Russian Journal of Bioorganic Chemistry最新文献

Objective: This study aimed to design and synthesize a series of novel carboxylic acid mono- and dihydrazones incorporating a 6-methyluracil moiety and to evaluate their potential as new therapeutic agents through in silico and in vitro assessments. Methods: Dihydrazones derived from adipic, azelaic, and sebacic acid hydrazides were synthesized. Their drug likeness and biological activity profiles (including cytotoxicity, antioxidant activity, acute toxicity, and hematotoxicity) were first predicted in silico using the OCHEM expert system. The subsequent in vitro evaluations included cytotoxicity screening against HepG2, A549, MCF-7, and HCT-116 cancer cell lines, and antioxidant activity assays (FRAP, ABTS, and DPPH). Results and Discussion: In silico predictions indicated promising properties for the compounds. However, in vitro cytotoxicity screening showed that most synthesized hydrazones were inactive against the tested cancer cell lines. An exception was 6-methyl-5-[(2-phenylhydrazono)methyl]pyridine-2,4(1H,3H)-dione, which exhibited moderate selective activity against HCT-116 cells (IC₅₀ = 71.75 ± 8.29 µM). In antioxidant assays, 3-{2-[(6-mеthyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methylene]hydrazinyl}benzoic acid demonstrated high activity, comparable to ascorbic acid, and was identified as a lead compound. Conclusions: The results confirm that hydrazones containing a 6-methyluracil fragment are promising candidates for drug development. The identified lead compound with potent antioxidant activity is a candidate for further in-depth investigation for potential therapeutic applications.

Objective: The pharmacophore hybridization strategy is an effective method to reduce side effects and overcome drug resistance by utilizing multiple mechanisms of action. In this context, we have applied this approach to synthesize isatin-1,2,3-triazole hybrids (Va–Vn) as potential in vitro VEGFR-2 inhibitors. Methods: Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was employed for the synthesis of isatin-1,2,3-triazole hybrids (Va–Vn). The compounds were screened for in vitro anticancer activity against MCF-7 and HepG2 cell lines using the MTT assay, with sunitinib as the reference drug. Additionally, in vitro tyrosine kinase VEGFR-2 inhibition assays and molecular docking studies were conducted for four potent compounds. Results and Discussion: Among all the compounds, Vb, Vc, Vj, and Vl exhibited greater activity than sunitinib, with IC₅₀ values ranging from 0.9 to 3.6 μM. Moreover, compounds Vl and Vj showed 2.8- and 1.5-fold higher in vitro VEGFR-2 inhibition compared to sunitinib, respectively. Molecular docking studies of these compounds with VEGFR-2 protein (PDB ID: 3VHE) revealed favorable binding interactions with the target protein. Conclusions: Compounds Vb, Vc, Vj, and Vl may serve as promising anticancer drug candidates targeting VEGFR-2.

Quinoline is a significant class of heterocyclic compounds that have demonstrated notable anti-inflammatory and other therapeutic effects. This review article provides a comprehensive analysis of the evolution of quinoline derivatives as anti-inflammatory agents, emphasizing their structural modifications and pharmacological advancements. Various strategies, including modification of existing quinoline scaffolds, hybridization with other heterocyclic rings, and exploration of novel quinoline-fused systems, have been employed to enhance their anti-inflammatory activity. Key findings highlight the identification of several quinoline derivatives with potent inhibitory effects on inflammatory mediators, such as cyclooxygenase (COX), tumor necrosis factor-alpha (TNF-α), interleukins, and nitric oxide (NO). In animal models, many compounds have demonstrated promising anti-inflammatory activity, with some molecules exhibiting superior efficacy and safety profiles compared to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Continued development and structural optimization of quinoline-based compounds hold great promise for discovering potent and innovative anti-inflammatory drugs with enhanced therapeutic efficacy and reduced adverse effects, ultimately contributing to improved treatment outcomes.

Objective: Dehydroabietic acid (DHAA) is an important natural triterpene resin acid with a wide range of pharmacological activities, including antibacterial, antifungal, antiviral, and anti-inflammatory effects, particularly in antitumor activity. The aim of this study was to synthesize a series of novel dehydroabietic acid 1,2,3-triazole derivatives and evaluate their antitumor activity. Methods: Click chemistry was employed to conjugate dehydroabietic acid (DHAA) with 1,2,3-triazole, yielding 12 DHAA derivatives containing 1,2,3-triazole with yields ranging from 64.5 to 90%. The structures of the target compounds were confirmed by ¹H, ¹³C NMR, and HR-MS (ESI). The initial antiproliferative activity of these compounds was assessed in vitro using two tumor cell lines (human cervical cancer cells, HeLa, and human breast carcinoma cells, MCF-7), with cisplatin used as a reference. Results and Discussion: The results indicated that three compounds, VII, VIII, and IX, exhibited significant antiproliferative activity against the tumor cell lines. Among them, compound VIII (4-(4-fluorophenyl)-1-(((1R,4aS)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methyl)-1H-1,2,3-triazole) demonstrated particularly remarkable activity, with an IC₅₀ value of 22.1 μM against HeLa cells and 23.2 μM against MCF-7 cells. Conclusions: This study provides useful strategies for the design and synthesis of novel antitumor agents. The synthesized compounds exhibit some inhibitory effects on tumor cell growth and proliferation while causing minimal damage to normal cells, warranting further investigation.

Objective: To characterize the antimicrobial resistance gene (ARG) profiles of the WHO 2024 N. gonorrhoeae reference strains and compare the CARD/RGI and NG-STAR genotyping methods. Methods: We performed in silico analysis of 29 reference genomes using the Resistance Gene Identifier (RGI) tool and the Comprehensive Antibiotic Resistance Database (CARD), benchmarking results against the NG-STAR scheme. Results and Discussion: β-Lactam and macrolide resistance genes were most prevalent. Key determinants included mtrA, penA, rpsJ, and mtrC. Strains WHO_Q and WHO_beta harbored the most ARGs (10 each). Concordance between CARD/RGI and NG-STAR was 39.4%, with CARD providing broader mechanistic coverage and NG-STAR offering superior allele-level resolution. Conclusions: The study provides a benchmark for genomic AMR prediction, demonstrating the complementary value of general-purpose and species-specific typing schemes for surveillance.

Objective: Diabetes and diabetes-induced diseases, such as cataracts, are growing global health problems, with ongoing research into better treatment options. In India, the prevalence of blindness is 15 per 1000 people, with cataracts alone accounting for 80% of cases. In this context, chalcones are frequently investigated by scientists as potential agents with diverse biological activities. Results and Discussion: Compounds IIa and IIc, which demonstrated ALR2 inhibition in in silico studies, were evaluated for the inhibition of rat lens aldose reductase, with Epalrestat used as the standard drug. Both compounds showed promising results, with IC₅₀ values lower than that of the standard drug. Compounds IIb and IId, which exhibited promising results as PPAR-γ agonists in in silico analysis, were further evaluated in vivo using streptozotocin (STZ) and high-fat diet (HFD)-induced diabetic mice. The disease control group showed mature cataracts, while the treated groups exhibited the opposite at the end of the study. The mice were assessed for various parameters, including blood glucose, serum total cholesterol, triglycerides, HDL, LDL, aldose reductase levels, antioxidant enzyme activity, and lipid peroxidation at the conclusion of the treatment, in comparison with standard drug-treated groups (Epalrestat and Pioglitazone). Levels of aldose reductase, blood glucose, triglycerides, cholesterol, and LDL in the lens were significantly decreased, whereas antioxidant enzymes, total proteins, soluble proteins, and HDL were significantly increased in the treatment groups. The higher dose (200 mg/kg) of compound IIb showed pronounced protection. Six chalcones were synthesized via the Claisen–Schmidt condensation reaction and evaluated for anti-diabetic activity in silico against ALR2 and PPAR-γ receptors. The promising compounds were then assessed for their relative antidiabetic activity in vitro and in vivo. Conclusions: The results suggest that compound IIb may be effective against hyperglycemia-induced activation of the polyol pathway, oxidative and osmotic stress, as well as the subsequent development of diabetic cataracts.

Objective: This study aimed to improve the DNA-nanomachine (DNM) platform based on the 10– 23 RNA-cleaving DNAzyme for efficient recognition of dsDNA at near-physiological temperatures. Two DNM variants with distinct scaffold architectures were designed and compared with the binary deoxyribozyme (BiDz) probe in terms of sensitivity and selectivity. Methods: In vitro fluorescence measurements and gel shift assays were used to assess the secondary structures, sensitivity, and selectivity of the designs. Results and Discussion: All three sensors successfully detected a synthetic HPV-16 ssDNA analyte, with BiDz demonstrating the highest sensitivity and the lowest limit of detection (10 pM). DNM-I exhibited higher background fluorescence due to partial self-activation, while DNM-II showed improved background control but slightly reduced sensitivity. Both DNMs retained excellent single-nucleotide selectivity (99.9%). Conclusions: The scaffold topology was found to strongly influence sensor performance, affecting catalytic activity and background fluorescence. The introduction of displaced strand-binding elements resulted in poorer performance compared to multiple-binding armed DNMs. Although both DNMs retained high selectivity, further optimization is required to achieve efficient dsDNA recognition at physiological temperatures.