Search Results (40)

Introduction: Inhibiting cyclooxygenase-2 (COX-2) is a potential strategy in inflammation therapy. Thus, developing COX-2 inhibitors plays a pivotal role in efficient inflammation treatment. This study discloses the synthesis of new heterocyclic compounds incorporating pyridine, pyran, and/or pyrazole moieties as COX-2 inhibitors. Methods: In this study, the Claisen–Schmidt reaction of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)ethan-1-one 1 and p-methoxybenzaldehyde in ethanol containing aqueous sodium hydroxide (10%) led to the formation of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)-3-(4-methoxyphenyl)prop-2-en-1-one) 2. The latter compound was allowed to react as a key precursor with various nucleophiles such as ethyl cyanoacetate, malononitrile, cyclohexanone, ethyl acetoacetate, hydrazine, cyano acid hydrazide, hydrazide, and/or thiosemicarbazide to yield new heterocyclic derivatives comprising pyridine, pyran, and/or pyrazole moieties 3–15, according to the Michael addition reaction. The newly synthesized compounds were depicted using spectroscopic techniques such as IR, ¹H-NMR, ¹³C-NMR, and MS. Moreover, their anti-inflammatory efficiency was in vitro evaluated by means of protein denaturation inhibition and cell membrane protection assay. Results: The results of 2^−ΔΔct values of COX-2 expression for compounds 6, 11, 12, and 13 were 6.6, 2.9, 25.8, and 10.1, respectively. Therefore, compound 12, followed by 13, 11, and 6, showed potent anti-inflammatory properties by in vitro evaluation. Further, an in silico molecular docking study was performed on the best-docked compounds and reference drug (Diclofenac) to investigate their binding affinities against the active site of the target enzyme. The obtained results from the in silico study aligned with the biological evaluation. Conclusions: The studies open new doors for designing new heterocycles containing pyridine, pyran, and/or pyrazole moieties as potent anti-inflammatory agents. Full article

A series of new quinazolin-2,4-dione derivatives incorporating amide/eight-membered nitrogen-heterocycles 2a–c, in addition, acylthiourea/amide/dithiolan-4-one and/or phenylthiazolidin-4-one 3a–d and 4a–d. The starting compound 1 was prepared by reaction of 4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-benzoyl chloride with ammonium thiocyanate and cyanoacetic acid hydrazide. The reaction of 1 with strong electrophiles, namely, o-aminophenol, o-amino thiophenol, and/or o-phenylene diamine, resulted in corresponding quinazolin-2,4-dione derivatives incorporating eight-membered nitrogen-heterocycles 2a–d. Compounds 3a–d and 4a–d were synthesized in good-to-excellent yield through a one-pot multi-component reaction (MCR) of 1 with carbon disulfide and/or phenyl isocyanate under mild alkaline conditions, followed by ethyl chloroacetate, ethyl iodide, methyl iodide, and/or concentrated HCl, respectively. The obtained products were physicochemically characterized by melting points, elemental analysis, and spectroscopic techniques, such as FT-IR, ¹H-NMR, ¹³C-NMR, and MS. The antibacterial efficacy of the obtained eleven molecules was examined in vitro against two Gram-positive bacterial strains (Staphylococcus aureus and Staphylococcus haemolyticus). Furthermore, Computer-Aided Drug Design (CADD) was performed on the synthesized derivatives, standard drug (Methotrexate), and reported antibacterial drug with the target enzymes of bacterial strains (S. aureus and S. haemolyticus) to explain their binding mode of actions. Notably, our findings highlight compounds 2b and 2c as showing both the best antibacterial activity and docking scores against the targets. Finally, according to ADMET predictions, compounds 2b and 2c possessed acceptable pharmacokinetics properties and drug-likeness properties. Full article

In this work, we present new methods of synthesis of different molecules including a 2-pyridone nucleus. First, we prepared a series of 1H-free 2-pyridones and N-alkyl 2-pyridones from ethyl cyanoacetate, aromatic aldehydes, various acetophenone derivatives and ammonium acetate or diamino-alkane. These molecules have served as building blocks that, in conjunction with acyl chloride derivatives, glycoside derivatives, etc. have resulted in various heterocyclic hybrid structures carrying a 2-pyridone ring. Moreover, based on the cyano group reactivity of the 2-pyridone ring, we synthesized 5-pyridone 1H-tetrazole in a single step by a cycloaddition reaction [3 + 2] between 3-cyano-2-pyridone nitriles and sodium azide in the presence of metal-free L-proline. Full article

Organic solid-state lasers are highly promising devices known for their low-cost fabrication processes and compact sizes and the tunability of their emission spectrum. These lasers are in high demand across various industries including biomedicine, sensors, communications, spectroscopy, and military applications. A key requirement for light-emitting materials used in a light-amplifying medium is a low threshold value of the excitation energy of the amplified spontaneous emission (ASE). A newly synthesized non-symmetric red-light-emitting laser dye, Ethyl 2-(2-(4-(bis(2-(trityloxy)ethyl)amino)styryl)-6-tert butyl-4H-pyran-4-ylidene)-2-cyanoacetate (KTB), has shown great promise in meeting this requirement. KTB, with its attached bulky trityloxyethyl groups, has the ability to form amorphous thin films from a solution using a wet-casting method. Recent experiments have demonstrated that KTB exhibits a low ASE threshold value. This study focused on investigating the optical and amplified spontaneous emission properties of KTB in poly(N-vinylcarbazole) (PVK), polysulfone (PSU), and polystyrene (PS) matrices at various concentrations. The results showed that as the concentration of the dye increased, a redshift of the photoluminescence and ASE spectra occurred due to the solid-state solvation effect. The lowest ASE threshold value of 9 µJ/cm² was achieved with a 20 wt% concentration of KTB in a PVK matrix, making it one of the lowest excitation threshold energies reported to date. Full article

Disulfides, as fundamental scaffolds, are widely present in peptides, natural products, and pharmaceutical molecules. However, traditional synthesis of disulfides often involves the utilization of toxic reagents or environmentally unfriendly reaction conditions. In this work, a green and efficient method was developed for synthesizing pyrrole disulfides using β-ketothioamides and ethyl cyanoacetate as substrates, with lipase serving as a catalyst. Under the optimal conditions (β-Ketothioamides (1 mmol), ethyl cyanoacetate (1 mmol), PPL (200 U), and EtOH (5 mL)), lipase leads to the formation of pyrrole disulfides in yields of up to 88% at 40 °C. The related mechanism is also speculated in this paper. This approach not only presents a new application of lipase in enzyme catalytic promiscuity, but also offers a significant advancement in the synthetic pathway for pyrrole disulfides and aligns with the current mainstream research direction of green chemistry, contributing to the further development of environmentally friendly biocatalytic processes. Full article

The synthesis of chiral spirooxindoles through different amino catalytic activation modes is described herein. Several alkenylisatins were obtained from the Knoevenagel reaction of isatin and activated methylene derivatives containing electron withdrawing groups such as ethyl cyanoacetate. A spirooxindole derivative was obtained from the oxa-Michael-Michael reaction between one of the synthesized alkenylisatins and 2-hydroxycinnamaldehyde. Currently, new methodologies that allow access to spirooxindole scaffolds are being explored, mainly though Diels-Alder reactions between 2-methylenindolin-2-ones and aldehydes via the trienamine activation mode. The following cascade reactions will be explored in the future to obtain the proposed polycyclic spirooxindole derivatives. Full article

The reaction between dithiomalondianilide (N,N’-diphenyldithiomalondiamide) and alkyl 3-aryl-2-cyanoacrylates in the presence of morpholine in the air atmosphere leads to the formation of alkyl 6-amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]- pyridine-5-carboxylates in 37–72% yields. The same compounds were prepared in 23–65% yields by ternary condensation of aromatic aldehydes, ethyl(methyl) cyanoacetate and dithiomalondianilide. The reaction mechanism is discussed. The structure of ethyl 6-amino-4-(4-methoxyphenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylate was confirmed by X-ray crystallography. Two of the prepared compounds showed a moderate growth-stimulating effect on sunflower seedlings. Three of the new compounds were recognized as strong herbicide safeners with respect to herbicide 2,4-D in the laboratory and field experiments on sunflower. Full article

Ricinine is an alkaloid of Ricinus communis that displays numerous biological properties. Ricinine (4-methoxy-1-methyl-2-oxo-dihydropyridine-3-carbonitrile)) and new N-analogues of Ricinine were obtained by the reaction of ethyl α-ethoxyethylidenecyanoacetate with various amines. Earlier, ethyl α-ethoxyethylidenecyanoacetate was easily prepared from ethyl cyanoacetate. Biologically, amines such as tryptamine and histamine were used in order to introduce a second pharmacophore on the target molecule. Full article

This study is dedicated to the comparative investigation of the catalytic activity of layer-like Faujasite-type (FAU) zeolite X obtained from three different synthesis routes (additive-free route, Li₂CO₃ route, and TPOAC route) in a liquid-phase Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate to ethyl trans-α-cyanocinnamate. It is shown that the charge-balancing cations (Na⁺ and K⁺) and the morphological properties have a strong influence on the apparent reaction rate and degree of conversion. The highest initial reaction rate could be found for the layer-like zeolite X synthesised by the additive-free route in the potassium form. In most cases, the potassium-exchanged zeolites enabled higher maximum conversions and higher reaction rates compared to the zeolite X catalysts in sodium form. However, very thin crystal plates (below 100 nm thickness), similar to those obtained in the presence of TPOAC, did not withstand the multiple aqueous ion exchange procedure, with the remaining coarse crystals facilitating less enhancement of the catalytic activity. Full article

To date, no fused heterocycles have been formed on folic acid molecules; for this reason, and others, our target is to synthesize new derivatives of folic acid as isolated or fused systems. Folic acid 1 reacted with ethyl pyruvate, triethyl orthoformate, ethyl chloroformate, thioformic acid hydrazide, and aldehydes to give new derivatives of folic acid 2–6a,b. Moreover, It reacted with benzylidene malononitrile, acetylacetone, ninhydrin, ethyl acetoacetate, ethyl cyanoacetate, and ethyl chloroacetate to give the pteridine fused systems 10–15, respectively. Ethoxycarbonylamino derivate 5 reacted with some nucleophiles containing the NH₂ group, such as aminoguanidinium hydrocarbonate, hydrazine hydrate, glycine, thioformic acid hydrazide, and sulfa drugs in different conditions to give the urea derivatives 16–20a,b. Compound 4 reacted with the same nucleophiles to give the methylidene amino derivatives 21–24a,b. The fused compound 10 reacted with thioglycolic acid carbon disulfide, malononitrile, and formamide to give the four cyclic fused systems 25–30, respectively. The biological activity of some synthesized showed moderate effect against bacteria, but no effect shown towards fungi. Full article

Within a series of dipeptide derivatives (5–11), compound 4 was refluxed with d-glucose, d-xylose, acetylacetone, diethylmalonate, carbon disulfide, ethyl cyanoacetate, and ethyl acetoacetate which yielded 5–11, respectively. The candidates 5–11 were characterized and their biological activities were evaluated where they showed different anti-microbial inhibitory activities based on the type of pathogenic microorganisms. Moreover, to understand modes of binding, molecular docking was used of Nicotinoylglycine derivatives with the active site of the penicillin-binding protein 3 (PBP3) and sterol 14-alpha demethylase’s (CYP51), and the results, which were achieved via covalent and non-covalent docking, were harmonized with the biological activity results. Therefore, it was extrapolated that compounds 4, 7, 8, 9, and 10 had good potential to inhibit sterol 14-alpha demethylase and penicillin-binding protein 3; consequently, these compounds are possibly suitable for the development of a novel antibacterial and antifungal therapeutic drug. In addition, in silico properties of absorption, distribution, metabolism, and excretion (ADME) indicated drug likeness with low to very low oral absorption in most compounds, and undefined blood–brain barrier permeability in all compounds. Furthermore, toxicity (TOPKAT) prediction showed probability values for all carcinogenicity models were medium to pretty low for all compounds. Full article

The compound (E)-2-cyano-3-(1H-indol-3-yl)-N-phenylacrylamide (ICMD-01) was designed and developed based on the structures of clinically relevant drugs indomethacin and paracetamol through the molecular hybridization strategy. This derivative was obtained by an amidation reaction between substituted anilines and ethyl 2-cyanoacetate followed by a Knoevenagel-type condensation reaction with indole aldehyde that resulted in both a viable synthesis and satisfactory yield. In order to assess the immunomodulatory and anti-inflammatory activity, in vitro assays were performed in J774 macrophages, and significant inhibitions (p < 0.05) of the production of nitrite and the production of cytokines (IL-1β and TNFα) in noncytotoxic concentrations were observed. The anti-inflammatory effect was also studied via CFA-induced paw edema in vivo tests and zymosan-induced peritonitis. In the paw edema assay, ICMD01 (50 mg kg⁻¹) showed satisfactory activity, as did the group treated with dexamethasone, reducing edema in 2–6 h. In addition, there was no significant inhibition of PGE₂, IL-1β or TNFα in vivo. Moreover, in the peritonitis assay that assesses leukocyte migration, ICMD-01 exhibited promising results. Therefore, these preliminary studies demonstrate this compound to be a strong candidate for an anti-inflammatory drug together with an improved gastrointestinal safety profile when compared to the conventional anti-inflammatory drugs. Full article

This work describes the utility of pyrazole-4-carbaldehyde 1 as starting material for the synthesis of a novel potent series of 5α-reductase and aromatase inhibitors derived from 1,2,3-triazole derivative. Condensation of 1 with active methylene and different amino pyrazoles produced the respective Schiff bases 2–4, 8 and 9. On the other hand, 1 was reacted with ethyl cyanoacetate and thiourea in one-pot reaction to afford the pyrazolo-6- thioxopyridin-2-[3H]-one (10). Moreover, α–β unsaturated chalcone derivative 11 was prepared via the reaction of compound 1 with P-methoxy acetophenone, which in turn reacted with each of ethyl cyanoacetate, malononitrile, hydrazine hydrate, and thiosemicarbazide to afford the corresponding pyridine and pyrazole derivatives 13, 14, 17, and 20. The structure of newly synthesized compounds was characterized by analytical and spectroscopic data (IR, MS and NMR). All new compounds were evaluated against 5α-reductase and aromatase inhibitors and the results showed that many of these compounds inhibit 5α-reductase and aromatase activity; compound 13 was found to be the highest potency among the tested samples comparing with the reference drugs. Full article

A series of novel pyridine and fused pyridine derivatives have been prepared starting from 6-(3,4-dimethylphenyl)-2-hydrazinyl-4-(thiophen-2-yl)-pyridine-3-carbonitrile 1 which on treatment with appropriate formic acid, acetic acid/acetic anhydride, benzoyl chloride and/or carbon disulfide afforded the corresponding triazolopyridine derivatives 2–5. Also, treatment of hydrazide 1 with diethyloxalate, chloroacetyl chloride, chloroacetic acid and/or 1,2-dichloroethane yielded the corresponding pyridotriazine derivatives 7–10. Further transformation of compound 1 with a different active methylene group, namely acetyl acetone, diethylmalonate, ethyl cyanoacetate, ethyl benzoylacetate and/or ethyl acetoacetate, produced the pyridine–pyrazole hybrid derivatives 11–15. These newly synthesized compounds (1–15) were subjected to in silico molecular docking screenings towards GlcN-6-P synthase as the target protein. The results revealed moderate to good binding energies of the ligands on the target protein. All the newly prepared products exhibited antimicrobial and antioxidant activity. Full article

4-(2-(4-Halophenyl)hydrazinyl)-6-phenylpyridazin-3(2H)-ones 1a,b were prepared and treated with phosphorus oxychloride, phosphorus pentasulphide and ethyl chloroformate to give the corresponding chloropyridazine, pyridazinethione, oxazolopyridazine derivatives 2–4, respectively. Compound 2 reacted with hydrazine hydrate to afford hydrazinylpyridazine 7. The reaction of 4-(2-(4-chlorophenyl)hydrazinyl)-3-hydrazinyl-6-phenylpyridazine (7) with acetic anhydride, p-chlorobenzaldehyde and carbon disulphide gave the corresponding pyridazinotriazine derivatives 8–10. On the other hand, 5-(4-chlorophenylamino)-7-(3,5-dimethoxybenzylidene)-3-phenyl-5H-pyridazino[3,4-b][1,4]thiazin-6(7H)-one (11) was prepared directly from the reaction of compound 3 with chloroacetic acid in presence of p-chlorobenzaldehyde. Compound 11 reacted with nitrogen nucleophiles (hydroxylamine hydrochloride, hydrazine hydrate) and active methylene group-containing reagents (malononitrile, ethyl cyanoacetate) to afford the corresponding fused compounds 12–15, respectively. Pharmacological screening for antiviral activity against hepatitis A virus (HAV) was performed for the new compounds. 4-(4-Chlorophenylamino)-6-phenyl-1,2-dihydropyridazino[4,3-e][1,2,4]triazine-3(4H)-thione (10) showed the highest effect against HAV. Full article