Journal of Heterocyclic Chemistry最新文献

Cancer is the second most common cause of mortality after cardiovascular diseases. Over the years, many chemotherapeutic agents have been developed, but the lack of target specificity and selectivity, toxicity to normal cells, and the problem of developing resistance limit their clinical usefulness. This has prompted the search for novel, safer, effective, and highly specific anticancer agents. Thiazolidinedione, a sulfur and nitrogen-containing five-membered heterocyclic ring, has shown promising anticancer potential in preclinical studies. Substitutions at different positions on the thiazolidinedione scaffold can overcome the problem of toxicity and drug resistance by targeting cancer with various mechanisms of action. This includes promoting apoptosis of the cancer cells, inhibiting signaling pathways, and cell proliferation in cancers by the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). The thiazolidinedione derivatives also act by inhibiting glyoxalase, TopI/II, GLUT, Bcl2, Ras/Raf, and tyrosine kinase involved in cancer pathogenesis. This review discusses the recent developments in synthetic strategies of thiazolidinedione scaffolds; their mechanism of action, anticancer potential, and structure–activity relationships (SAR) will provide guidance for future directions in cancer research. The recent advancements in the development of thiazolidinedione derivatives as anticancer agents will pave the way for medicinal chemists to direct the synthesis of novel thiazolidinedione derivatives for future clinical use.

Glycosides containing d-allose have been synthesized. Suitable glycosyl donors and promoters or additives are dependent on the nature of the aglycone. For (+)-catechin, using glycosyl fluorides as the glycosyl donor and BF₃ · OEt₂ as the promoter was the optimal choice. On the other hand, glycosyl bromide and tetrabutylammonium bromide (TBAB) or benzyltrietylammonium chloride (TEBAC) as the glycosyl donor and additive, respectively, proved to be the best combination for synthesizing glycosides containing l-ascorbic acid via Lemieux's halide ion-catalyzed glycosidation reaction.

A simple and efficient electrochemical synthesis of 4-halomethyl benzoxazines via halocyclization of olefinic amides with ⁿBu₄NX as a halogen source has been reported for the first time. The crucial use of BTPPO as a mediator effectively mitigates the high oxidation potential of the substrate. The absolute structures of products were confirmed by single crystal X-ray diffraction characterization. The plausible reaction mechanism was investigated based on the corresponding radical trapping and CV experiments.

Quinazoline and quinazolinones are among the most significant nitrogenous heterocycles in medicinal chemistry, with a broad range of biological properties. There are several traditional methods to generate them in the literature. Most of them include the generation of enormous amounts of waste, laborious workup, and poor-yield products, all of which contribute to the impact on the environment. Therefore, it would be ideal to employ moderate, straightforward methods to construct such a strong nucleus. However, during the past fifteen years, visible light-mediated transformations have also garnered a lot of interest as an environmentally friendlier and greener alternative since they use photons as a clean energy source. This study investigates a range of representative synthetic protocols from 2021 forward to date, therefore expanding our understanding of visible light-driven quinazoline and quinazolinone derivative synthesis. It also generates ideas for potential future developments. This compendium is organized based on the type of heterocyclic scaffold that was synthesized. The scopes, limits, and mechanistic research of various study findings are also discussed.

The efficiency of combining experimental methods and quantum chemical calculations (DFT and ab initio) for optimizing conditions and predicting mechanisms for the interaction of acyclic and cyclic derivatives of indole-2,3-quinodimethane with heterodienophiles is demonstrated. For the reactions of acyclic derivatives of indole-2,3-quinodimethane with nitriles and carbon disulfide, indoles, [b]-fused with nitrogen- and sulfur-containing six-membered rings, were synthesized. Quantum chemistry methods have shown that the addition of nitriles and carbon disulfide to indole-2,3-quinodimethane derivatives occurs through cyclic transition states involving a lithium atom. Calculations have substantiated the choice of a non-polar aprotic solvent to increase the yield of γ-carbolines. It has been shown for the first time that the replacement of the oxygen atom in cyclic derivatives of quinodimethane—pyrano[4,3-b]indol-3(5H)-ones by sulfur leads to a complete change in the direction and mechanism of their reaction with dimethyl acetylenedicarboxylate: instead of the usual [4+2] cycloaddition in the case of an oxygen-containing substrate, cascade processes are realized, including alkyne-thiocarbonyl metathesis and [3+2] cycloaddition.

This research investigates the design, synthesis, characterization, and biological assessment of a novel series of (E)-3-(3-morpholino-1-(m-tolyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (11a-o). The compounds (11a-o) were synthesized via a multi-step reaction sequence with 87%–96% yield in the final step and structurally confirmed using advanced spectroscopic techniques, including ¹H-NMR, ¹³C-NMR, FT-IR, and ESI-MS. Analytical data confirm that the compound exhibits a purity of ≥ 95%. The biological evaluation encompassed antimicrobial, antimalarial, and antitubercular activity screening. Antimicrobial assays demonstrated notable antibacterial efficacy, with compounds 11h and 11j exhibiting superior potency compared to standard antibiotics against Escherichia coli and Staphylococcus aureus . Moderate antifungal activity was observed, with compound 11d displaying the highest inhibitory effect against Aspergillus niger. In antimalarial studies, compound 11i demonstrated exceptional activity (IC50 = 0.25 μg/mL) against Plasmodium falciparum, showing potency comparable to chloroquine. Additionally, compounds 11a and 11i exhibited significant antitubercular activity against Mycobacterium tuberculosis H37Rv. A structure–activity relationship (SAR) analysis revealed that specific chemical modifications, particularly electron-withdrawing substitutions and morpholino moieties, played a crucial role in enhancing antimalarial activity. These findings highlight the potential of these derivatives as promising lead compounds for further development into effective therapeutics targeting drug-resistant bacterial, fungal, malarial, and tubercular infections.

The leading cause of death in diabetic patients is diabetic cardiomyopathy (DCM). Despite the availability of anti-diabetic medications which effectively curb the hyperglycemia, the drug molecule which alleviates the severity of DCM along with the maintenance of a normoglycemic profile of diabetic patients is still unexplored. In this study, a series of thiazolidinedione-pyrimidine hybrid compounds were synthesized, and their anti-diabetic potential was explored in STZ-NA induced diabetic Wistar rats. The role of these compounds in DCM was also evaluated. The most potent compound, PT-5, showed significant reduction in blood glucose levels (from 129 to 115 mg/dL in 2 h) in comparison to the standard drug Pioglitazone (135–117 in 2 h). The biochemical estimations of AST, ALT, ALP, Troponin T, Cκ-MB, CRP, and LDH levels illustrated that the levels appreciably came back to normal in the PT-1, PT-5, and PT-13 treatment groups. The cardioprotective role was further validated by cardiac tropism indices and levels of antioxidants in cardiac tissue. The biochemical assessments were further validated through histopathological studies. This research indicates that these derivatives hold promise for the development of new potential antidiabetic agents.

Computational approaches have become increasingly popular in peptide synthesis. In this study, we report the computationally assisted design and synthesis of a cyclosenegalin A analogue. The original cyclosenegalin A was previously synthesized with low yield and exhibited no antimicrobial activity. To address these limitations, computational tools such as PEP-FOLD4, iAMPpred, and AI4AMP were employed to design the analogue, aiming to facilitate cyclization and enhance antimicrobial properties. The computational analysis of cyclosenegalin A and its analogs identified c-AVKPGLK as the most promising candidate for further development. It demonstrated strong antimicrobial potential with the highest antibacterial and antifungal activity, along with a compact structure favorable for cyclization. The linear precursor of c-AVKPGLK also formed a stable β-turn structure, making it well-suited for synthesis. The synthesis was conducted using a combination of solid-phase and liquid-phase peptide synthesis. The linear precursor was synthesized using the Fmoc strategy with HATU as the coupling agent and 2-chlorotrityl chloride resin. Head-to-tail cyclization was performed in dilute concentration using a dropwise method with HATU as the coupling agent. The linear precursor synthesis achieved a yield of 97.76%, while the cyclization process yielded 23.38%. The final compound, c-AVKPGLK, was characterized using HR-ToFMS, ¹H NMR, ¹³C NMR, HMQC, HMBC, TOCSY, and ROESY.