Medicinal Chemistry (Volume 22 - Issue 3)

Research Progress of G Protein-coupled Receptor 52 on Central Nervous System Diseases

2026-04-14

The G protein-coupled receptor 52 (GPR52) is a Gs-coupled receptor and is located principally in the striatum alongside D₂ receptor and in the pre-frontal cortex alongside D₁ receptor. Its stimulation leads to potentiation of intracellular cAMP levels, producing effects on cAMP levels similar to those of a Gi-coupled D₂ receptor antagonist in the striatum and a Gscoupled D₁ receptor agonist in the prefrontal cortex. This dual mechanism suggests that GPR52 activation could result in antipsychotic effects akin to D₂ antagonism and pro-cognitive effects resembling D1 agonism. As a result, GPR52 has emerged as a promising therapeutic target for central nervous system (CNS) disorders, including schizophrenia and substance use disorder. Additionally, knocking out (KO) GPR52 not only significantly reduces mutant huntingtin protein (mHTT) levels in the striatum but also rescues Huntington’s disease-associated behavioral phenotypes in a knock-in Huntington’s disease mouse model, which provides evidence that GRP52 may also serve as a potential target for Huntington’s disease. This review summarizes the current state of small-molecule ligand/drug discovery for GPR52, focusing on the latest findings about the role of GPR52 in schizophrenia and Huntington’s disease.

Recent Advances in Synthetic Pathways and Therapeutic Potential of Acridine and Acridone Derivatives

2026-04-14

Cancer, bacterial, parasitic, viral, and neurological diseases like Alzheimer's continue to pose serious health risks around the world. We need new therapeutic agents that are more targeted, effective, and safer. Because of their wide range of biological actions, acridine and its derivatives have become increasingly popular among the numerous intriguing chemical classes. Over time, several synthetic analogs of these substances have shown great promise, exhibiting noteworthy antitumor properties (e.g., N-(2-(dimethylamino) ethyl) acridine-4-carboxamide (DACA) and triazole acridone (C-1305)), as well as strong antimicrobial (e.g., 4-amino-N-[amino(imino) methyl]-benzene sulphonamide), antiviral (e.g., derivatives of acridine sulphonamide), and anti- Alzheimer's (e.g., Citrusinine-I) properties. These substances have therapeutic potential, but side effects frequently prevent them from being used in clinical settings. This review discusses all the new developments in acridine and acridone derivatives since 2024. It focuses on how they are made and might be used in medicine. By shedding light on these innovations, the study aims to offer a fresh perspective on their role in shaping the future of medicinal chemistry and drug development. This work's main goal is to investigate and evaluate the most current progress in the synthesis as well as biological uses concerning derivatives of acridine along with acridone, especially those that have been published after 2024. The target of the study is to demonstrate the compounds' medicinal perspective by highlighting their antiviral, anticancer, antibacterial, and anti-Alzheimer effects. Furthermore, the research aims to tackle the difficulties related to their adverse effects, offering valuable perspectives for the creation of safer and more efficient medications in the field of medicinal chemistry in the future.

Exploring Recent Advances in the Pharmacological Activities of Pyrazole Compounds: A Comprehensive Review

2026-04-14

Pyrazole-based compounds have gained considerable attention in recent years due to their diverse and potent pharmacological properties. This review provides an up-to-date examination of the therapeutic potential of various substituted pyrazole derivatives, highlighting their roles in combating diseases such as cancer, tuberculosis, fungal and viral infections, inflammation, and others. Unlike previous reviews, this article emphasises newly reported analogues with significant bioactivity and structure-activity relationships (SAR), which may pave the way for future drug development. The novelty of this work lies in its integrated perspective that bridges medicinal chemistry innovations with therapeutic relevance, providing researchers with a valuable resource for designing next-generation drug candidates based on the pyrazole scaffold.

Screening of Novel Inhibitors Targeting the Non-ATP-binding Domain of Staphylococcus aureus SecA1

2026-04-14

Objective: Staphylococcus aureus (S. aureus) has been one of the pathogenic bacteria for clinical infections, and there is an urgent need for the development of novel anti-S. aureus drugs. SecA is a conserved and essential protein in bacteria and is considered as an ideal target for development. Current screening of inhibitors against SecA has focused on the ATP-binding structural domain, which increases the risk of drug side effects, so a novel screening strategy based on the non-ATP-binding structural domain was chosen in this paper.

Methods: A three-dimensional structural model of S. aureus SecA1N75 was constructed, and molecular docking was utilized to screen small molecules with strong interactions with the non- ATP binding domains from a compound library, and four candidate compounds were finally targeted. Molecular dynamics simulations of the candidate molecules were performed to evaluate their drug potential.

Results: The four candidate compounds formed stable interactions with key residues of the SecA binding pocket. Molecular dynamics simulations further showed that the candidate molecules bound to the receptor in a stable conformation with nM-level inhibition constants, displaying potent SecA inhibitory activity. It lays the foundation of a lead compound for the development of antimicrobial drugs targeting SecA.

Conclusion: In this thesis, an inhibitor screening strategy based on non-ATP binding structural domains was successfully constructed, which breaks through the limitations of traditional methods to screen candidate molecules with high activity and low risk of potential side effects, and provides an innovative solution to meet the challenge of S. aureus drug resistance.

Novel Pyrrolopyrimidines as Inhibitors of CLK4 and HER2: Targeting Promising Anticancer Pathways

2026-04-14

Introduction: Dysregulated cellular signaling pathways involving protein kinases are critically implicated in cancer development. Consequently, protein kinases have emerged as key targets for novel anticancer therapies. A range of kinase inhibitors, including small molecules and monoclonal antibodies, has been developed. Although early strategies focused on achieving high specificity to minimize adverse effects, resistance to these targeted therapies has limited their effectiveness. As a result, broader-spectrum inhibitors that act on multiple cancer-related kinases are now considered more promising therapeutic options.

Method: We developed twenty-five new pyrrolopyrimidine derivatives featuring diverse substitution patterns to assess their potential as small-molecule inhibitors of the protein kinases CLK4 and HER2, both of which are significant therapeutic targets in metastatic breast cancer. Pyrrolopyrimidine derivatives were synthesized and purified by column chromatography. Their protein kinase inhibitory activity was evaluated through a radioactive ATP-competition assay.

Results: The compounds were obtained through a multi-step synthetic procedure, concluding with substitution reactions. The effects of different substituents on the inhibitory properties of the observed protein kinases are analyzed and discussed.

Discussion: Aniline-substituted derivatives exhibited the most potent activities, which were further modulated by N-substituted pyrroles.

Conclusion: We identified both selective and dual inhibitors of the target kinases, demonstrating activity in the nanomolar range.