Mini Reviews in Medicinal Chemistry - Online First

Marine organisms produce a diverse array of secondary metabolites with significant pharmacological potential, particularly in the development of anti-cancer, anti-microbial, anti-fungal, and anti-viral therapies. Despite challenges in isolation and cultivation, marine-derived compounds, such as Didemnin B, Psammaplin A, and Dolastatin, have shown promise in cancer treatment, while other metabolites exhibit potent activity against drug-resistant bacteria, fungi, and viruses. These compounds have excellent potential for treating various infections, for example, MRSA (eicosapentaenoic acid and fridamycin), Candida albicans (aurantoside K), and HIV-1 and HIV-2 (sulfoquinovosyl diacylglycerol). These unique compounds offer new avenues in drug discovery, addressing current limitations in traditional therapies. This review provides an overview of the pharmacological potential of marine organisms, focusing on their applications in overcoming drug resistance and developing novel treatments for cancer, infections, and viral diseases. Sustainable approaches for harvesting these compounds are essential for future research.

The drug discovery process is highly intricate and complex. Driven by unprecedented advances in AI technology, the application of artificial intelligence in drug discovery (AIDD) is showing significant growth, and AIDD has the potential to fundamentally change and revolutionize traditional drug development models in the foreseeable future. We selected 7061 literature studies on artificial intelligence used in drug discovery from the Web of Science Core Collection database from 2000 to 2024, and adopted bibliometric tools, such as Citespace, VOSviewer, and RStudio, to select nodes for knowledge graph generation and visualization analysis by using country, institution, author, and keywords. The results showed that from 2017 to 2024, the literature on the use of artificial intelligence for drug discovery exploded, with the United States having the largest number of papers, and China's number of papers growing rapidly and surpassing the United States in the last two years. Molecular docking, virtual screening, algorithm optimization, interpretable AIDD, protein language modeling, drug targets, and protein interaction prediction were found to be the research hotspots in this field in recent years. AI has been widely used in the field of drug research and development. Based on the quantitative analysis of the literature on the use of artificial intelligence in drug discovery, this paper has revealed the current research status in this field, clarified the current research hotspots and future research trends, and provided certain references for researchers to plan future research directions.

The method of discovering new drugs is costly, time-consuming, laborious, and associated with a high failure rate. Various techniques have been applied in modern drug discovery to resolve these issues and discover novel pharmacologically active agents. Natural products are one of the sources of drugs that have long been used to treat various illnesses. Kojic acid (KA) is a naturally produced bioactive chemical with a 3-hydroxy-4-pyranone skeleton made by numerous aerobic microbes, such as Aspergillus and Penicillium. KA is a potent tyrosinase inhibitor used in cosmetics to lighten skin by reducing hyperpigmentation. In this review, beyond its cosmetic applications, it exhibits versatile biological activities, including anticancer, antibacterial, antifungal, antioxidant, antiviral, anti-inflammatory, anticonvulsant, anti-Alzheimer's disease, antidiabetic, and metal-chelating properties. KA and its analogs have been reported as promising radioprotective agents capable of mitigating the harmful effects of ionizing radiation. By integrating KA with pharmacologically active scaffolds, researchers have developed potent hybrids, such as amino-chloroquinoline-KA derivatives, which demonstrate vigorous β-hematin inhibitory activity and significant efficacy against both delicate and resilient strains of P. falciparum to chloroquine. The approach taken to prepare this review article involved collecting, assessing, and synthesizing relevant literature from different databases. This review systematically explores the comprehensive therapeutic potential of KA and its derivatives, including Mannich base, thiazoles, and 1,2,3-triazoles, for various activities, with Michael Adducts and dinuclear ruthenium complexes which exhibits promising antitumor activity. Combining current knowledge will provide a comprehensive foundation for the rational design and development of clinically relevant agents based on KA pharmacophores.

In the ongoing battle between the immune system and cancer, a unique subset of T cells has quietly emerged as a key player. Tissue-Resident Memory T (TRM) cells, strategically positioned within tissues, are redefining our understanding of localized immune defense and tumor control. This review aims to bridge this knowledge gap by synthesizing current concepts of T cell immune surveillance with foundational aspects of TRM cell biology. We explored clinical evidence supporting the prognostic and therapeutic relevance of TRM cells in various cancer contexts, including their emerging roles in enhancing responses to immunotherapy. Furthermore, we discussed innovative strategies that exploit TRM-phenotype cells for patient stratification, disease staging, and therapeutic development. Key challenges such as the absence of standardized T cell nomenclature and the limited understanding of how TRM markers relate to tumor biology are critically examined. By integrating basic science and clinical observations, this review provides a comprehensive overview of the field and highlights promising avenues for future research to harness TRM cells in precision oncology.

Since its discovery in 1979, the tumor suppressor p53 has been widely studied and expressed in various organisms, including yeast. Yeast has proven to be a very informative model and an effective system for studying the roles and functions of this protein and gene. This review is a compilation of our team's studies involving p53 expression in yeast. These researches investigated certain aspects, essentially the apoptotic function of p53. Our main contribution to the study and understanding of the p53 gene in the yeast context is the confirmation of a negative effect of p53 on cell growth in both Saccharomyces cerevisiae and Pichia pastoris strains, which ultimately led to apoptotic cell death. This involves a high dose of p53 and the NLS signal, which enables p53 to target both the mitochondria and the nucleus. Prior to that, obtaining the whole protein required a cDNA without its UTR. Thus, a yeast model was developed, allowing verification of p53 activity. Cancer mutants and their revertants could thereby be assessed. This has evolved into a real antioxidant/anti-apoptotic molecular screening mechanism. Two primary applications were achieved: testing the co-expression with the thioredoxin 2 gene (TRX2) and assessing the impact of Nigella sativa seed extracts. Furthermore, the high yield of yeast P53 production allowed its use in serological cancer diagnosis.

Fragment-based drug discovery (FBDD) has emerged as a transformative strategy in modern medicinal chemistry, offering a rational and efficient alternative to traditional high-throughput screening (HTS). By utilizing small, low-molecular-weight fragments with moderate binding affinity, FBDD enables systematic optimization into potent lead compounds with improved physicochemical properties. Its modular and ligand-centric nature has proven particularly advantageous in accelerating early-stage drug discovery. The COVID-19 pandemic highlighted the adaptability of FBDD, as fragment screening and computational modeling rapidly identified inhibitors of the SARS-CoV-2 main protease (M^pro). Integration with artificial intelligence (AI) and cloud-based platforms further enhanced the speed and global accessibility of fragment campaigns, setting a precedent for collaborative, open-science initiatives. Beyond infectious diseases, FBDD has demonstrated significant promise in oncology, antibacterial therapy, and neurodegenerative disorders, reflecting its versatility across diverse therapeutic landscapes. Recent technological advances have expanded the scope of FBDD. High-resolution cryo-electron microscopy and AI-driven structural prediction now enable the exploration of previously inaccessible or dynamic protein targets. Emerging modalities, such as PROTACs and RNA-targeted therapeutics, also intersect with fragment-based strategies, opening avenues for addressing so-called “undruggable” proteins. Despite persistent challenges, including the need for sensitive biophysical methods and sophisticated infrastructure, the approach continues to evolve. Looking ahead, the convergence of FBDD with machine learning, open-access fragment libraries, and global research collaboration positions it as a scalable, adaptive platform for drug discovery. As future health threats demand rapid innovation, FBDD is poised to remain a cornerstone of both academic and industrial research pipelines.

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 intelligence-driven 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.

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.

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.

Stress granules (SGs) are membraneless cytoplasmic condensates formed through liquid-liquid phase separation (LLPS) in response to diverse cellular stressors. These dynamic macromolecular complexes serve as critical signaling hubs that orchestrate adaptive responses by sequestering translationally stalled mRNAs, RNA-binding proteins, and key signaling molecules. Substantial evidence implicates SGs in the pathogenesis of numerous disorders, where they dysregulate essential cellular pathways, including stress-induced cell death cascades. While regulated cell death constitutes a physiological process vital for tissue homeostasis, aberrant or excessive cell death represents a pathogenic driver in neurodegeneration, ischemic injuries, autoimmune disorders, infectious diseases, and oncological pathologies. Consequently, deciphering the molecular governance of cell death holds great potential for developing novel therapeutics. Although proteomic analyses reveal that SGs sequester multiple cell death regulators, the precise mechanisms through which these components modulate death pathways remain incompletely resolved. This review systematically examines the causal relationships between SGs dynamics and major cell death modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis. By synthesizing recent advances in SG biology and cell death regulation, we elucidate how stress-adapted SG proteomes functionally contribute to death pathway activation or suppression. This mechanistic synthesis not only resolves current controversies regarding SGs’ function in different cell death models but also identifies targetable vulnerabilities at the SGs-death pathway interface, offering innovative frameworks for treating SGs-associated pathologies.

Anthelmintic resistance in livestock is an escalating global concern, as synthetic anthelmintics tend to lose their efficacy within 2–10 years of their routine usage. This rapid development of resistance results in significant economic losses and threatens the sustainability of livestock production systems. Gastrointestinal (GI) parasitism, a primary health challenge in ruminants, significantly impairs productivity, fertility, and overall animal welfare. Environmental factors such as high humidity, temperature fluctuations, and poor management practices further predispose animals to certain parasitic infections. In recent years, the search for alternative solutions has led to a growing interest in plant-derived anthelmintics. These botanical compounds, rich in bioactive phytochemicals, offer a promising and eco-friendly approach to controlling parasites by targeting their metabolism, reproduction, and structural integrity. Unlike synthetic drugs, herbal anthelmintics are often associated with fewer side effects, reduced toxicity, and a lower risk of developing possible resistance. Several medicinal plants, such as Azadirachta indica, Allium sativum, Artemisia absinthium, and Fumaria parviflora, have demonstrated potent anthelmintic properties in both in vitro and in vivo studies.

Furthermore, synergistic effects among multiple phytochemicals can enhance efficacy and broaden the spectrum of activity against diverse helminths. This review highlights the efficacy, mechanisms of action, and practical applications of herbal remedies in controlling parasitic infections in ruminants. Emphasizing the integration of natural remedies into sustainable livestock health programs, this approach holds great potential to reduce reliance on synthetic drugs while improving animal health, productivity, and farm profitability.

Lung cancer remains a significant contributor to cancer mortality for several reasons. First, lung cancer is a molecularly heterogeneous disease. When combined with the dramatic resistance to treatment mediated by a tumor microenvironment (TME) that is inherently immunosuppressive, this explains the continued high mortality associated with lung cancer. The new era of treating non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), as well as achieving long-lasting treatment responses, is driven by immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4. This treatment revolution may, in the future, be applied to isolated cases of relapse and recurrent disease, resulting in sustained therapeutic responses.

In this review, we outline recent advances, including novel agent combinations and combination regimens tested in clinical trials that have become milestones, such as Nivolumab, Pembrolizumab, Durvalumab, and emerging bispecific combinations. Targeted therapeutic delivery is now possible through nanotechnology and biomaterials, such as polymer nanoparticles and smart hydrogels, which allow high local drug concentration at the tumor site while reducing systemic toxicity.

Predictive biomarkers, including PD-L1 expression, tumor mutational burden (TMB), circulating tumor DNA (ctDNA), and radiomic features, are increasingly used to select patients and assess treatment responses in real time. Despite these advances, resistance to immunotherapy and immune-related adverse events (irAEs) remain major challenges, emphasizing the need for ongoing innovation in personalized management, toxicity mitigation, and treatment strategies.

Industry leaders are now exploring artificial intelligence to optimize treatment selection and predict adverse events and outcomes early. Ultimately, improved survival rates and enhanced patient experiences may be achieved through the integration of novel biomarkers, precision technologies, and more effective immunotherapies for lung cancer patients. Significant research is still required to overcome resistance mechanisms, optimize combination therapies, and enable individualized care in this rapidly advancing field.

Despite recent advances in both preclinical and clinical cancer therapies, the growing problem of treatment resistance remains one of the most critical challenges in oncology. To overcome the drawbacks of current oncologic treatments, there is a pressing need for new approaches and potential therapeutic strategies. The interaction between the host microbiome and cancer has recently attracted significant research. Among the various routes of microbiome-cancer interaction, microbiome-derived exosomes also offer an intriguing avenue. Exosomes, which are small extracellular vesicles, originate from several distinct types of cells, including microbiome-associated cells. These vesicles participate in intra- and intercellular communication as well as alteration of the tumour microenvironment. Emphasising their possible functions as treatment response modifiers and mediators, this review seeks to explain an intricate link between cancer therapy resistance and exosomes produced from the microbiome. Preclinical studies reveal that microbiome-derived exosomes operate through horizontal transfer of resistance-conferring enzymes and TLR4/MYD88-dependent signalling, demonstrating 2-5 fold upregulation of resistance-associated miRNAs in drug-resistant models. Clinical evidence shows Akkermansia muciniphila improves anti-PD-1 immunotherapy outcomes. Fusobacterium nucleatum-derived vesicles promote oxaliplatin resistance through autophagy activation. We investigate how microbiota-derived exosomes might leverage resistance to conventional cancer treatments and their consequences for these treatments. However, limitations include inter-individual microbiome variability, challenging isolation protocols, and regulatory hurdles under FDA guidelines. We examine the possible applications of microbiome-derived exosomes as therapeutic and diagnostic tools, thereby reflecting the applicability of these findings in clinical practice. This offers an interesting path for new therapeutic approaches meant to solve treatment resistance and raise patient survival.

Neurological disorders (NDs) are diseases that arise due to deformities mainly in the central nervous system (CNS) and also affect the nerves throughout the human body. NDs, including Alzheimer’s disease (AD), Parkinson′s disease (PD), Multiple Sclerosis (MS), and a variety of brain malignancies, pose a major healthcare challenge and are the main cause of mortality on the global scale. There are very limited treatment options for the majority of the NDs, and the currently available drugs commonly fail to penetrate the BBB and deliver the drug to the target effectively. These challenges have necessitated the advent of new drug delivery methods that can cross the BBB with ease and deliver the drug by accurately targeting the diseased area in a safe and biocompatible manner. Nanoparticle-based drug delivery strategies offer significant advantages in BBB penetration and drug delivery due to their unique properties. Carbon dots, among nanoparticles with a size below 10 nm, are highly biocompatible, fluorescent molecules that offer ease of functionalization, drug conjugation, and effective detection within biological systems. The literature is rich in reviews on the synthesis, characterization, and application of CDs. However, a review specifically focused on the therapeutic potential of CDs in major NDs is missing. This review aims to fill that gap by presenting a detailed account of the carbon dot-based therapeutic approaches in the treatment of major NDs. It briefly discusses the properties of CDs, the main routes of synthesis, major raw materials, and key synthesis parameters that affect their properties, while placing a greater emphasis on their therapeutic potential. The review provides a detailed assessment of literature from the past 15 years on the development and current challenges in the application of CDs as therapeutic and drug delivery agents. Our analysis reveals that limited research has been conducted on CD-based therapeutics in NDs, particularly in MS and brain tumors, where original research is scarce. This review article highlights the major developments in the therapeutic uses of carbon dots in NDs, addresses a critical research gap, and provides a comprehensive overview of various studies related to carbon-dot-based therapeutic approaches for major NDs.

Mitochondria, commonly termed the 'cellular powerhouse', produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In addition to their role in energy synthesis, mitochondria are crucial for maintaining calcium homeostasis, mediating cellular signaling, regulating cell proliferation and apoptosis, and supporting various other physiological processes. In recent years, mitochondria have gained prominence as a critical target for the treatment of metabolic disorders. Research has demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of metabolic diseases, such as insulin resistance, diabetes, metabolic syndrome, cardiovascular diseases, and endocrine tumors. Consequently, understanding the mechanisms of mitochondrial homeostatic imbalance and developing mitochondria-targeted therapeutics hold promise for innovative treatments of metabolic disorder-related diseases. This article seeks to elucidate recent advancements in the understanding of mitochondrial dysfunction's role in metabolic diseases and offers a comprehensive overview of current therapeutic strategies and approaches for addressing this dysfunction.

Individuals diagnosed with inflammatory bowel disease (IBD) face a significantly heightened risk of developing colorectal cancer (CRC), primarily due to persistent intestinal inflammation that fosters neoplastic transformations across the colon. This narrative review delves into the potential of certain fruits, such as black raspberries, Amazonian açaí, apples, grapes, cocoa, Ziziphus jujuba, and Moringa oleifera, in mitigating IBD-induced CRC. Preclinical studies indicate that these fruits possess anti-inflammatory and antioxidant properties that may disrupt carcinogenic pathways. Notably, black raspberries have demonstrated the ability to modulate epigenetic markers by demethylating tumor suppressor genes and inhibiting DNA methyltransferases (DNMT), like DNMT1 and DNMT3B. This epigenetic modulation influences the Wnt signaling pathway, crucial in CRC development, and affects cellular processes, such as proliferation, apoptosis, and angiogenesis. Animal models further support these findings, showing that black raspberries can suppress β-catenin signaling, reduce chronic inflammation, and decrease tumor incidence. This comprehensive analysis underscores the promising role of specific fruits in CRC prevention among IBD patients and highlights the need for further research to translate these findings into clinical applications, potentially benefiting both public health and the nutraceutical industry.

In the management of solid tumors, ionizing radiation is a critical therapeutic modality, particularly when surgical intervention is impractical due to patient-related factors, such as compromised health or elevated mortality risk. However, its non-selective action can cause serious side effects that negate the therapeutic benefits. Efforts have thus been made to identify pharmacological agents that can selectively protect normal tissues from exposure to ionizing radiation. Seven decades of study, however, have shown that the desired success has not been achieved in obtaining an ideal radioprotective agent. Moreover, even at optimal doses, the FDA-approved drug, amifostine (also known as WR-2721 [S-2- (3-aminopropyl-amino) ethyl phosphorothioic acid], exhibits significant toxicity. An ideal radioprotective agent can also be beneficial in environments where individuals are exposed to prolonged, low-dose radiation. Considering this, there is a pressing need to develop methods of shielding cells and patients from the deleterious effects of radiation, and a non-toxic radioprotective drug can be useful in both clinical and occupational contexts. Studies have shown that the fruits of Emblica officinalis and its cardinal phytochemicals, such as gallic acid, ellagic acid, quercetin, geraniin, corilagin, and kaempferol, have been demonstrated to mitigate radiation-induced side effects. Research has also demonstrated that fruits can reduce the severity of radiation-induced mucositis in head and neck cancer patients undergoing curative treatment. Currently, there are no clinically effective non-toxic medications that are beneficial in mitigating radiation-induced ill effects. In lieu of this, for the first time, this review compiles the positive effects of fruits, phytochemicals, and their byproducts, chyawanprash and triphala, on radiation-induced damage, the mechanisms by which these effects occur, and the gaps that must be filled in order for future research to help people and the agricultural and nutraceutical industries.