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A one-pot reaction of an equimolar mixture of 4-methoxyaniline, phenyl isothiocyanate, and 2-bromoacetylbenzofuran in absolute ethanol in the absence of any catalysts afforded 4-(benzofuran-2-yl)-3-(4-methoxyphenyl)-N-phenylthiazol-2(3H)-imine with an 83% yield. Under similar conditions, 4-flouroaniline provided a mixture of the expected 4-(benzofuran-2-yl)-3-(4-fluorophenyl)-N-phenylthiazol-2(3H)-imine and unexpected 4-(benzofuran-2-yl)-N-(4-fluorophenyl)-3-phenylthiazol-2(3H)-imine at an overall 73% yield. The structures of the synthesized heterocycles were confirmed using NMR spectroscopy. The products were recrystallized from dimethylformamide to afford samples suitable for structural determination via single-crystal diffraction. The molecules of the products share a common backbone and have similar conformations. They also display some common intermolecular interactions, including C–H···X (X = N, O, π) and π···π contacts. The molecules differ due to the methoxy and fluoro substituents on their phenyl rings, resulting in variations in the extended network in the crystals. Electron density maps and Hirshfeld surfaces have been used to rationalize the intermolecular contacts.

Background The cannabinoid 1 (CB1) receptor is the primary target of Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the psychoactive component of cannabis sativa (commonly known as “kif” in Morocco). Methods Here, we identified novel CB1 agonists using virtual screening approaches. First, we developed a pharmacophore model based on the known CB1 agonist AM11542 and screened a database of over three million compounds. Molecular docking using AutoDock Vina identified 61 hits with binding affinities of less than -9.00 Kcal/mol. Subsequent ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) analysis narrowed the selection to 18 promising candidates. Results Among these, three agonists exhibited strong characteristics, including a favorable inhibition constant (Ki) and key hydrogen-bond interactions with critical residues in the CB1 binding pocket: PUBChem157251136 (Ki=2.09 nM), ZINC64438485 (Ki= 0.262 nM) and ZINC64438506 (Ki =0.244 nM). These agonists formed stable hydrogen bonds with CB1 binding pocket residues (Ser383, Ser173, His178 and Thr197). Molecular dynamics simulations (100 ns, GROMACS) demonstrated structural stability (RMSD < 1 nm) and low conformational flexibility (RMSF < 1 nm) for all complexes. MM-GBSA binding free energy calculations further confirmed the thermodynamic stability of all complexes, with interaction energies ranging from -30.59 to -49.98 kcal/mol. These comprehensive simulations confirm that all identified agonist complexes maintain stable binding conformations with optimal interaction profiles characteristic of CB1 receptor activation. Conclusion These results could pave the way for researching and developing new quinazolinz-2, 4(1H, 3H)-Dione derivatives as a new class of CB1 receptor agonists.

Regioselective synthesis of novel 2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium derivatives has been developed by annulation reactions of 8-quinolinesulfenyl halides with vinyl chalcogenides (vinyl ethers, divinyl sulfide, divinyl selenide and phenyl vinyl sulfide) and tetravinyl silane. The novel reagent 8-quinolinesulfenyl bromide was used in the annulation reactions. The influence of the substrate structure and the nature of heteroatoms on the direction of the reactions and on product yields has been studied. The opposite regiochemistry was observed in the reactions with vinyl chalcogenides and tetravinyl silane. The obtained condensed heterocycles are novel water-soluble functionalized compounds with promising biological activity.

Epilepsy, a predominant neurological disorder affecting about 1% of the worldwide population, demands effective treatment options. An antiepileptic drug called brivaracetam has proven amazing efficacy in preventing epilepsy progression, garnering attention for novel synthesis methods. Despite recent progress in conventional synthesis routes, challenges such as expensive catalysts, inconvenient substrates, and hazardous solvents persist. In this context, we share the first finding that immobilized penicillin G acylase (IPGA) can catalyze the polarity reversal conjugate addition reaction. This synthesis is straightforward and does not require any purification. Yield up to 92.41% was achieved at 55 °C using dimethyl sulfoxide as a solvent. The catalytic specificity of IPGA was demonstrated through control experiments. Nonetheless, this research demonstrates the potential of IPGA and other biocatalysts to enable sustainable and effective organic synthesis processes and showcase the promiscuity of existing enzymes. Graphical abstract

Background The cannabinoid 1 (CB1) receptor is the primary target of Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the psychoactive component of cannabis sativa (commonly known as “kif” in Morocco). Methods Here, we identified novel CB1 agonists using virtual screening approaches. First, we developed a pharmacophore model based on the known CB1 agonist AM11542 and screened a database of over three million compounds. Molecular docking using AutoDock Vina identified 61 hits with binding affinities of less than -9.00 Kcal/mol. Subsequent ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) analysis narrowed the selection to 18 promising candidates. Results Among these, three agonists exhibited strong characteristics, including a favorable inhibition constant (Ki) and key hydrogen-bond interactions with critical residues in the CB1 binding pocket: PUBChem157251136 (Ki=2.09 nM), ZINC64438485 (Ki= 0.262 nM) and ZINC64438506 (Ki =0.244 nM). These agonists formed stable hydrogen bonds with CB1 binding pocket residues (Ser383, Ser173, His178 and Thr197). Molecular dynamics simulations (100 ns, GROMACS) demonstrated structural stability (RMSD < 1 nm) and low conformational flexibility (RMSF < 1 nm) for all complexes. MM-GBSA binding free energy calculations further confirmed the thermodynamic stability of all complexes, with interaction energies ranging from -30.59 to -49.98 kcal/mol. These comprehensive simulations confirm that all identified agonist complexes maintain stable binding conformations with optimal interaction profiles characteristic of CB1 receptor activation. Conclusion These results could pave the way for researching and developing new quinazolinz-2, 4(1H, 3H)-Dione derivatives as a new class of CB1 receptor agonists.

6-Benzyl-4-styrylbenzo[4′,5′]imidazo[2′,1′:6,1]pyrido[2,3- d ]pyrimidines and their conjugates with uracil, 5-fluorouracil, and 6-azauracile were synthesized. In addition to the previous findings, it was found that the reaction of 4-methyl-2-phenyl-5,6-dihydrobenzo[4′,5′]imidazo[2′,1′:6,1]pyrido[2,3- d ]pyrimidine with aromatic aldehydes in acetic anhydride, depending on the nucleophilicity of the aldehyde carbonyl group, involved both C 6 H 2 methylene group at the α-position with respect to the benzimidazole fragment and the 4-methyl group. The results of molecular docking study of the synthesized compounds and their effect on the methylation of tumor DNA are presented.

A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS2 in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained ensures post-modifications in view of N-bridgeheaded heterobicyclic structures.

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 21/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF4. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-2-[(chloroethyl)thio]-1-methyl-1H-imidazole-silver(I)tetrafluoroborate (6, monoclinic, space group P 21/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 21/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.

5-Acetyl-4-hydroxy-2 H -1,3-thiazine-2,6(3 H )-dione reacted with cyclohexyl and benzyl (4-aminophenyl)carbamates in boiling ethanol in the presence of a catalytic amount of glacial acetic acid to give the corresponding Schiff bases, cyclohexyl and benzyl (4-{[( E )-1-(4-hydroxy-2,6-dioxo-3,6-dihydro-2 H -1,3-thiazin-5-yl)ethylidene]amino}phenyl)carbamates. Heating of the latter in dimethylformamide for 2 h was accompanied by evolution of COS with the formation of cyclohexyl and benzyl {4-[6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]phenyl}carbamates. The condensation of the title compound with benzene-1,2-diamine in propan-2-ol, followed by addition of 5-arylfuran-2-carbaldehyde and trifluoroacetic acid afforded 5-(2-{5-[4-bromo(nitro)phenyl]furan-2-yl}-2,3-dihydro-1 H -1,5-benzodiazepin-4-yl)-4-hydroxy-2 H -1,3-thiazine-2,6(3 H )-diones. 5-(( E )-3-{5-[4-Bromo(nitro)phenyl]furan-2-yl}prop-2-enoyl)-4-hydroxy-2 H -1,3-thiazine-2,6(3 H )-diones were synthesized by condensation of 5-acetyl-4-hydroxy-2 H -1,3-thiazine-2,6(3 H )-dione with 5-[4-bromo(nitro)phenyl]furan-2-carbaldehydes in chloroform in the presence of catalytic amounts of pyridine and piperidine.

Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title compounds. The procedure involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned intermediates by the reaction of them with propargyl bromide in N,N-dimethylformamide (DMF) in presence of a potassium carbonate and the subsequent formation of a second triazole ring by copper catalyzed cyclisation reaction with azido compounds. The products were characterized by 1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC) with 1H–15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.