In the current study, a novel series of 1,2,4-oxadiazoles were designed, synthesized, and evaluated for their biological activities. A cell-based antiproliferative screening was accomplished on the newly synthesized 1,2,4-oxadiazoles along with our previously reported aryl(alkyl)azoles (AAAs) containing middle heterocyclic cores thiazole and oxazole. Among the tested compounds, naphthyl- thiazoles demonstrated higher antiproliferative activity and B3 was identified as the most potent compound with IC50 values in the range of 2.03-3.6µM against SH-SY5Y neuroblastoma, HT-29 colorectal adenocarcinoma, and fibroblast cells (ten folds more potent than 5-FU and irinotecan). Further investigation revealed that B3 strongly inhibits tubulin polymerization with an IC50 of 0.79µM, outperforming the reference drug colchicine (IC50=1.46µM). In addition, evaluation of B3 on the expression level of BAX, BCL2, and CYCLIN D1 genes indicated the suppression of the cell cycle in the genome level. Interestingly, the 1,2,4-oxadiazole congeners displayed optimal anticonvulsant activity with significantly reduced cytotoxicity. Among the oxadiazole series, compound D4 featuring a 1,2,4-triazole head group demonstrated the highest activity in the maximal electroshock (MES) and pentylenetetrazol (PTZ) tests, with ED50 values of 2.23 and 24.60mg/kg, respectively. In vivo evaluations suggested that D4 exerts its anticonvulsant effects by enhancing GABAA currents. In conclusion, our findings indicated that B3 in the thiazole congeners is a promising drug candidate for cancer treatment with a well-defined mechanism of action. Moreover, D4 and its congeners containing oxadiazole core are much safer anti-seizures which have potential for preclinical considerations as novel anticonvulsants.

The objective of this review was to explore the trends and chemical characteristics of acridines and their derivatives, analyze their contribution to the scientific literature and international cooperation, identify the most influential authors and articles, and provide an overview of the knowledge produced in elucidating their mechanisms of action. To this end, a bibliometric analysis was performed using RStudio software, along with a systematic review focusing on articles indexed in the "Web of Science" and "Scopus" databases. The keywords used were "acridine$", "Synthesi$", "Structure$", and "Biologic* Application$" for the period from 2020 to 2024. Relevant articles were carefully selected from these databases, and a bibliometric analysis was carried out to comprehensively discuss the most relevant biological activities associated with acridines. The results showed that, during the analyzed period, China and India led in the number of publications, followed by Brazil in third place. However, a decline in the number of publications was observed in the last two years of the period. Keyword analysis revealed that antitumor activity remains the most extensively studied aspect of acridines and their derivatives.

Achieving enzyme catalysis at high substrate concentrations is a substantial challenge in industrial biocatalysis, and the role of glycosylation in post-translational modifications that modulate enzyme substrate inhibition remains poorly understood. This study provides insights into the role of N-glycosylation in substrate inhibition by comparing the catalytic properties of d-lactonohydrolase (d-Lac) derived from Fusarium moniliforme expressed in prokaryotic and eukaryotic hosts. Experimental evidence indicates that recombinant d-Lac expressed in Pichia pastoris (PpLac-WT) exhibits higher hydrolysis rates at a substrate concentration of 400g/L, with reduced substrate inhibition and enhanced stability compared to the recombinant d-Lac expressed in Escherichia coli (EcLac-WT). Mutant PpLac-M1 achieves a conversion rate of 40% at a substrate concentration of 400g/L, with a space-time yield of d-pantoic acid reaching 91.1g/L/h. Proteomics analysis reveals that residues N29 and N278, located approximately 10-20Å from the active site undergo N-glycosylation in PpLac-WT. Using microsecond-scale molecular dynamics simulations and Markov state models, we elucidate the effects of glycosylation on the conformational flexibility of two key loops at the entrance of the binding pocket. Specifically, the loops in PpLac-WT can transition between open and closed states, whereas those in EcLac-WT tend to remain open. In high substrate concentration conditions, the open state causes congestion, leading to substrate inhibition. Shortest-path map analysis confirms that substrate entry is dynamically controlled by residue N29 on the loops surrounding the active site. Our findings enhance the understanding of the effects of glycosylation on enzyme conformational dynamics and provide insights into mitigating inhibition at high substrate concentrations.

Positron Emission Tomography (PET) has emerged as a powerful imaging technique in molecular medicine, enabling the non-invasive visualisation and quantification of biological processes at the molecular level. Antibody-based PET imaging has recently gained prominence, offering specific targeting capabilities for various diseases. This scientific article delves into the intricate chemistry underlying antibody conjugation strategies for PET, providing a comprehensive understanding of the key principles and advancements in this rapidly evolving field. The article begins with a detailed exploration of various antibody conjugation methodologies, encompassing both covalent and non-covalent approaches. The chemical intricacies of bioconjugation reactions, such as amine and thiol chemistry, click chemistry, and bioorthogonal chemistry, are thoroughly discussed in the context of antibody modification. Additionally, the article critically analyses recent advancements in radiolabeling strategies for PET, including using radionuclides with favourable decay characteristics. This discussion covers both traditional radioisotopes and emerging alternatives, demonstrating their potential to raise the effectiveness of PET imaging agents based on antibodies. Ultimately, this article aims to contribute to the ongoing efforts to advance the field toward more effective diagnostic tools for personalized medicine.

Targeting endoplasmic reticulum (ER) stress-induced apoptosis has attracted considerable research interest in anti-cancer drug development. Nur77 is a potential therapeutic target in many cancers and several Nur77 modulators have recently been identified as effective anticancer agents by activating ER stress. As an ongoing work, this study reports a new series of novel N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as potent Nur77 modulators that cause ER stress-induced apoptosis. Among this new series, most compounds show improved cytotoxicity against liver cancer (HepG2 and Huh7) and breast cancer (MCF-7 and MDA-MB-231) cell lines. The representative analog 15h dramatically induces Nur77 expression and cell apoptosis, showing excellent growth inhibition of HepG2 and MCF-7 cells (IC50<5.0μM). Mechanistically, 15h binds (KD=0.477μM) and activates Nur77-mediated ER stress through the PERK-ATF4 and IRE1 signaling pathways, thereby inducing cell apoptosis. In vivo, 15h treatment strongly suppresses HepG2 xenograft tumor growth (tumor shrink by 54.06%). In summary, we synthesize a series of novel indole derivatives, among which 15h has significantly improved pharmacological activity against various cancer cells. We further identify 15h as a novel ligand of Nur77, which may serve a therapeutic lead for developing new cancer therapy.

Tuberculosis is a highly infectious disease and it is a global threat in particular affecting people from developing countries. It is thought that nearly one-third of the global population lives with this causative bacterium in its dominant form. The spread of HIV and the development of resistance to both multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) aggravates the spread of the disease and needs novel drugs which combat this disease effectively. Triazole-containing anti-tubercular drugs are promising and need further tuning to develop as a potent scaffold for tuberculosis. In this review, we highlight the structural activity relationships of triazole-containing drugs and detailed understanding for the researchers in the field of medicinal chemistry to further explore these triazole-based compounds as well as synthesize new compounds for antitubercular activity against drug-sensitive and resistant strains.