The p38δ mitogen-activated protein kinase is an important signal transduction enzyme. p38δ has recently emerged as a drug target due to its tissue-specific expression patterns and its critical roles in regulation of cellular processes related to cancer and inflammatory diseases, such as cell proliferation, cell migration, apoptosis, and inflammatory responses. However, potent and specific p38δ inhibitors have not been defined so far. Moreover, in cancer disease, p38δ appears to act as a tumor suppressor or tumor promoter according to cancer and cell type studied. In this review, we outline the current understanding of p38δ roles in each cancer type, to define whether it is possible to delineate new cancer therapies based on small-molecule p38δ inhibitors. We also highlight recent advances made in the design of molecules with potential to inhibit p38 isoforms and discuss structural approaches to guide the search for p38δ inhibitors.

Glycogen synthase kinase-3β (GSK-3β) is a potential target in the field of Alzheimer’s disease drug discovery. We recently reported a new class of 9H-pyrimido[4,5-b]indole-based GSK-3β inhibitors, of which 3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide-based derivatives and studied their structure–activity relationships against GSK-3β supported by 1 µs molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)-3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC₅₀ values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties.

H. pylori infection remains one of the most widespread bacterial diseases globally and a leading risk factor for peptic ulcer disease and gastric cancer. Despite decades of research, the treatment of H. pylori still depends on multidrug antibiotic regimens, whose efficacy is waning due to the rise in antimicrobial resistance. Although significant progress has been made in understanding H. pylori pathogenesis, most studies targeting bacterial enzymes have focused almost exclusively on urease, a well-characterized virulence factor, while other metabolic and structural pathways remain comparatively underexplored. Targeting essential enzymes involved in bacterial metabolism and structural integrity may disrupt vital processes, potentially reducing off-target effects on the host microbiota and overcoming resistance mechanisms. To address this gap, this systematic review, conducted according to PRISMA 2020 guidelines, synthesized experimental studies published between 2014 and 2024 that investigated enzyme-targeted compounds against H. pylori, excluding those focused on urease. Literature searches in PubMed and the Web of Science identified 49 eligible studies exploring enzymes across multiple metabolic pathways. The main pathways identified included purine metabolism, the shikimate and futalosine pathways, and nitrogen metabolism, along with several other enzymatic systems, such as thioredoxin, thymidylate, and peptidoglycan biosynthesis, all of which represent promising targets for selective inhibition in H. pylori. The reported inhibitors exhibited micromolar to submicromolar activity and, in some cases, demonstrated potent antibacterial effects with minimal cytotoxicity. However, most studies remained limited to in vitro assays, and only three included animal tests. These findings highlight enzymatic inhibition as a promising approach for the rational design of narrow-spectrum microbiome-sparing agents. Advancing these discoveries through in vivo validation and druggability assessment will be essential to translating enzyme-based inhibition into effective therapeutic options against H. pylori.