Mini reviews in medicinal chemistry最新文献

Breast cancer (BC) remains a leading cause of mortality worldwide, with treatment complicated by tumor heterogeneity, drug resistance, and therapy-related toxicities. Despite advances in chemotherapy, immunotherapy, and surgery, these challenges continue to limit therapeutic outcomes. Among emerging strategies, prodrugs have shown promise. These pharmacologically inactive compounds are designed to undergo enzymatic or chemical conversion in the body, releasing the active drug selectively in target tissues, thereby improving drug delivery, enhancing efficacy, and reducing systemic toxicity. Prodrug strategies targeting specific molecular features of tumors, such as the tumor microenvironment (TME), offer potential solutions to issues like poor drug solubility and bioavailability. Combining prodrugs with other therapeutic modalities, including immunotherapy and precision medicine, is actively being investigated to overcome drug resistance and enhance treatment response. Nevertheless, challenges remain, including the complexity of designing prodrugs that can be efficiently activated within the TME, as well as scalability and manufacturing costs. Future research leveraging nanotechnology, personalized medicine, and artificial intelligencedriven drug discovery is expected to drive innovations in prodrug-based therapies. Integrating these approaches may enable more effective and individualized treatments for BC, particularly in cases refractory to conventional therapies. This review highlights the current status, challenges, and future directions of prodrug development in breast cancer therapy, underscoring their potential to transform the treatment landscape.

Vitamin-drug conjugates are formed by linking a drug to a vitamin, either directly or through a spacer, to facilitate recognition and binding to receptors overexpressed on bacterial, cancer, or targeted cells. This strategy, often described as a "Trojan horse" approach, enhances intracellular drug accumulation and helps overcome resistance. Drugs conjugated with essential nutrients, such as vitamins, are actively taken up by cells for survival, thereby increasing therapeutic efficacy. Vitamin C-drug conjugates, including derivatives of diclofenac, aspirin, and naproxen, have demonstrated improved transport across the blood-brain barrier via SVCT-mediated uptake, offering potential for the treatment of neurodegenerative disorders. Similarly, conjugation with antivirals such as saquinavir improves oral absorption and systemic bioavailability by bypassing efflux mechanisms. Beyond small-molecule drugs, vitamin conjugates with polymers, lipids, peptides, natural compounds, and proteins have emerged as innovative strategies for targeted delivery. The incorporation of vitamin C into nanostructures, such as gold nanoparticles, enhances oxidative stability and promotes intracellular delivery through endocytosis. Protein conjugates, utilizing carriers such as HSA, BSA, and β-lactoglobulin, facilitate systemic transport, while peptide conjugates leverage the antioxidant activity of vitamin C in conjunction with peptide-based targeting, providing synergistic benefits in cosmetics and dermatology. Collectively, these studies highlight vitamin C conjugation as a versatile platform for precision medicine and targeted therapy.

Background: Pyrazolopyrimidines are a fascinating class of heterocyclic compounds that have attracted considerable interest for their potential in cancer therapy. Their unique scaffold allows flexible chemical modifications, enabling them to interact with various cancer-related proteins- especially kinases that regulate tumor growth and survival.

Objective: This review highlights recent advancements in the design, synthesis, and biological evaluation of pyrazolopyrimidine derivatives, emphasizing their role as targeted anticancer agents.

Methods: We analyzed recent literature (2000-2025) covering synthetic strategies, anticancer targets, in silico studies on anticancer targets and their mechanisms, off-target mechanisms, and patent information. The review also focuses on how these methods guide the optimization of Structure- Activity Relationships (SAR) and improve compound efficacy.

Results: Numerous pyrazolopyrimidine derivatives demonstrated significant anticancer activity across various cell lines, including breast, liver, colorectal, and haematological malignancies. Mechanistic investigations revealed that these derivatives target key oncogenic pathways, such as CDKs, EGFR (including resistant mutants), mTOR, TOPO II, and HDACs. They exert anticancer effects by inducing apoptosis, arresting cells at S or M phases, and downregulating proliferation markers. Several studies also report favourable selectivity for cancer cells, improved bioavailability, and metabolic stability, supporting their drug-like properties.

Conclusion: Pyrazolopyrimidines represent a versatile and promising class with strong in vivo efficacy, selectivity, and a favorable toxicity profile. Their ability to engage multiple targets and overcome resistance highlights their potential for integration in oncology. However, further systematic in vivo and clinical studies are essential to translate their potential into therapeutic success.

Despite progress in cancer research, cancer continues to be a leading cause of mortality worldwide; hence, therapeutic strategies must constantly improve. Drug discovery has revealed that heterocyclic moieties are fundamental and unique scaffolds because of their structural versatility and ability to interact with key biological targets. In these cyclic compounds, heteroatoms are a signature that serves to modulate cellular pathways relevant to tumor progression, apoptosis, and proliferation. Hybridization between the aromatic ring and the non-aromatic ring in a heterocyclic structure has resulted in the development of novel heterocyclic derivatives with increased anticancer activity, increased selectivity, and reduced adverse effects in the clinic, and has recently been used extensively in medicinal chemistry. Research has been directed towards the improvement of their molecular frameworks and integration of computational modelling for drug design, as well as advanced drug delivery systems to improve their therapeutic potential. As this field is progressing rapidly, this review attempts to comprehensively analyze the role of heterocyclic moieties in the development of anticancer drugs, the latest advances, and prospects. This study will contribute to ongoing efforts to design more effective and targeted cancer therapies by summarizing key findings and emerging trends.

This comprehensive review critically evaluates the emerging therapeutic potential of small-molecule Trace Amine-Associated Receptor 1 (TAAR-1) agonists as a novel, diseasemodifying strategy for neurodegenerative psychosis. From a medicinal chemistry perspective, we assess Structure-Activity Relationship (SAR) data across a broad spectrum of chemotypes, including thyronamine analogues, pyrimidinone-benzimidazoles, guanfacine derivatives, thiophenedihydropyran (Ulotaront), piperidine-carboxamides, sulfonamides, and biguanides. Our analysis establishes a unified strutural model centered on four essential structural elements, such as (1) a protonatable primary or secondary amine crucial for forming a salt bridge with the conserved Asp103 residue, (2) an aromatic or heteroaromatic core enabling pivotal π-stacking interactions with key hydrophobic residues (Phe186, Phe195, Trp264, Phe267, Phe268), (3) compact, meta-substituted hydrophobic groups (e.g., methyl, chloro, isopropyl) that optimally occupy subpockets defined by Ile104, Ile290, or Val184, and (4) a strong preference for (S)-enantiomers to maximize binding complementarity. The compiled SAR reveals that agonist potency (EC₅₀ values in the nM to μM range) and selectivity are critically dependent on these features, with auxiliary hydrogen-bond acceptors or donors (e.g., near Ser107 or Tyr294) further stabilising the active receptor conformation. Conversely, structural deviations such as ortho-substitution, bulky N-alkylation, or R-enantiomers significantly compromise activity. Strategic bioisosteric replacements, such as methylene bridges and aminoethoxy chains, are highlighted for their role in enhancing metabolic stability. This robust pharmacophore underpins the rational design of advanced clinical candidates like Ulotaront, which demonstrate dual neuroprotective and symptomatic benefits over conventional antipsychotics, offering a clear roadmap for the development of next-generation TAAR-1-targeted therapeutics for complex neuropsychiatric disorders.

The global rise in infectious diseases poses a significant threat to human health, creating an urgent need for novel therapeutic agents capable of effectively managing these conditions. Molecular hybridization has emerged as a promising strategy for designing bioactive compounds with enhanced efficacy. Quercetin, a naturally abundant flavonoid with a well-defined structural framework, offers multiple modification sites that can be exploited to generate hybrid molecules exhibiting diverse biological activities. This review compiles and analyzes research published between 2005 and 2024, focusing on the role of quercetin-based hybrids in disease management. For each study included, details were extracted on chemical structure, synthesis methodology, type of biological activity evaluated, experimental models used, and principal findings. The information was synthesized qualitatively, with particular emphasis on the relationship between structural modifications and biological effects, as well as the therapeutic relevance of these derivatives. Findings from the reviewed literature highlight that quercetin hybrids can target a broad spectrum of diseases, including infectious, inflammatory, and degenerative conditions, as well as various cancers. Structural tailoring of quercetin not only improves its pharmacological properties but also helps overcome limitations such as poor solubility and bioavailability. These insights provide a rational basis for the design of novel quercetin hybrids with specific biological attributes, positioning them as potent, nature-inspired therapeutic candidates for future drug development.

MicroRNAs (miRNAs) are integral to the regulation of gene expression pertinent to cardiovascular health, affecting various biological processes, such as cell adhesion, inflammation, and lipid metabolism. Certain miRNAs (miR-1, miR-133a, miR-133b, miR-208a, etc.) have been associated with a range of cardiovascular disorders, including atherosclerosis, arrhythmias, and myocardial infarction, indicating their potential utility as therapeutic targets and biomarkers. Nevertheless, the therapeutic application of miRNAs is constrained by their inherent instability and suboptimal cellular uptake, which can be attributed to their negative charge and vulnerability to degradation. To mitigate these challenges, a variety of delivery systems have been developed, encompassing both viral vectors (such as adeno-associated viruses, adenoviruses, and lentiviral vectors) and non-viral vectors (including liposomes and polymer nanoparticles). Besides, the integration of nanoparticles, extracellular vesicles, and a hydrogel system can enhance the stability, targeting, and efficiency of miRNA delivery. Furthermore, advanced systems, such as intelligent responsive delivery mechanisms and multifunctional joint delivery systems, are currently under investigation to improve therapeutic outcomes. Notably, studies exploring poly (β-amino esters) as a non-viral gene delivery vector have demonstrated potential in advancing gene therapy for cardiovascular diseases. This article reviews the role of miRNAs in cardiovascular disease pathogenesis and therapy, discusses recent progress in miRNA delivery strategies, and summarizes clinical challenges and highlights the critical need for continuous innovation in delivery systems to enhance treatment efficacy, ensure safety, and facilitate industrial scalability.

The increasing rise of multidrug-resistant bacteria necessitates an urgent need for the discovery of novel antibacterial agents. Natural products have long been a source for identifying and isolating novel antibacterial agents. Anacardic acids (AAs), a phenolic lipid isolated from solventextracted cashew nutshell liquid (CNSL) of Anacardium occidentale (Family Anacardiaceae), have garnered potential attention for their potent antibacterial properties. Besides Anacardium occidentale, different analogues of AAs have also been isolated from various natural sources. These natural and structurally optimized derivatives exhibited potential antibacterial properties against other bacterial strains. Although AAs are associated with a high level of antimicrobial activity against P. acnes, S. mutans, S. pyogenes, H. pylori, and methicillin-resistant S. aureus, their poor physicochemical properties are a major concern for their clinical translation. Encapsulating AAs in nanoformulations could be beneficial, as it can improve their poor pharmacokinetic properties, prevent enzymatic degradation during transport in the body, and facilitate site-specific release, thereby enhancing their therapeutic potential. Among the different nanocarriers studied, zein nanoparticles loaded with anacardic acid showed strong antibiofilm activity against E. faecalis, S. aureus, and P. aeruginosa. In contrast, the DNase-chitosan-coated solid lipid nanoparticles (Ana-SLNs-CH-DNase) demonstrated superior activity in disrupting mature S. aureus biofilms. Additionally, we have discussed the structure-activity relationship and mechanism of action of AAs, where it was found that AAs disrupt cell membrane functioning, inhibit bacterial respiration, quorum sensing, and cellular respiration, among other effects. These findings suggest that AAs and their analogues exhibit promising antibacterial activity, while nanoformulations offer a promising strategy to optimize their therapeutic potential.

Parkinson's Disease (PD) is a neurological disease marked by the buildup of α-synuclein. The main symptom of the disease is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Gene therapy may be a treatment option for PD and has been used in clinical trials to treat a variety of illnesses in the human brain. Currently, the majority of gene therapy clinical studies are being conducted to treat PD. The primary objective is to enhance medications that address motor issues. Patients with PD have been the subjects of several gene therapy treatment techniques that have been developed and tested. Genes are typically transported to neurons in brain regions relevant to PD, such as the striatum, using viral vectors. It may only be necessary to administer these gene delivery methods once, and they may induce expression to persist for an extended time. Several neurotrophic factors, including neurturin, GDNF, BDNF, CDNF, and VEGF-A, have demonstrated promising outcomes in preclinical models as potential disease-modifying targets that may slow disease development. Currently available treatment regimens for PD mostly comprise the administration of levodopa (L-DOPA), dopamine agonists or MAO-B inhibitors, or surgery in the form of deep brain stimulation or neuroablative surgery, among other options. Many different targeting moieties for PD treatment, as well as current treatment techniques and gene therapy methodologies, are covered in this review article. The research reviewed the relevant literature on the potential role of gene therapy for the treatment of PD. The research articles are obtained through various databases, including ScienceDirect, Scopus, PubMed, and Google Scholar. This review includes various targeting moieties for the treatment of PD, current PD treatment strategies, PD treatment using gene therapy, comparison of risk-benefit ratios of gene therapy vs. DBS/drugs, and gene vector technology in the treatment of PD. This review compiles data on Parkinson's disease, its current treatment strategies, and the potential role of gene therapy in its treatment.

Neem gum, a biocompatible and biodegradable polysaccharide, has broad applications in drug delivery and tissue engineering. Its hydrophilic and bioadhesive properties make it ideal for controlled drug release and scaffold fabrication. This review examines the role of neem and its derivatives in pharmaceutical formulations, wound healing, and regenerative medicine, while addressing stability, scalability, and regulatory considerations. Future directions include the integration of nanotechnology and chemical modifications for enhanced biomedical applications. Neem gum has been developed into various forms, including hydrogels, nanoparticles, films, and coatings, for targeted drug delivery and tissue regeneration. Its antimicrobial, antioxidant, and anti-inflammatory properties enhance wound healing and infection control, but challenges like batch variability and mechanical limitations remain. Neem gum is a promising natural biomaterial for pharmaceutical and biomedical applications. Further research on stability, large-scale processing, and clinical validation is essential for commercialisation and clinical use.