflammation, and Apoptosis.

The present study was directed to investigate the effect of precotreatment with (E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide (7-hyd.HC), a novel potent synthesized coumarin, on isoproterenol- (ISO-) induced myocardial infarction (MI) in rats. The hydrazone compound was characterized by IR, 1D, and 2D NMR analyses. Experimental induction of MI in rats was established by ISO (85 mg/kg/day, s.c) for two consecutive days (6th and 7th days). 7-hyd.HC or sintrom was given for 7 days prior and simultaneous to ISO injection. 7-hyd.HC offered a cardiopreventive effect by preventing heart injury marker leakage (LDH, ALT, AST, CK-MB, and cTn-I) from cardiomyocytes and normalizing cardiac function and ECG pattern, as well as improving lipid profile (TC, TG, LDL-C, and HDL-C), which were altered by ISO administration. Moreover, 7-hyd.HC precotreatment significantly mitigated the oxidative stress biomarkers, as evidenced by the decrease of lipid peroxidation and the increased level of the myocardial GSH level together with the SOD, GSH-Px, and catalase activities. 7-hyd.HC inhibited the cardiac apoptosis by upregulating the expression of Bcl-2 and downregulating the expression of Bax and caspase-3 genes. In addition, 7-hyd.HC reduced the elevated fibrinogen rate and better prevented the myocardial necrosis and improved the interstitial edema and neutrophil infiltration than sintrom. Overall, 7-hyd.HC ameliorated the severity of ISO-induced myocardial infarction through improving the oxidative status, attenuating apoptosis, and reducing fibrinogen production. The 7-hyd.HC actions could be mediated by its antioxidant, antiapoptotic, and anti-inflammatory capacities.

Preparation, characterization and degradation study of novel sulfonated furanic poly(ester-amide)s.

A series of novel-sulfonated furanic polyesteramides have been synthesized by polycondensation in the melt-phase. The copolymers were obtained with reasonable molecular weights and high inherent viscosities between 0.2 and 0.4 dL/g. The hydrolytic degradability of polyesteramides was enhanced by the increasing of amide units in the copolymers backbone.

Cardioprotective effects of (E)-4-hydroxy-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide: a newly synthesized coumarin hydrazone against isoproterenol-induced myocardial infarction in a rat model.

The current study was carried out to evaluate the effect of pretreatment and co-treatment with a newly synthesized coumarin hydrazone, (E)-4-hydroxy-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide (hereinafter EK6), against isoproterenol-induced myocardial infarction in rats. Changes in biochemistry, cardiac biomarkers, electrocardiography, and histopathology after treatment with EK6 or acenocoumarol (Sintrom) were studied. Animals were randomly divided into 4 groups: vehicle control (C), isoproterenol + Sintrom (ISO + Sin), isoproterenol + EK6 (ISO + EK6), and isoproterenol (ISO). Myocardial infarction was induced by subcutaneous ISO administration at a dose of 85 mg·kg-1·day-1 with a drug-free interval of 24 h on days 6 and 7. Treatment with ISO led to significant elevation (p < 0.05) in serum levels of cardiac injury biomarkers, namely cardiac troponin-T, lactate dehydrogenase, creatine kinase-MB, alanine aminotransferase, and aspartate aminotransferase compared with levels in the vehicle control. A change in the lipid profile was also observed as a significant increase in total cholesterol and triglycerides. Furthermore, ISO caused significant alterations in the electrocardiogram pattern, including significant ST-segment elevation, significant decreased R wave amplitude, and significant increase in heart rate (16%) as well as marked changes in the histopathology of the heart tissue. Pretreatment and co-treatment with newly synthesized coumarin hydrazone restored all ISO-induced biochemical, lipid, cardiac, and histopathological changes in rats with myocardial infarction.

TBAF-Triggered Aldol-Type Addition of α-Triethylsilyl-α-diazoacetone.

Aldol-type addition of α-triethylsilyl-α-diazoacetone was achieved under nucleophilic activation by tetrabutylammonium fluoride (TBAF). The use of a semistoichiometric amount of TBAF (protocol P1) provided the corresponding ß-hydroxy-α-diazoacetone as the sole product. Alternatively, the use of a catalytic amount of TBAF led to a mixture of ß-hydroxy- and ß-silyloxy-α-diazoacetone products, which was cleanly desilylated with Et3N·3HF (protocol P2). The weakly basic conditions employed tolerate a wide range of substrates and constitute a high-yielding, convenient complementary procedure to the low-temperature LDA-promoted aldol-type addition of diazoacetone.

Small Iminocoumarin Derivatives as Red Emitters: From Biological Imaging to Highly Photoluminescent Non-doped Micro- and Nanofibres.

The fluorescence properties of four derivatives of 3-thienyl-2-(N-dicyanovinyl)iminocoumarin, bearing a diethylamino group in the 7-position or a methoxy group in the 6, 7 and 8 positions, were compared in solution and in the solid state. The 7-diethylamino derivative was strongly fluorescent in various solvents, with marked solvatochromism. Its fluorescence was quenched by aggregation. In contrast, the methoxy derivatives were only moderately or weakly fluorescent in solution, but two of them were strongly photoluminescent in the crystalline state, owing to favourable molecular packing. The 6-methoxy derivative even exhibited spectacular crystallization-enhanced emission, examples of which are particularly rare for this type of dyes. Dyes were tested for biological use. The 7-diethylamino derivative led to particularly strong fluorescence staining of the cytoplasm of HCT-116 colon cancer cells. No fading was observed over prolonged illumination by the microscope light beam, but a phototoxic effect was detected. The use of the dyes as red-emitting materials was also investigated. Using easy-to-implement preparation methods, the compounds self- assembled to give one-dimensional nano- and microsized particles, including millimeter-long microfibres that exhibited clear wave-guiding properties. This study shows the value of these low molecular-weight molecules for the preparation of new orange and red-emitting fluorescent materials based on totally pure dye.

Simple and convenient access to α,α,α-trisubstituted amides by double addition of Grignard reagents to acyl cyanohydrins.

The double addition of Grignard (alkyl, aryl, alkenyl, alkynyl) reagents to acyl cyanohydrins was performed under unusually smooth conditions with a concomitant O-N acyl transfer, providing a very simple and general access to α,α,α-trisubstituted amides.