Mini reviews in medicinal chemistry最新文献

Natural products (NPs) have long served as a rich inspirational source for drug discovery and development, offering diverse chemical structures and biological activities. Among these, topsentin, a marine alkaloid derived from marine sponges, has emerged as a promising scaffold due to its remarkable pharmacological properties and structural versatility. This review explores the significance of topsentin and its derivatives in drug discovery efforts. It discusses the diverse biological activities of topsentin and its analogs, including anticancer, antimicrobial, anti-inflammatory, and antiviral properties, highlighting their potential therapeutic applications. Moreover, it also focuses on the structural features of topsentin that contribute to its pharmacological profile, emphasizing its importance in the design and development of novel therapeutic agents. Structural modifications and synthetic strategies employed to enhance the pharmacological properties of topsentin derivatives are also discussed. Overall, this review underscores the significance of topsentin as a promising scaffold in drug discovery.

Benzimidazole and its derivatives have been extensively investigated for their antifungal activity, playing a crucial role in drug development. Initially, known for their agricultural applications, these compounds have evolved into significant therapeutic agents in medical mycology. The antifungal activity of benzimidazole was first identified in fungicides used in agriculture, especially for the management of fungal diseases in crops. Over time, its mode of action, mainly acting on fungal microtubules, led to its application in veterinary and human medicine. Early preclinical studies demonstrated effectiveness against dermatophytes and systemic fungal infections, paving the way for further research. Modern benzimidazole derivatives have been structurally modified to improve their antifungal activity, bioavailability, and safety profile. These compounds are now used to treat fungal infections in both clinical and agricultural applications. However, challenges, such as resistance development and toxicity concerns, have made it imperative to continue research to maximize their therapeutic value. Benzimidazole remains a cornerstone in antifungal drug development, and its earlier and current applications reinforce its relevance. Medicinal chemistry and pharmacology must move forward to overcome the limitations and expand their clinical utility. This review analyzes past discoveries and current advancements, offering insight into the future trajectory of benzimidazole-based antifungal therapy.

Introduction: Poly (ADP-ribose) polymerase (PARP) regulates transcription, replication, DNA repair, and the cell cycle. This study examines the multiple functions of PARP beyond DNA repair, including its role in immunological modulation, chemokine signaling, and the regulation of gene expression, particularly during angiogenesis and the epithelial-to-mesenchymal transition.

Methods: PARP inhibitors are approved for treating malignancies by targeting vulnerabilities associated with homologous recombination (HR) insufficiency, such as that caused by BRCA1/2 malfunction. By contrasting the "double-strand break (DSB)" and "single-stranded DNA (ssDNA) gap" models of synthetic lethality, PARP inhibitors are used to treat BRCA1/2-deficient cancers. We examine how ssDNA gaps and DNA polymerase theta (POLθ) interact to influence treatment outcomes.

Results: This review highlights that advanced research is required to bridge the gap between laboratory models and real-world scenarios, focusing on the therapeutic implications of PARP1 efficacy and resistance mechanisms in BRCA-mutated cancers.

Conclusion: With an emphasis on specific metastatic sites and PARP-selective inhibitors, we conclude by highlighting recent clinical developments in PARP inhibitors for the prevention and treatment of distant metastases. Because of their promising results in preventing metastatic cancer, PARP inhibitors may be used more frequently in the early stages of cancer.

Fragment-based drug discovery (FBDD) has emerged as a transformative strategy in modern medicinal chemistry, offering a rational and efficient alternative to traditional highthroughput 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 (Mpro). 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.

Cancer remains a major global health concern that demands the development of novel strategies for early identification, accurate treatment, and continuous monitoring of therapeutic outcomes. The search for new approaches to cancer management has led to the emergence of an exciting multidisciplinary field that integrates biotechnology, medicine, and nanotechnology. Biosensors- devices that convert biological responses into quantifiable signals-have undergone significant advancements through innovations in nanotechnology, biochemistry, and engineering. These developments have improved their sensitivity and specificity for detecting cancer biomarkers, making them essential not only for early diagnosis but also for guiding personalized treatment strategies and ultimately improving patient outcomes. This review provides a comprehensive overview of biosensors, beginning with their historical development and fundamental principles, including mechanisms and key components. Various biosensor types, such as electrochemical, optical, mass-based, piezoelectric, thermal, magnetic, and plasmonic sensors, are discussed in detail, highlighting their roles in cancer detection. The integration of biomarkers into biosensing for cancer diagnostics and theranostic applications is examined, with emphasis on recent advancements in transdermal and imaging-based biosensors. Additionally, the challenges associated with biosensor technology-including sensitivity, specificity, reproducibility, and clinical translation-are addressed. The review concludes with future perspectives, focusing on innovations such as AI-driven biosensing, nanomaterial-based enhancements, and the potential for personalized cancer diagnostics. Overall, this work aims to provide a holistic understanding of biosensor applications in oncology while identifying key areas for further research and development.

The increasing prevalence of diabetes-associated cognitive dysfunction (DACD), driven by accelerated aging and unhealthy lifestyles, poses a significant global public health challenge. The current understanding of DACD pathogenesis remains incomplete, and effective interventions are lacking, underscoring the urgent need to elucidate its mechanisms and develop targeted therapies. Recent studies highlight bitter compounds as promising multifunctional agents due to their welldocumented metabolic regulation, neuroprotection, broad availability, and established safety in the management of diabetes mellitus (DM). This review outlines established mechanisms of pathogenicity in DACD and summarizes the pharmacological effects of bitter compounds. These effects include anti-inflammatory actions, reduced oxidative stress, and improvements in mitochondrial dysfunction. Bitter compounds can also lower blood glucose levels, reduce advanced glycation end products (AGEs), and increase insulin sensitivity. Additionally, they modulate gastrointestinal hormones and the gut microbiota, contributing to metabolic regulation and neuroprotection. By decreasing amyloid-beta (Aβ) deposition and inhibiting tau hyperphosphorylation, bitter compounds address metabolic and memory impairments associated with DACD. Despite their potential, challenges such as low bioavailability, target specificity, and interspecies variability hinder their clinical translation. Future research should prioritize interdisciplinary collaboration, advanced delivery systems (e.g., nanocarriers), and rigorous preclinical/ clinical validation to optimize therapeutic efficacy. This work provides critical insights into the use of bitter compounds as novel candidates for DACD prevention and treatment.

Antimicrobial peptides are tiny molecular polypeptides that help living things fight off foreign microbes. According to recent studies, they come from a wide range of sources and can be found in a wide range of creatures, including microbes, plants, and animals. The method of action has the ability to act on intracellular targets in addition to the traditional membrane permeability mechanism. In terms of technology, antimicrobial peptides offer special benefits. They may successfully suppress a range of bacteria in the antibacterial area and are anticipated to address the issue of drug-resistant bacteria. Antiviral medications, such as those that block the herpes virus or influenza, are predicted to become a new generation of antiviral medications when they can precisely target cancer cells without harming healthy cells. This holds enormous promise for the field of biological medicine. However, it also faces problems such as production, safety, and activity retention, which limit its further development and large-scale application. The introduction of non-natural amino acids can address this issue because the natural antibacterial peptide is easily degraded by the protease. In addition, by introducing non-natural amino acids with special structures and properties, not only can the interaction between AMP and a target be optimized, but also the functional range of AMP can be expanded, and diversified innovation of functions is realized. This study primarily examined the use of non-natural amino acids in the creation of antimicrobial peptides. By exploiting the unique properties of these amino acids, we address current limitations of antimicrobial peptides and provide theoretical guidance for their further development and broad application.

Introduction: Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex, affects nearly 10 million people annually and remains the second-deadliest infectious disease after HIV/AIDS. The rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains has reduced the efficacy of existing therapies, underscoring the urgent need for novel therapeutic scaffolds. Coumarins, naturally occurring oxygenated heterocycles with diverse pharmacological activities, have emerged as promising candidates for anti-TB drug discovery due to their structural versatility.

Methods: A systematic search was conducted in Scopus, Web of Science, PubMed, Google Scholar, Scielo, and ScienceDirect using terms such as "coumarin anti-tuberculosis," "coumarin MIC," and "coumarin derivatives Mycobacterium." Eligible studies included natural, semi-synthetic, and synthetic coumarin derivatives with structural characterization, drug-likeness, and ADME-Tox compliance. In vitro studies focused on standard and resistant M. tuberculosis strains, while in vivo data were included from healthy animal models under ethical conditions. Clinical studies were considered for adults with confirmed pulmonary TB. Exclusion criteria encompassed unstable, toxic, and poorly soluble compounds, non-compliant animal models, and patients with significant comorbidities or treatment non-adherence.

Results: Natural coumarins such as scopoletin (MIC: 42 μg/mL) and indicanine B (MIC: 18.5 μg/mL) demonstrated moderate inhibition, while ferulenol and murralonginol derivatives showed weaker activity. Semi-synthetic modifications produced moderate improvements in potency, whereas synthetic conjugates exhibited the strongest effects. Coumarin-oxime (MIC: 0.04 μg/mL), pyrimidine (0.05 μg/mL), and thiazoline derivatives (0.09 μg/mL) surpassed isoniazid in vitro. Structural features such as oxime groups, triazole linkages, and halogen or methyl substitutions were associated with enhanced efficacy.

Discussion: These findings highlight coumarins as valuable scaffolds for novel anti-TB agents. SAR insights provide a roadmap for rational drug design, although limited in vivo and clinical evidence necessitates further validation.

Conclusion: Coumarin derivatives, particularly synthetically optimized conjugates, exhibit potent anti-TB activity and represent a promising platform for combating MDR- and XDR-TB.

Introduction: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

Methods: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

Results: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

Discussion: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

Conclusion: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.

Alzheimer's disease (AD) is a complex and progressive brain disorder marked by memory loss, cognitive decline, and behavioral changes. One of its defining features is the build-up of amyloid plaques, clumps of β-amyloid (Aβ) peptides, in the brain, along with the formation of neurofibrillary tangles. These Aβ peptides are generated when the amyloid precursor protein (APP) is cleaved by enzymes, with β-secretase (BACE1) playing a key role in the first step of this process. Because BACE1 starts the cascade that leads to harmful Aβ build-up, it has become an important target in the search for effective Alzheimer's treatments. As Aβ accumulates in neurons, it disrupts communication between brain cells and triggers oxidative stress, which worsens damage and accelerates disease progression. This is often exacerbated by imbalances in metal ions, such as copper and iron. While tacrine, an early acetylcholinesterase inhibitor, has shown benefits in managing AD symptoms, its limitations have led researchers to explore improved versions. One promising direction is the development of tacrine-based hybrid molecules. By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease.