Pyrazinones remain a comparatively underexplored class of nitrogen heterocycles, despite their recurrence in bioactive natural products and their emergence as a privileged scaffold engaging viral polymerases, kinases, proteases, and G-protein-coupled receptors. Unlike prior reviews, typically confined to a single therapeutic class or to synthetic methodology alone, this review is the first to integrate the natural occurrence, synthetic access, structure-activity relationships, and clinical translatability of pyrazinone derivatives within a single framework, and in doing so identifies structural determinants that recur across nine otherwise unrelated therapeutic areas rather than being specific to any one target. Three such determinants emerge consistently: halogenation at C-3/C-5 improves potency and metabolic stability across kinase, protease, and antifungal series alike; hydrogen-bond donor/acceptor substituents are well tolerated at N-1/C-6 but sharply disruptive when placed adjacent to the lactam at N-3/C-2, reflecting a conserved role for this region in target recognition; and lipophilic extensions at N-1/C-6 raise cellular potency at the recurring cost of selectivity. Inherent limitations are critically examined, including lactam-lactim tautomeric equilibria, challenges in regioselective functionalization, and the trade-off between aqueous solubility and membrane permeability, alongside ADMET considerations such as metabolic stability and off-target toxicity. A central finding of this synthesis is that, across almost every therapeutic class surveyed, reported activity data remain confined to in vitro measurements, without matching pharmacokinetic or translatability data, indicating that the principal bottleneck to clinical progression is evaluative rather than a shortage of potent chemical matter. Clinically relevant examples, including the antiviral drug favipiravir and the clinical-stage candidates RWJ-671818 and BI 730357, nonetheless demonstrate that this bottleneck is surmountable and illustrate the scaffold's translational potential. Recent advances, emerging resistance mechanisms, and future directions, including multi-target-directed ligand design, structure-based optimization, and AI-assisted drug design, are also discussed. By consolidating this fragmented literature into a single cross-scaffold structure-activity framework and by pinpointing where pharmacokinetic and toxicological characterization, rather than potency optimization, most limits clinical translation, this review provides a practical, decisionoriented resource for researchers designing the next generation of pyrazinone-based therapeutics.

Antibiotic resistance has become a major global public health challenge, creating an urgent need for the development of new antimicrobial agents. This article reviews the latest research on nitrogen-heterocyclic antimicrobial agents, including pyrazole, imidazole, triazole, thiazole, indole, and quinolone. The article analyzes synthetic strategies, antibacterial activities, and structure-activity relationships for various derivatives. Eight key antibacterial scaffolds, namely compounds 21aa, 30a, 40, 63S, 91, 105, 123, and 127a, were identified as exhibiting outstanding performance. Future research should focus on evaluating the in vivo pharmacodynamics, pharmacokinetics, clinical translation challenges, and safety of these key antibacterial scaffolds, thereby promoting the clinical translation of nitrogen-heterocyclic antibacterial candidate drugs.

The structural variety and associated biological potential of pyrimidine derivatives have made them attractive to medicinal chemists. Due to the various biological activities of Pyrimidine derivatives and structural derivatives of DNA, many researchers have been prompted to explore this area. Substituted Pyrimidine derivatives have a broad range of pharmacological applications, including antimicrobial, anticancer, and anti-inflammatory activities. The pyrimidine ring and its fused derivatives, which include pyrazolo[3,4-d]pyrimidine, pyrido[2,3- d]pyrimidine, quinazoline, and furo[2,3-d] pyrimidine, have generated a great deal of attention due to the high variety of biological potential that they possess. In addition, fused pyrimidines are intended as bioisosteres of purines. As a result, numerous substances, including pyrimidines and fused pyrimidine derivatives, have demonstrated promising anticancer potential. The emergence of multidrug resistance in cancer cells has significantly reduced the effectiveness of numerous anticancer drugs, posing a challenge to cancer treatment. To avoid this issue, researchers are continuously focusing on target-based drug discovery as a promising pathway for developing novel anticancer agents with improved efficacy and selectivity. Specifically, this review will explore various pyrimidine derivatives, examining positional substitutions and fusion with other heterocyclic rings to elucidate how these compounds interact with molecular targets involved in cancer development and progression. By understanding these interactions, researchers can design more potent pyrimidine -based drugs with better target selectivity. Moreover, the review will also explain the structure-activity relationships of various pyrimidine derivatives, providing insights into the structural features that contribute to their anticancer activity. In the past few years, numerous novel pyrimidine derivatives have been developed and studied for their anticancer activities. The primary objective of this review is to evaluate the structureactivity relationship (SAR) of pyrimidine derivatives developed as anticancer agents over the past decade.

Following the publication of this article [1], it was noted that some chemical structures were misnumbered during processing of the text. This has now been corrected in the text and Table 5. The original article can be found online at: https://www.eurekaselect.com/article/144767.

Cancer and neurodegenerative disorders remain major public health challenges worldwide. Increasing incidence across age groups, together with persistently high mortality in many settings, contributes to substantial socioeconomic burdens on individuals, families, and healthcare systems. Histone Deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues on histone tails. As a key post-translational modification, histone deacetylation modulates chromatin organization and gene transcription. In many contexts, HDACmediated deacetylation is associated with increased chromatin compaction, which may limit transcription-factor accessibility and reduce transcriptional output. Beyond chromatin regulation, HDACs have been implicated in cell-cycle progression, apoptosis, inflammation, immune responses, redox homeostasis, and neuronal development. Given their involvement in disease mechanisms, Histone Deacetylase Inhibitors (HDACis) have attracted attention as potential epigenetic therapeutics with pleiotropic effects. By counteracting aberrant deacetylation, HDACis may help restore acetylation-dependent transcriptional programs and reactivate genes implicated in disease. They may also affect dysregulated signaling pathways and have been reported to exhibit antiproliferative, anti-inflammatory, neuroprotective, and anticancer effects. Accumulating preclinical and emerging clinical evidence suggests that HDACis are being evaluated for therapeutic activity in a range of malignant and neurodegenerative diseases. This review summarizes recent advances in HDACis, with emphasis on structural classification, key chemical features, molecular mechanisms, and clinical translation in oncology and neurodegeneration. By integrating these aspects, the article aims to provide a conceptual reference for targeted drug discovery and rational combination strategies for these challenging conditions.

As the primary active constituent of the traditional Chinese medicinal herb Ligusticum chuanxiong, Tetramethylpyrazine (TMP) has demonstrated broad therapeutic potential across multiple disease areas. Its clinical applications span cardiovascular and cerebrovascular disorders, oncology, hepatorenal protection, and respiratory diseases. The mechanisms of action involve antiplatelet aggregation, anti-inflammatory, antioxidant, and anti-apoptotic effects, as well as modulation of autophagy and multiple signaling pathways. Despite its pleiotropic efficacy, the clinical utility of TMP is constrained by unfavorable pharmacokinetic properties, including rapid metabolism and limited oral bioavailability. To overcome these limitations, researchers have developed various TMP derivatives, which exhibit significantly improved metabolic stability and enhanced pharmacological activity. This review summarizes recent advances in TMP and its derivatives over the past five years, aiming to provide insights for the future development of novel TMP-based therapeutics.