1,2,4-Oxadiazoles have emerged as a significant class of heterocyclic compounds in medicinal chemistry due to their diverse biological activities and versatile applications in drug discovery. Herein is reported an in-depth analysis of the structural properties, synthetic methodologies, and pharmacological significance of 1,2,4-oxadiazoles. The compound's unique five-membered ring containing three heteroatoms offers remarkable stability and tunable physicochemical properties, making it an attractive scaffold for the development of novel therapeutic agents, as confirmed by already approved drugs. The review highlights the broad spectrum of biological activities associated with 1,2,4-oxadiazoles, including antimicrobial, anti-inflammatory, anticancer, antiviral, and central nervous system related activities. These diverse effects underscore the scaffold's potential for targeting multiple disease pathways. Several studies demonstrate that structural modifications on the oxadiazole ring can significantly influence its pharmacokinetic and pharmacodynamic profiles, enabling the design of selective and potent drug candidates. Additionally, it has explored recent advances in synthetic strategies for constructing the 1,2,4-oxadiazole core, such as cyclization reactions involving amidoximes, nitrile oxides, and other precursors. Modern approaches using transition-metal catalysis, microwave-assisted synthesis, and green chemistry techniques are also discussed, emphasizing their importance in improving efficiency and scalability for pharmaceutical applications. Furthermore, the role of 1,2,4-oxadiazole as bioisostere replacement for esters and amides is highlighted, particularly in enhancing metabolic stability and modulating target selectivity. Application of computational methods, including molecular docking and QSAR modeling, have been also covered in understanding ligand-receptor interactions and guiding lead optimization. This review underscores the growing prominence of 1,2,4-oxadiazoles in modern drug design and their potential to address unmet medical needs. With continued research and innovation, these scaffolds are poised to play a pivotal role in the next generation of therapeutic agents across multiple disease areas.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc amidase that catalyzes the second step of the biosynthesis of lipid A, which is an outer membrane essential structural component of Gram-negative bacteria. Inhibitors of this enzyme can be attributed to two main categories, non-hydroxamate and hydroxamate inhibitors, with the latter being the most effective given the chelation of Zn²⁺ in the active site. Compounds containing diacetylene or acetylene tails and the sulfonic head, as well as oxazoline derivatives of hydroxamic acids, are among the LpxC inhibitors with the most profound antibacterial activity. The present article describes the synthesis of novel functional derivatives of hydroxamic acids—bioisosteric to oxazoline inhibitors—containing 1,2,4- and 1,3,4-oxadiazole cores and studies of their cytotoxicity, antibacterial activity, and antibiotic potentiation. Some of the hydroxamic acids we obtained (9c, 9d, 23a, 23c, 30b, 36) showed significant potentiation in nalidixic acid, rifampicin, and kanamycin against the growth of laboratory-strain Escherichia coli MG1655. Two lead compounds (9c, 9d) significantly reduced Pseudomonas aeruginosa ATCC 27853 growth in the presence of nalidixic acid and rifampicin.

Natural cytokinines are a promising group of cytoprotective and anti-tumor agents. In this research, we synthesized a set of aryl carbamate, pyridyl urea, and aryl urea cytokinine analogs with alkyl and chlorine substitutions and tested their antiproliferative activity in MDA-MB-231, A-375, and U-87 MG cell lines, and cytoprotective properties in H₂O₂ and CoCl₂ models. Aryl carbamates with the oxamate moiety were selectively anti-proliferative for the cancer cell lines tested, while the aryl ureas were inactive. In the cytoprotection studies, the same aryl carbamates were able to counteract the CoCl₂ cytotoxicity by 3–8%. The possible molecular targets of the aryl carbamates during the anti-proliferative action were the adenosine A2 receptor and CDK2. The obtained results are promising for the development of novel anti-cancer therapeutics.

Carfilzomib (CFZ) is a cornerstone in the treatment of relapsed multiple myeloma (MM). However, its efficacy is limited by resistance mediated by the overexpression of the ABC-transporter P-glycoprotein (P-gp). The signaling pathways driving the emergence of P-gp in MM remain unclear. To investigate this, we generated CFZ-resistant AMO-1/CFZ cells with P-gp overexpression by long-term selection. RNA sequencing of control AMO-1 and AMO-1/CFZ, sorted into two subpopulations, P-gp HIGH and P-gp LOW, implicated the Ras/MEK/ERK pathway as the most likely signaling cascade involved in P-gp upregulation. We therefore evaluated two clinically used MAPK pathway inhibitors, cobimetinib and ulixertinib, for their ability to re-sensitize AMO-1/CFZ cells to CFZ. Co-administration at non-toxic concentrations enhanced sensitivity 5-fold with cobimetinib and 17-fold with ulixertinib. Analysis of the combined MTT assay results, rhodamine efflux experiments, molecular docking, and Western blotting revealed distinct actions. Ulixertinib primarily functions as a potent direct P-gp inhibitor. Conversely, non-toxic concentrations of cobimetinib sensitizes cells by suppressing MAPK signaling, though it also exhibits P-gp inhibition at higher concentrations. At the IC₅₀ concentration, both inhibitors reduced P-gp expression. In conclusion, combining CFZ with MAPK pathway inhibitors like cobimetinib or ulixertinib represents a promising strategy to overcome P-gp-mediated resistance in MM.

Introduction. Carfilzomib (CFZ) is a second-generation proteasome inhibitor and serves as a constant component of multiple myeloma recurrence therapy. However, the mechanisms of development of resistance to CFZ have not been sufficiently studied. Aim. To investigate the mechanisms of development of CFZ resistance in multiple myeloma cells. Materials and methods. The study was performed in 2 multiple myeloma cell lines: АМО-1 and its CFZ-resistant subline АМО-1/CFZ. Cytotoxicity of the compounds was evaluated using the MTT assay, gene expression levels using real-time polymerase chain reaction. To evaluate protein expression, flow cytometry and western blot were used. Protein location was determined using immunocytochemistry, interaction with P-glycoprotein (P-gp) was evaluated using rhodamine accumulation assay. Results. We have obtained a cell subline АМО-1/CFZ which was 46-fold more resistant to CFZ than initial cell line АМО-1. Genes of proteasome subunits did not change significantly compared to АМО-1. We have determined that CFZ is a substrate for P-gp and promotes its expression at the levels of messenger RNA and protein. Concurrent treatment of АМО-1/CFZ cells with nontoxic concentrations of P-gp inhibitor elacridar and CFZ led to complete restoration of sensitivity to this proteasome inhibitor. Activity of YB-1 protein, one of the possible transcription factors of P-gp, did not change in the resistant subline АМО-1/CFZ. Conclusion. Therefore, P-gp hyperexpression mediates CFZ resistance in АМО-1/CFZ cells. However, molecular mechanisms leading to P-gp hyperexpression remain unknown.