Russian Journal of Bioorganic Chemistry最新文献

Objective: The current study aims to synthesize novel pyrazole-containing 1,2,3-triazole derivatives via a one-pot method and evaluate their antibacterial activity against Bacillus subtilis, Staphylococcus aureus, and Staphylococcus epidermidis strains. Methods: The target 1,2,3-triazoles were obtained through a one-pot reaction involving 1-methyl-1H-pyrazol-4-amine, triflyl azide (TfN₃), and various terminal alkynes via in situ generation of 4-azido-1-methyl-1H-pyrazole. The antibacterial activity of the newly synthesized compounds was assessed using the broth microdilution method. Results and Discussion: The structures of the synthesized compounds were confirmed by ¹H, ¹³C NMR, and mass spectrometry. Compound 4l exhibited potent activity against the tested bacterial strains with MIC values ranging from 3.12 ± 0.41 to 9.7 ± 0.51 µg/mL. Compound 4k also demonstrated good activity against B. subtilis and S. aureus with MIC values of 5.9 ± 0.20 and 7.5 ± 0.56 µg/mL, respectively. These results are comparable to the standard antibiotic dicloxacillin. Conclusions: A new series of pyrazole-containing 1,2,3-triazoles was synthesized and evaluated for in vitro antibacterial activity. Several compounds showed promising efficacy against the tested strains. The most active compounds were subjected to in silico studies. With further structural optimization, these compounds have the potential to be developed as future therapeutic candidates.

Pediococcus pentosaceus is an emerging probiotic candidate within the lactic acid bacteria (LAB). This homofermentative, Gram-positive bacterium of the genus Pediococcus (class Bacilli, phylum Firmicutes) plays a significant role in food biotechnology. It enhances the organoleptic properties, nutritional value, and shelf life of food products, particularly fermented foods, through acidification and the production of antimicrobial compounds such as bacteriocins (e.g., pediocin). Beyond biopreservation, P. pentosaceus exhibits beneficial biological activities, including antioxidant, anti-inflammatory, and immunomodulatory properties. As a putative probiotic, it can modulate the gut microbiota, influence metabolic pathways, and contribute to host health. This review summarizes the current knowledge on the multifaceted health benefits of Pediococcus pentosaceus, exploring its antimicrobial mechanisms, probiotic potential, and therapeutic applications.

Objective: A novel series of antioxidant-conjugated mutual prodrugs of naproxen (RJ-01-01–RJ-01-10) was designed and synthesized to mitigate the gastrointestinal (GI) adverse effects associated with the parent drug, naproxen. Methods: The study included molecular docking, synthesis and characterization, in vitro hydrolysis, and biological evaluation. Results and Discussion: The synthesized prodrugs demonstrated high stability in simulated gastric fluid (SGF, pH 1.2), with minimal hydrolysis to the parent naproxen (18.62–24.14%), indicating reduced potential for gastric irritation. Conversely, in simulated intestinal fluid (SIF, pH 7.4), a significantly higher hydrolysis rate (75.07–84.01%) was observed, facilitating drug release and intestinal absorption. In docking studies, compounds RJ-01-04, RJ-01-05, RJ-01-06, RJ-01-08, and RJ-01-09 exhibited the highest binding energies (–13.68, –12.23, –13.74, –12.01, and –13.06 kcal/mol, respectively) compared to naproxen. During in vitro evaluation, RJ-01-04 showed significantly more potent COX-2 inhibition (IC₅₀ = 44.18 ± 1.7 µM) than naproxen (IC₅₀ = 61.48 ± 0.8 µM) and comparable COX-1 inhibition (IC₅₀ = 55.34 ± 0.6 vs. 59.43 ± 0.5 µM for naproxen), indicating dual inhibitory activity. In AGS cells, RJ-01-04 reduced reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) activity more effectively than naproxen, demonstrating enhanced antioxidant effects. Western blot analysis confirmed downregulation of COX-2 and COX-1 protein expression in AGS cells treated with RJ-01-04. Cytotoxicity assessment (MTT assay) in HEK293 cells revealed that RJ-01-04 exhibited significantly lower cytotoxicity than naproxen. Conclusions: These findings support the mutual prodrug strategy as a promising approach to improve the therapeutic profile of naproxen through antioxidant conjugation.

Objective: The aim of this work was to synthesize quinoline derivatives and hybrid compounds in which the quinoline nucleus is linked to either a 2,4,6-triarylpyrimidine or a 4,5,6,7-tetrahydrobenzo[b]thiophene moiety. The synthesized compounds were then screened for their antibacterial and fungicidal activities. These biological evaluations were complemented by a theoretical molecular docking study. Methods: The antimicrobial and antifungal activity of quinoline derivatives was studied by the agar diffusion method against hospital strains of Escherichia coli and Staphylococcus aureus bacteria and Candida albicans fungi. The docking study was conducted against the RNA-dependent RNA polymerase (RdRp) complex with the SARS-CoV-2 virus NSP7 and NSP8 proteins, the kinase domain of the human epidermal growth factor receptor (EGFR), and doubly phosphorylated human mitogen-activated protein kinase 14 (MAPK14) in complex with the activating transcription factor (ATF2). Results and Discussion: 4-Methoxybenzaldehyde functionalized at position 2 of the benzene ring with a 4-methyl-2-sulfanylquinoline fragment was used as the starting material to obtain substituted 1-arylprop-2-en-1-ones, which were further converted into 4-substituted-2-cyano-4-oxobut-2-enoate and hybrid compounds—4-methyl-2-sulfanylquinoline–2-phenyl-6-arylpyrimidines and 4-methyl-2-sulfanylquinoline–tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one. Some of the synthesized derivatives showed pronounced antibacterial activities against S. aureus and E. coli and antifungal activities against C. albicans. The molecular docking data predict antiviral and antitumor activities in the synthesized compounds, highlighting their promise for further research. Conclusions: A series of novel 4-methyl-2-sulfanylquinoline derivatives and their hybrid structures with pyrimidine and tetrahydrobenzothienopyrimidinone scaffolds were successfully synthesized. Several compounds demonstrated pronounced antibacterial and antifungal activity in experimental assays. Furthermore, molecular docking studies predicted promising antiviral and antitumor potential. These combined experimental and in silico results provide a strong rationale for further investigation of these quinoline derivatives as lead compounds for the development of novel antimicrobial and antiviral agents.

Objective: Despite the widespread use of LbCas12a in genome editing and diagnostic systems, its non-specific activities, particularly the potential to activate collateral activity after introducing a nick in only one strand of the target DNA, or the presence of other nuclease activities such as exonuclease activity, remain poorly characterized. A deeper understanding of these activities is necessary to define the enzyme’s limitations and optimize its application, especially in sensitive diagnostic systems for nucleic acid analysis. Methods: The analysis of non-specific exonuclease activity and the potential for introducing a single-strand nick to activate collateral activity with a guide RNA mutation using the novel TTAА PAM was conducted via fragment analysis. Results and Discussion: Our data demonstrate that LbCas12a exhibits 3′→5′ exonuclease activity in vitro, which is distinct from its canonical collateral cleavage. Furthermore, we found that with the novel TTAA PAM, even in the presence of a single-nucleotide mismatch, the nuclease is unable to cleave either strand of the target DNA. We discuss potential mechanisms for the initiation of this exonuclease activity and its implications for the enzyme’s efficiency in diagnostic applications. Conclusions: The identification of LbCas12a’s exonuclease activity in vitro underscores the importance of considering this factor when developing highly sensitive assays. Mitigating non-specific hydrolysis, potentially through the use of engineered elements like the novel TTAA PAM, could lead to significant improvements in diagnostic performance.

Objective: Rolling circle amplification (RCA) is a sensitive and specific method of isothermal amplification of nucleic acids. RCA from the genomic DNA is complicated by the fact that the template target is present in the form of a long double-stranded DNA molecule that is difficult to access for ligase. One of the ways to prepare DNA for RCA analysis is the pre-amplification of genomic DNA by PCR, which leads to the formation of shorter products (amplicons) from which the ligation of the detecting oligonucleotide “padlock probe” is performed. The disadvantage of this method is the pre-amplification with thermal cycling (multiple melting of duplexes), which requires specialized equipment. Methods: A combined HDA-RCA approach is proposed to increase the sensitivity of RCA analysis in the study of full-genomic double-stranded DNA samples. Results and Discussion: It has been demonstrated that the use of pre-amplification increases the sensitivity of RCA in genomic DNA analysis. The PCR protocols are well reproducible, however, pre-amplification by PCR requires thermal cycling. With the HDA, it is possible to carry out pre-amplification in an isothermal mode, facilitating the unification of all stages into one, that is, the creation of a “one-pot” system for genomic DNA analysis using the RCA method. Conclusions: The possibility of using the proposed combined HDA-RCA method for detecting genome DNA in a sample is demonstrated. It has been demonstrated that pre-amplification using HDA increases the sensitivity of the RCA analysis, opening up the possibility of developing test systems for point-of-care diagnostics and in a single test tube without transferring material (“one-pot”).

Objective: To synthesize and characterize a new series of CF₃-substituted benzothiazepines and evaluate their anticancer activity. Methods: The compounds 5a–5n were synthesized and characterized using FT-IR, NMR spectroscopy, and elemental analysis. Their anticancer activity was evaluated against A549, MCF-7, and HepG2 cell lines using the SRB assay. Results and Discussion: The compounds demonstrated moderate to good activity against all tested cell lines. Notably, compound 5j showed significant activity against all three cell lines. Conclusions: These findings highlight the potential of this series for the development of novel anticancer agents.

Objective: To address the serious challenge of antibiotic resistance, this study aimed to synthesize a series of novel naphthoquinone-4-aminosulfonamide derivatives and evaluate their anti-Helicobacter pylori (H. pylori) activity. Methods: The target derivatives were synthesized using benzenesulfonyl chlorides, N-Boc-1,4-butanediamine, and 2-chloro-1,4-naphthoquinone as starting materials. All synthesized compounds were characterized by HRMS and NMR spectroscopy. Antibacterial activity was assessed using the broth microdilution method. Results and Discussion: Nine target compounds were successfully synthesized. All compounds exhibited significant inhibitory activity against H. pylori, with minimum inhibitory concentration (MIC) values ranging from 4 to 16 μg/mL. Conclusions: These results indicate the potential of the synthesized derivatives as promising candidates for novel anti-H. pylori therapies.

Objective: Breast cancer is one of the most prevalent malignancies among women worldwide and a leading cause of cancer-related mortality. The emergence of resistance to existing therapies underscores the need for novel agents. Methods: In this study, gefitinib, a well-established tyrosine kinase inhibitor used in non-small cell lung cancer treatment, was structurally modified to generate a series of 1,2,3-triazole hybrids. All synthesized compounds were characterized and evaluated for their antiproliferative activity against the MCF-7 breast cancer cell line and the LO2 normal hepatic cell line. Results and Discussion: The biological assessment revealed that hybrids 2c and 2l exhibited the most potent anti-proliferative effects against MCF-7 cells, with IC₅₀ values of 8.51 and 8.93 μM, respectively, while showing lower cytotoxicity toward LO2 cells. Both compounds significantly reduced MCF-7 cell viability. Apoptosis analysis demonstrated that compound 2l notably induced apoptotic cell death. Gene and protein expression profiling indicated that 2c and 2l modulated the expression of markers associated with oxidative stress, autophagy, DNA damage, and apoptosis. Staining assays for DNA damage and autophagosome formation further corroborated the anti-proliferative effects of 2c and 2l in MCF-7 cells. Conclusions: These findings suggest that the gefitinib-1,2,3-triazole hybrids 2c and 2l are promising candidates for further investigation as potential anti-tumor agents against breast cancer.

Aminoquinoline derivatives, renowned for their versatile biological activities, are crucial scaffolds in medicinal and material chemistry. These compounds are integral to developing antimalarial, antibacterial, anticancer, and immunomodulatory agents, with prominent examples including chloroquine, neratinib, and imiquimod. Furthermore, aminoquinoline moieties serve as precursors for Schiff bases and their corresponding metal complexes, which exhibit properties such as selective fluorescence sensing, catalytic activity, and enhanced therapeutic potential. This review covers recent advances in synthesizing aminoquinoline-based Schiff bases and their metal complexes, focusing on their structural diversity, coordination chemistry, and reaction mechanisms. It highlights their significant roles in fluorescence-based detection of metal ions (e.g., Fe³⁺, Al³⁺, Hg²⁺) and their application in anticancer, antimicrobial, and antitubercular therapies. The complexation of Schiff base ligands with metal ions often enhances their pharmacological profiles, leading to superior activity compared to the free ligands. By discussing synthetic methodologies, characterization techniques, and bioactivity evaluations, this review provides a comprehensive overview of the potential of aminoquinoline derivatives in drug development and sensor technology, paving the way for innovative applications in therapeutics and diagnostics.