Journal of Heterocyclic Chemistry最新文献

Diverse libraries of Imidazo[1,2-a]pyrazine-Benzimidazoles, Imidazo[1,2-a]pyrazine-tetrahydropyrimidine, and Imidazo[1,2-a]pyrazine-1,3,4-Oxadiazoles were synthesized via simple and practical cyclocondensation protocols. Structures of target compounds were established by ¹H and ¹³C NMR and mass spectral analysis. These newly synthesized compounds were tested for their in vitro anticancer activity against human breast cancer (MCF-7), lung cancer (A-549), and liver cancer (HepG2) cell lines using Cisplatin as the standard reference. The phenyl-substituted benzimidazole derivative 9d displayed outstanding activity against all three cell lines, with IC₅₀ values of 4.95 ± 0.5 μM (MCF-7), 9.21 ± 0.7 μM (A-549), and 10.02 ± 1.2 μM (HepG2), outperforming cisplatin (5.68 ± 0.3, 13.64 ± 0.8, and 11.82 ± 1.2 μM, respectively). Compound 9d was further evaluated through molecular docking against the crystal structure of EGFR, which had shown promising binding energy and protein-ligand interactions. Furthermore, compound 9a demonstrated promising activity with IC₅₀ value of 13.38 ± 1.1 μM against HepG2 cells. The methyl carboxylate pyrimidine derivative 9f and the propyl-substituted oxadiazole derivative 10c exhibited the strongest activities, with IC₅₀ values of 13.36 ± 1.1 and 10.35 ± 0.8 μM, respectively. The isopropyl substituted derivative 10d displayed good activity against MCF-7 and HepG2 cells with an IC₅₀ value of 8.92 ± 0.4 and 12.45 ± 1.2 μM, respectively.

Quinine-derived bifunctional squaramide catalyzed the asymmetric addition of different alcohols to pyrazolone-derived Boc-ketimines, providing chiral pyrazolones containing a tetrasubstituted stereocenter bearing a new N,O-acetal motif. The products were isolated in satisfactory yields (up to 91%) and with moderate levels of enantioselectivity (up to 79:21 er) by using 5 mol% of the chiral squaramide catalyst across a broad substrate scope. Importantly, enantioenriched N,O-aminals can be efficiently recovered from the mother liquors by a simple recrystallization. The reaction was extended to other nucleophiles, thiophenol and N-methylaniline, providing the corresponding N,S- and N,N-acetals in moderate to good yield but low enantioselectivity.

A novel multicomponent reaction strategy was employed to achieve high-yield synthesis of new cyclopentapyrrol derivatives. The methodology involved the use of vinilydene Meldrum's acid, ethyl 2-amino-4-dioxo-4-arylbutanoates, alkyl bromides and primary amines. The reaction was carried out at the reaction temperature in an aqueous medium. The antioxidant properties of the newly synthesized compounds are attributed to the presence of the NH functional group, and were confirmed through two standard evaluation methods. The antibacterial activity of the synthesized cyclopentapyrrols was assessed using the disc diffusion technique against two Gram-negative bacterial strains. Additionally, these compounds demonstrated inhibitory effects against Gram-positive bacteria. This synthetic approach offers several advantages, including high product yields, short reaction times, and straightforward product isolation procedures.

In this work, we report new fused phenanthroline-naphthoquinone and pyranoquinoline-naphthoquinone for the synthesis of naphtho[2,3-b][1,10]phenanthrolines and benzo[6,7]chromeno[3,2-f]quinolines respectively. The one-pot three-component condensation of 2-hydroxy-1,4-naphthoquinone, aryl aldehydes, and 8-aminoquinoline or 6-hydroxyquinoline is used for the synthesis of these two polycyclic heterocyclic ring systems. Formation of products proceeds through tandem Knoevenagel and Michael reactions, followed by concomitant cyclization and dehydration. Availability of the starting materials, operational simplicity, cleaner reaction profile, and the isolated products in pure form are the advantages of this protocol. The structure of all the products was characterized by spectroscopic techniques such as ¹H and ¹³C NMR, IR spectral, and elemental analysis data.

Unnatural amino acids (UAAs) play a crucial role in advancements in medicinal chemistry and biotechnology. This review focuses on α-amino acids containing five-membered N-heterocycles in their side chains, including pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole derivatives, which are of particular interest as structural analogues of histidine. Based on literature from 1965 to 2024, only 27 amino acids containing unsubstituted 5-membered N-heterocycles in their side chains were reported, among which 12 are the closest unnatural analogues of histidine. In addition, this review outlines strategies for the functionalization of N-heterocyclic rings with diverse substituents. Three major strategies to obtain such types of compounds can be highlighted: (1) Construction of a heterocycle onto an amino acid precursor; (2) Transformation of C- or N-substituents at the N-heterocycles to the amino acid side chain; (3) Direct CC or CN bond formation with the N-heterocycle. Unnatural histidine analogues represent a neglected subclass of amino acids; therefore, this overview highlights the significance of these compounds in expanding chemical diversity.

A mild and efficient method has been developed for the synthesis of pyrazole-4-azetones from pyrazole-4-carbazaldehyde and 4-amino-thiazole under mild conditions. Herein, we represent the first report that enables access directly to the core structure of pyrazole-4-azetone using 2-amino-thiazole. It is presumably acts as a nitrogen source proceeding via the formation of a Schiff base as an intermediate followed by a dehomologative annulation process. The present method has been generalized to a broad range of functional groups with good to excellent yields.

Halogen bonding, a directional and tunable non-covalent interaction, has recently gained attention as a sustainable alternative to hydrogen bonding in organic synthesis. Herein, we introduce a novel and sustainable halogen bond-driven strategy for the synthesis of 3,3′-bis(indolyl)methane (BIM) derivatives, employing carbon tetrabromide (CBr₄) as a halogen bond donor in acetonitrile. This metal-free protocol operates under mild conditions, offering high efficiency, broad substrate scope, and excellent yields. By applying this method, we successfully synthesized BIMs, that closely resemble naturally occuring bioactive molecules such as arundine, turbomycin and arsindoline, highlighting the potential medicinal relevance of this approach.

A mild and efficient (3 + 2) cycloaddition reaction between Morita–Baylis–Hillman adducts derived from isatins and maleimides, as well as 2-arylideneindane-1,3-diones, has been developed. This method facilitates the synthesis of a diverse range of dispirocyclic frameworks that incorporate both a spiro oxindole motif and a spiro indane-1,3-dione motif, along with a cyclopenta[c]pyrrole motif. High yields (up to 95%) are achieved, accompanied by excellent regio- and diastereoselectivities (all cases > 25:1 dr). Furthermore, the relative configuration and structure of a representative product was unequivocally confirmed by X-ray crystallography. Additionally, a molecular docking study was carried out to explore the potential biological activities of the products.

In this work, one facile approach for the synthesis of guanidinobispyrimidine derivatives promoted by Cs₂CO₃ was reported, delivering 22 new compounds (3a–3v) in moderate to good yield (62%–88% yield). Afterwards, the plausible reaction pathway, including two nucleophilic processes, was proposed based on the capture of possible intermediate A₁. Furthermore, biological activity evaluation revealed that most of these newly prepared guanidinobispyrimidines, including compounds 3g, 3o, 3r, and 3 s, can strongly inhibit the growth of MCF-7 (human breast cancer cell line) with IC₅₀ value ranging from 0.81 to 8.02 μM, which is comparable to natural product lycorine (IC₅₀ = 3.7 μM). Among them, compound 3g exhibited the best inhibitory activity against MCF-7 with IC₅₀ value of 0.81 ± 0.21 μM. Meanwhile, these guanidinobispyrimidines also exhibited good safety to normal cells, including MCF-10A (normal human breast epithelial cells) and SH-SY5Y (human neuroblastoma cell line). All these results demonstrate the enormous application potential of this newly developed approach in the development of new breast cancer cell inhibitors in the future.