Journal of Heterocyclic Chemistry最新文献

In this study, the (3 + 2) cycloaddition 32CA reaction between N-t-butyl nitrone 1 and nitroethene 2 was comprehensively investigated using density functional theory (DFT), electron localization function (ELF), atoms-in-molecules (AIM) analysis, and ADMET profiling. The reaction paths were examined in terms of regio- and stereoisomeric outcomes, with four possible cycloadducts being characterized. DFT-based reactivity indices indicated a strong polar nature of the reaction, with the global electrophilicity index (ω) and nucleophilicity index (N) suggesting that nitroethene acts as a strong electrophile and the nitrone as a strong nucleophile. A significant global electron density transfer (GEDT) from the nitrone 1 to nitroethene 2 was observed at the transition states (0.19–0.23 e), confirming a polar character and forward electron density flux (FEDF). Topological analysis of ELF along the reaction coordinate revealed asynchronous one-step two-stage mechanisms, supported by the appearance of pseudoradical centers and disynaptic basin evolution. TSs were confirmed by intrinsic reaction coordinate (IRC) calculations. Molecular docking against the HPV-related 1MH1 protein and ADMET predictions demonstrated that compound 5 displayed the most favorable binding energy and drug-like properties. This integrated theoretical investigation offers new mechanistic insights and supports potential pharmacological applications of the synthesized nitroisoxazolidines.

A divergent strategy has been developed for the reactions between Morita–Baylis–Hillman (MBH) carbonates and isoquinolines. When MBH carbonates, derived from o-acylamino-aryl aldehydes and acrylonitrile, were reacted with isoquinolines, the reaction proceeded via a (3 + 2) cycloaddition/aromatization pathway to afford a diverse array of completely aromatic pyrrolo[2,1-a]isoquinolines in moderate to good yields (51%–91%) with excellent chemo- and regioselectivity. In contrast, when the substrates were changed to MBH carbonates synthesized from o-acylamino-aryl aldehydes and methyl acrylate, and 3,4-dihydroisoquinolines were employed as reaction partners, the reaction underwent a formal (3 + 2) cycloaddition to provide pyrrolo[2,1-a]isoquinolines bearing two adjacent tertiary stereogenic centers in good yields (up to 93%) with excellent chemo-, regio-, and diastereoselectivity (all cases > 25:1 dr). Notably, these reactions proceeded under nearly identical reaction conditions, with no observable competitive side products.

Herein, we report a three-component radical cascade cyclization reaction for the synthesis of iodo- and nitro-di-functionalized 4-enyl-2-pyrrolidones with 1,6-enynes under metal-free and catalyst-free conditions. In this reaction, the (Z) configuration products with high stereoselectivity are obtained. Meanwhile, this strategy is useful for the synthesis of di-functionalized lactams, and heterocyclic products have huge potential biological activities. The control experiments indicate that the cascade cyclization is realized by radical reactions, as well as the detailed reaction mechanism and regioselectivities have been explained by DFT studies.

An efficient tandem reaction method catalyzed by aqueous onion extract comprising enaminone formation followed by Michael addition-cyclization is disclosed by 1,3-diketone 1, primary amine 2, and β-nitroalkene 3. In this work, diverse structures of enaminones and β-nitroalkenes 3 were involved to produce various multi-substituted pyrroles 6 in excellent yields (up to 97%). The structure of compound 6d was confirmed by single-crystal X-ray diffraction. This method has been applicable for a broad range of substrates and good functional group tolerance. Further, this proposed methodology has added advantages such as a simple, short reaction time, easy workup procedure, and environmentally benign manner. The in vitro antioxidant activity studies of the produced compounds, 6a–6y, were examined. When compared to 6e–6g, 6l, 6m, 6q, 6r, 6t, and 6u, the compounds such as 6h, 6i, 6j, 6k, and 6x have shown excellent IC₅₀ value with standard (1.80 × 10⁻⁴ M). In addition, compound 6h has demonstrated exceptional IC₅₀ value (1.58 × 10⁻⁴ M) among the synthesized compounds.

In our pursuit of developing effective anticancer drugs, a dipyridyl thiourea derivative (1) was designed and synthesized via a one-pot reaction at room temperature. The structure of the synthesized compound was confirmed using FT-IR, ¹H NMR, mass spectrometry, elemental analysis, and single-crystal X-ray crystallography. Both ¹H NMR spectral analysis and single-crystal X-ray analysis revealed the formation of strong intramolecular hydrogen bonds in 1. Hirshfeld surface analysis was also employed to quantify various interactions within the structure. Density Functional Theory (DFT) calculations, performed at the B3LYP/6-31G(d) level with solvent effects in THF, revealed a planar geometry favoring π⋯π stacking. The HOMO–LUMO gap of 4.58 eV indicated moderate reactivity and good charge delocalization. HOMO charge density was localized on the sulfur atom, while LUMO was delocalized across the aromatic core. The cytotoxic potential of compound 1 was assessed using the Trypan Blue exclusion assay against Dalton's Lymphoma (DL) cells, a murine T-cell lymphoma model, revealing a dose-dependent inhibition with an IC₅₀ of 22.5 μM. Furthermore, minimal cytotoxicity was observed in normal peripheral blood mononuclear cells (PBMCs), highlighting the selectivity of 1. Moreover, molecular docking studies further demonstrated favorable binding of compound 1 at the trimeric interface of mouse tumor necrosis factor, stabilized predominantly by hydrophobic interactions and a few hydrogen bonds. These findings collectively support the potential of 1 as a selective anticancer agent, warranting further biological validation.

Oxadiazoles have gathered significant courtesy in recent years due to their diverse pharmacological activities and synthetic versatility. Despite the extensive selection of heterocyclic derivatives, 1,3,4-oxadiazole has been essential to medical chemistry. Many synthesized compounds containing the oxadiazole nucleus are employed in antibacterial, antifungal, analgesic, anticonvulsant, HIV activity, antiinflammatory, plant growth-promoting agents, and herbicidal characteristics that have been investigated for derivatives of 1,3,4-oxadiazole, which have been essential in the development of pharmaceutically significant compounds. Inspired by these findings, scientists from all around the world are working to synthesize novel heterocycles with an oxadiazole moiety in the hopes of enhancing their medicinal and biological potential. The insights presented aim to act as a valuable resource for researchers and chemists involved in the synthesis of novel therapeutic representatives based on 1,3,4-oxadiazole scaffolds. In an effort to generate fresh ideas for the creation of more potent and less hazardous 1,3,4-oxadiazole-based scaffolds, ideally, this review would be very beneficial.

One of the most common neurological conditions in the world, epilepsy, increases a person's risk of dying young by three times when compared to the general population. This has led to the development of new antiepileptic drugs, although safety and potency are concerns. Additionally, Schiff base derivatives (commonly referred to as imines or azomethines) are a significant player in the medical treatment of epilepsy. Apart from being essential linkers and intermediates, this adaptable moiety also acts as a basic scaffold in the building of compounds with biological activity. Numerous Schiff base derivatives have been shown to regulate and cure neurological illnesses by blocking enzymes, receptors, and other targets. To cure epilepsy, researchers are concentrating on creating novel derivatives based on Schiff bases since they serve as a linker for various pharmacophores. Thus, this study sheds light on the current therapeutic expansion of derivatives based on Schiff bases as well as their synthesis schemes, all of which will assist researchers in creating effective prospective antiepileptic medications with advantageous pharmacological action.

Coumarins are known for their biological significance. Various coumarin derivatives are found in nature and they show intriguing biological activities. Several methods are reported in the literature for the construction of coumarins. Recently, an interesting feature of the motif has been realized that it can trap free radical species, especially alkyl radicals, thus it acts as a radical scavenger. Various alkylated coumarin derivatives have been constructed using coumarin as a sink for these radical species. In this review, recent developments in regioselective functionalization of coumarin derivatives using various precursors for the generation of alkyl radicals through distinct approaches have been compiled and critically reported to give a perspective about the development of new coumarin derivatives and their future scope.