Despite being present in many drugs, guanylhydrazones and semicarbazones are two functional groups that have been little investigated as potential therapeutic strategies for the treatment of Alzheimer's disease (AD). For this reason, we initiated the synthesis and evaluation of these compounds as potential anticholinesterase agents, aiming to offer new alternatives for drug development against AD. In the severe phase of AD butyrylcholinesterase (BChE) becomes the main enzyme responsible for the hydrolysis of acetylcholine (ACh). Therefore, in this project, we present the results of BChE inhibitory activity, enzyme kinetics, cytotoxicity, and molecular modeling studies for three guanylhydrazone and two semicarbazone derivatives that were previously synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Among the compounds tested, guanylhydrazones (1, 2, and 3) showed inhibitory activity against BChE, exhibiting a mixed non-competitive inhibition profile. Specifically, compound 2 (phenanthrenequinone) demonstrated superior inhibitory potency with an IC50 of 0.68 μM, compared to compound 1 (acridinone) with an IC50 of 3.87 μM, and compound 3 (benzodioxole) with an IC50 of 101.7 μM. In contrast, semicarbazones (4 and 5) showed no BChE inhibition up to the highest concentration tested (300 μM). Importantly, all five compounds were found to be non-cytotoxic. Our results suggest that these compounds have potential as drug prototypes targeting different phases of AD. Compounds 3, 4, and 5 may be more effective in the early phase, when AChE activity remains high; compound 1 could be useful in the intermediate phase; and compound 2 appears particularly promising for the severe phase, when BChE plays a more dominant role.

• MeSH
• Acetylcholinesterase metabolism   chemistry   MeSH
• Alzheimer Disease * drug therapy   MeSH
• Butyrylcholinesterase metabolism   chemistry   MeSH
• Cholinesterase Inhibitors * chemistry   pharmacology   metabolism   therapeutic use   chemical synthesis   MeSH
• Hydrazones * chemistry   pharmacology   MeSH
• Kinetics MeSH
• Humans MeSH
• Models, Molecular MeSH
• Drug Design * MeSH
• Semicarbazones * chemistry   pharmacology   metabolism   MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

DC-SIGN, a C-type lectin receptor expressed on immune cells, is considered a promising target for immunomodulatory and antiviral therapies. While mannose-based glycomimetics have been extensively studied as DC-SIGN ligands, fucose-based strategies remain underexplored. This study explores the fucosylation of linear alcohols and sugars using eight different fucosyl donors, aiming at designing strategies for the development of fucose-based glycomimetics targeting DC-SIGN. Four types of leaving groups and two different acyl-based protecting groups on the donors were tested. The glycosylation of 3-azidopropan-1-ol exclusively yielded the β-anomer, demonstrating high stereoselectivity. The azido group in the product is versatile, allowing for direct click chemistry reactions or reduction to an amine for further functionalization. Both types of reactions were demonstrated in a model reaction. In the glycosylation of a sugar, a disaccharide moiety of Lewis X antigen was selected as a target molecule. Only one of the eight tested fucosyl donors worked well in this reaction and provided the product in a reasonable yield. The disaccharide was also equipped with the 3-azidopropyl linker, facilitating future modifications. Finally, NMR studies confirmed compatibility of the linker with canonical Ca2+-dependent carbohydrate binding to DC-SIGN, suggesting potential for further development of fucose-based glycomimetics targeting this C-type lectin receptor.

• MeSH
• Fucose * chemistry   MeSH
• Glycosides * chemistry   chemical synthesis   pharmacology   metabolism   MeSH
• Glycosylation MeSH
• Lectins, C-Type * metabolism   antagonists & inhibitors   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Adhesion Molecules * metabolism   antagonists & inhibitors   MeSH
• Receptors, Cell Surface * metabolism   antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CHNOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by tert-butyl groups: CH=NOtBu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH2OCH2 → CH2CH2CH2) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD50 values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only in vivo. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes * chemical synthesis   chemistry   pharmacology   therapeutic use   MeSH
• Atropine therapeutic use   pharmacology   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Mice MeSH
• Nerve Agents * toxicity   MeSH
• Organophosphorus Compounds * toxicity   MeSH
• Oximes chemistry   MeSH
• Pyridinium Compounds * chemical synthesis   chemistry   therapeutic use   pharmacology   MeSH
• Soman toxicity   MeSH
• Trimedoxime chemistry   chemical synthesis   pharmacology   therapeutic use   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The polymerase acidic (PA) subunit of the influenza virus, an endonuclease of the RNA-dependent RNA polymerase, represents a viable target for anti-influenza therapies, as evidenced by the efficacy of the FDA-approved drug Xofluza. A characteristic feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions within the enzyme's catalytic site. Previously, our studies identified luteolin and its C-8-glucoside orientin as potent endonuclease inhibitors. This report details our subsequent investigation into the structural modifications of the phenyl moiety attached to the C-8 position of luteolin. The inhibitory potencies (IC50 values) quantified with AlphaScreen technology indicated that substituting the C-8 glucose moiety of orientin resulted in compounds with comparable inhibitory potency. From a series of eighteen compounds, acid 12 with 3-carboxylphenyl moiety at the C-8 position was the most potent inhibitor with nanomolar potency.

• MeSH
• Antiviral Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Endonucleases * antagonists & inhibitors   metabolism   MeSH
• Enzyme Inhibitors * pharmacology   chemical synthesis   chemistry   MeSH
• Luteolin * pharmacology   chemical synthesis   chemistry   MeSH
• Molecular Structure MeSH
• Drug Design * MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH

Dual reporters encoding two distinct proteins within the same mRNA have had a crucial role in identifying and characterizing unconventional mechanisms of eukaryotic translation. These mechanisms include initiation via internal ribosomal entry sites (IRESs), ribosomal frameshifting, stop codon readthrough and reinitiation. This design enables the expression of one reporter to be influenced by the specific mechanism under investigation, while the other reporter serves as an internal control. However, challenges arise when intervening test sequences are placed between these two reporters. Such sequences can inadvertently impact the expression or function of either reporter, independent of translation-related changes, potentially biasing the results. These effects may occur due to cryptic regulatory elements inducing or affecting transcription initiation, splicing, polyadenylation and antisense transcription as well as unpredictable effects of the translated test sequences on the stability and activity of the reporters. Unfortunately, these unintended effects may lead to misinterpretation of data and the publication of incorrect conclusions in the scientific literature. To address this issue and to assist the scientific community in accurately interpreting dual-reporter experiments, we have developed comprehensive guidelines. These guidelines cover experimental design, interpretation and the minimal requirements for reporting results. They are designed to aid researchers conducting these experiments as well as reviewers, editors and other investigators who seek to evaluate published data.

• MeSH
• Eukaryota genetics   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Protein Biosynthesis genetics   MeSH
• Genes, Reporter * MeSH
• Guidelines as Topic MeSH
• Research Design standards   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Interleukin-2-inducible T-cell kinase (ITK) and Bruton's tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds. Several compounds demonstrated selective cytotoxicity against ITK- or BTK-expressing cells. Compound 3d exhibited high cytotoxicity in ITK-positive Jurkat (IC50 = 3.58 μM) and BTK-positive Ramos (IC50 = 3.06 μM) cells, while compound 3j showed strong cytotoxicity in Ramos (IC50 = 1.38 μM) and Jurkat (IC50 = 4.16 μM) cells. Compounds 3a and 3e were selectively cytotoxic in Jurkat cells (IC50 = 9.36 μM and 10.85 μM, respectively), while compounds 3f and 3g were highly cytotoxic in Ramos cells (IC50 = 1.82 μM and 1.42 μM, respectively). None of the active compounds exhibited cytotoxicity in non-cancer cell lines (IC50 > 50 μM), demonstrating their selectivity for malignant cells. Enzyme inhibition assay showed that 3d is a selective ITK inhibitor (IC50 = 0.91 μM) with no detectable BTK inhibition, aligning with its strong activity in ITK-positive cells. In contrast, compound 3j did not inhibit ITK or BTK enzymatically, suggesting an alternative mechanism of action. These findings highlight 3d as a promising ITK inhibitor and warrant further investigation to elucidate its mechanism of action.

• MeSH
• Protein Kinase Inhibitors * pharmacology   chemical synthesis   chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Oxindoles pharmacology   chemistry   chemical synthesis   MeSH
• Cell Proliferation drug effects   MeSH
• Agammaglobulinaemia Tyrosine Kinase * antagonists & inhibitors   metabolism   MeSH
• Antineoplastic Agents * pharmacology   chemical synthesis   chemistry   MeSH
• Drug Design * MeSH
• Drug Screening Assays, Antitumor * MeSH
• Molecular Docking Simulation MeSH
• Spiro Compounds chemistry   pharmacology   chemical synthesis   MeSH
• Protein-Tyrosine Kinases * antagonists & inhibitors   metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND AND OBJECTIVES: Gingivitis and periodontitis are common periodontal diseases that can significantly harm overall oral health, affecting the teeth and their supporting tissues, along with the surrounding anatomical structures, and if left untreated, leading to the total destruction of the alveolar bone and the connective tissues, tooth loss, and other more serious systemic health issues. Numerous studies have shown that propolis can help reduce gum inflammation, inhibit the growth of pathogenic bacteria, and promote tissue regeneration, but with varying degrees of success reported. For this reason, this comprehensive systematic review aims at finding out the truth concerning the efficacy of propolis mouthwashes in treating gingivitis and periodontitis, as its main objective. DATA SOURCES: Research findings from 6 different databases: China National Knowledge Infrastructure (CNKI), PubMed®, Europe PMC, Cochrane Central Register of Controlled Trials (CENTRAL), BioMed Central, and Google Scholar, were retrieved and examined in addition to a manual search in the references lists. STUDY SELECTION AND SYNTHESIS: The PICOS framework was used to select and exclude studies. The focus was on clinical randomized controlled trials (RCTs) that examined the effectiveness of propolis-containing mouthwashes in comparison with propolis-free ones for the treatment of gingivitis and periodontitis, employing related periodontal indices. Animal studies, microbiological studies, in-vitro studies, retrospective studies, case-control studies, cohorts, case reports, case series, reviews, letters, editorials, meta-analyses, and non-clinical randomized controlled trials (non-RCTs), all were excluded. A meta-analysis was not performed and data were only studied qualitatively due to the obvious heterogeneity amongst the studies. Data from the selected studies were extracted, and then the revised Cochrane's risk of bias tool (RoB 2.0) was utilised by two of the authors, independently, to evaluate the risk of bias in each study. RESULTS: At first, 151 results were reached, but then after removing duplicates, 99 records remained, and were later screened, assessed, and studied in full details based on the set PICOS criteria. Out of these 99 articles, ten studies were included in this systematic review, encompassing a total of 453 patients with an age range of (13-70) years old. Propolis mouthwashes with different protocols of application were the intervention whereas placebo or the rest of the tested mouthwashes such as, chlorhexidine, sodium fluoride with cetylpyridinium chloride, sterile distilled water, hydrogen peroxide, were the ones to which propolis mouthwashes were compared. Treatment duration extended from 14 days to 3 months and the follow-up period differed from 14 days to 3 months. In general, propolis mouthwashes decreased plaque accumulations and gingival inflammation in gingivitis patients based on the employed indices. On the other hand, the aforementioned tested mouthwashes other than propolis were deemed equally effective or even superior to propolis in some studies. As an overall assessment for the risk of bias, four studies were assigned as having a low risk of bias. Two studies were deemed to have some concerns, while four studies were identified as having a high risk of bias. CONCLUSIONS: Despite the fact that propolis has shown positive effects in terms of controlling gingival and periodontal inflammation especially when used with mechanical methods, studies lack certainty and their power of evidence is low with no agreed gold standards. These conclusions come, for sure, within the limitations of this review, like having substantial variability amongst the included studies and the presence of studies with a high risk of bias. The findings demonstrate that propolis-based mouthwashes showed promising clinical outcomes in reducing plaque and gingival inflammation. However, it is highly recommended to conduct more rigorous trials with patient-reported outcome measures, extended follow-up periods, larger samples sizes, better-designed methodologies, typified propolis use, and with the implementation of similar indices in order to obtain more reliable, conclusive, and generalisable results. PROSPERO REGISTRATION NUMBER: CRD42024524523.

• Publication type
• Journal Article MeSH

Protein synthesis (translation) consumes a substantial proportion of cellular resources, prompting specialized mechanisms to reduce translation under adverse conditions. Ribosome inactivation often involves ribosome-interacting proteins. In both bacteria and eukaryotes, various ribosome-interacting proteins facilitate ribosome dimerization or hibernation, and/or prevent ribosomal subunits from associating, enabling the organisms to adapt to stress. Despite extensive studies on bacteria and eukaryotes, understanding factor-mediated ribosome dimerization or anti-association in archaea remains elusive. Here, we present cryo-electron microscopy structures of an archaeal 30S dimer complexed with an archaeal ribosome dimerization factor (designated aRDF), from Pyrococcus furiosus, resolved at a resolution of 3.2 Å. The complex features two 30S subunits stabilized by aRDF homodimers in a unique head-to-body architecture, which differs from the disome architecture observed during hibernation in bacteria and eukaryotes. aRDF interacts directly with eS32 ribosomal protein, which is essential for subunit association. The binding mode of aRDF elucidates its anti-association properties, which prevent the assembly of archaeal 70S ribosomes.

• MeSH
• Archaeal Proteins * chemistry   metabolism   ultrastructure   MeSH
• Dimerization MeSH
• Cryoelectron Microscopy * MeSH
• Ribosome Subunits, Small, Archaeal chemistry   metabolism   MeSH
• Models, Molecular MeSH
• Protein Multimerization MeSH
• Pyrococcus furiosus * metabolism   MeSH
• Ribosomal Proteins * chemistry   metabolism   MeSH
• Ribosomes metabolism   ultrastructure   chemistry   MeSH
• Protein Binding MeSH
• Publication type
• Journal Article MeSH

A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a-f and 6a-f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a-h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a-d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a-f and 6a-f and 1,2,3-triazole derivatives 7a-h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a-f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 μM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.

• MeSH
• Anti-Bacterial Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Quinolines * chemistry   pharmacology   chemical synthesis   MeSH
• Enterococcus faecalis drug effects   MeSH
• Humans MeSH
• Microbial Sensitivity Tests * MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Drug Design MeSH
• Staphylococcus aureus drug effects   MeSH
• Sulfonamides * pharmacology   chemistry   chemical synthesis   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: The widespread importance of the synthesis and modification of anticancer agents has given rise to many numbers of medicinal chemistry programs. In this regard, triazine derivatives have attracted attention due to their remarkable activity against a wide range of cancer cells. This evaluation covers work reports to define the anticancer activity, the most active synthesized compound for the target, the SAR and, when described, the probable MOA besides similarly considered to deliver complete and target-pointed data for the development of types of anti-tumour medicines of triazine derivatives. Triazine scaffold for the development of anticancer analogues. Triazine can also relate to numerous beneficial targets, and their analogues have auspicious in-vitro and in-vivo anti-tumour activity. Fused molecules can improve efficacy, and drug resistance and diminish side effects, and numerous hybrid molecules are beneath diverse stages of clinical trials, so hybrid derivatives of triazine may offer valuable therapeutic involvement for the dealing of tumours. OBJECTIVE: The objective of the recent review was to summarize the recent reports on triazine as well as its analogues with respect to its anticancer therapeutic potential. CONCLUSION: The content of the review would be helpful to update the researchers working towards the synthesis and designing of new molecules for the treatment of various types of cancer disease with the recent molecules that have been produced from the triazine scaffold. Triazine scaffolds based on 1,3,5-triazine considerably boost molecular diversity levels and enable covering chemical space in key medicinal chemistry fields.

• MeSH
• Humans MeSH
• Neoplasms drug therapy   MeSH
• Antineoplastic Agents * pharmacology   chemistry   therapeutic use   MeSH
• Drug Screening Assays, Antitumor MeSH
• Triazines * pharmacology   chemistry   therapeutic use   MeSH
• Drug Development methods   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH