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Mini Reviews in Medicinal Chemistry - Volume 25, Issue 19, 2025

Volume 25, Issue 19

Volume 25, Issue 19, 2025

    • Small Molecule Influenza Virus Fusion Inhibitors Targeting Viral Hemagglutinin: Chemical Insights and Antiviral Evaluation

      https://doi.org/10.2174/0113895575401074250923075239

      Influenza viruses are major human pathogens that cause widespread respiratory infections, affecting millions of people globally and contributing to significant morbidity and mortality. Several currently available anti-influenza drugs are facing increasing levels of viral resistance. Therefore, the discovery of therapeutics targeting novel mechanisms of action is becoming increasingly important. A key viral protein involved in the infection process is the envelope glycoprotein Hemagglutinin (HA), which facilitates both host cell receptor binding and membrane fusion, two essential steps required for viral entry and replication. Due to its central role in the early stages of infection, HA has emerged as a highly promising target for antiviral drug development. Many small-molecule HA inhibitors have been identified with potential anti-influenza activity by stabilizing the HA structure and preventing its conformational change during the membrane fusion process. This review presents a detailed chemical evaluation of these HA-targeting compounds based on studies reported in the literature, highlighting their core chemical scaffolds and structural features. The antiviral efficacy of these compounds is discussed based on and data, along with insights into their mechanisms of action. A comprehensive literature search was conducted, and studies meeting the predefined inclusion criteria were thoroughly reviewed. By focusing on the chemical structure of these inhibitors, this review provides information for the rational design of new therapeutic agents aimed at preventing or limiting influenza virus infections.

    • Synthesis and Biological Properties of Isatin-indole Hybrids: A Review

      https://doi.org/10.2174/0113895575407443250919042610
      Introduction

      Isatin (1-indole-2,3-dione) and indole are versatile scaffolds with diverse pharmacological activities, including antimicrobial, anticancer, antiviral, anticonvulsant, anti-inflammatory, and analgesic effects. Isatin-indole hybrids have emerged as multifunctional agents with significant potential in drug discovery.

      Methods

      A literature survey (2010-2025) across major databases (PubMed, Google Scholar, ACS, ) included reports on synthesis, biological evaluation, and structure–activity relationship (SAR) analysis.

      Results

      Numerous synthetic approaches, including both conventional and green methods, have yielded a diverse range of isatin-indole derivatives. Many exhibited potent antimicrobial, anticancer, antioxidant, and antitubercular activities, with SAR studies highlighting the impact of substitution patterns on activity and selectivity.

      Discussion

      This review aims to provide a comprehensive overview of hybrid molecules in which the isatin core is covalently linked to an indole scaffold. It focuses on their synthesis, diverse biological activities and structure-activity relationship (SAR) studies from 2001 onwards.

      Conclusion

      This review provides a concise summary of the latest developments and future outlook for the therapeutic potential of isatin-indole hybrids in the development of potent bioactive drugs.

    • Breaking Barriers in Breast Cancer: Multi-Targeted Therapeutic Insights

      https://doi.org/10.2174/0113895575409206250918080644
      Introduction

      Breast cancer accounts for one of the leading causes of cancer deaths in women globally. Breast cancer is characterized by molecular heterogeneity, and different patients show various responses to therapy. In addition to hormone therapies, there are targeted agents and immunotherapies, but resistance to therapy and recurrence remain a critical clinical problem for patients.

      Methods

      This review is aimed at presenting innovations in multi-targeted therapies against breast cancer. It also includes an understanding of the biological mechanisms in pathways of this disease in relation to these agents to address treatment failure. The molecular pathways examined are ER, HER2, EGFR, VEGFR, PI3K/AKT/mTOR, MAPK, PARP, and CDK4/6. Additionally, KAT6A is identified as a molecular target along with new clinical agents that are being reviewed, as well as combinations of strategies using molecular profiling and pathology reports.

      Results

      The major signaling pathways that control breast cancer progression and resistance, and/or sensitivity to therapy. KAT6A, a histone acetylase, was amplified in all of the ER+ breast cancers, suggesting that it can be used as a biomarker for assessing the effectiveness of CDK4/6 inhibitors and is an epigenetic therapeutic target in mammary cell lines. KAT6A is being developed as a selective KAT6 inhibitor; however, it seems most benefits may come from additional inhibitors of Menin, which could help overcome endocrine therapeutic resistance. We also reviewed CDK4/6 Mutations and resistance invariably associated with palbociclib, as well as immunotherapy with antibody-drug conjugate, including trastuzumab deruxtecan (DS-8201).

      Discussion

      Multi-pathway targeting holds promise to overcome shortcomings of current monotherapies. Due to the complexity of the breast cancer molecular landscape, we must plan for and potentially target resistance mechanisms. The use of KAT6A as a biomarker, along with the use of novel inhibitors, may help inform treatment decisions and improve outcomes. Additionally, this review has identified the need to position the surveillance and addressing of our resistance mechanisms for current therapies, like CDK4/6 inhibitors and antibody-drug conjugates, rationalized combinations.

      Conclusion

      The future of breast cancer therapy lies in combination strategies that are developed molecular profiling and guided by resistance biomarkers. Integrative, biomarker-driven treatment approaches will provide a rationalized and likely more effective means of treating advanced and refractory breast cancer in our effort to improve patient outcomes in a targeted and personalized approach.

    • Chalcones as Emerging Antibacterial Scaffolds: A Mini Review

      https://doi.org/10.2174/0113895575414987250918162246

      The mounting threat of antimicrobial resistance has intensified the global search for novel antibacterial agents, and chalcones - the aromatic ketones characterized by an α, β-unsaturated carbonyl system has emerged as promising scaffolds against the threat of antimicrobial resistance. This review presents a detailed exploration of chalcones as potent antibacterial agents, emphasizing their structural versatility, mechanisms of action, and therapeutic potential. With a modular backbone that supports diverse substitutions and heterocyclic extensions, chalcones can be easily synthesized and chemically optimized to target a broad spectrum of bacterial pathogens, including multidrug-resistant strains such as MRSA and VRE. Mechanistically, chalcones exert antibacterial effects through multiple pathways, like disrupting bacterial membranes, inhibiting cell wall biosynthesis, interfering with DNA replication DNA gyrase and topoisomerase IV, and suppressing protein synthesis. Their amphipathic nature and ability to bind critical bacterial enzymes offer an advantage in circumventing classical resistance mechanisms. Structure-activity relationships and computational studies have further elucidated the influence of electron-donating and electron-withdrawing groups, positional isomerism, and heterocyclic integration on antibacterial potency. A review of recent literature underlines the efficacy of chalcone derivatives against Gram-positive and Gram-negative strains, with many compounds demonstrating promising activity, such as compound 85 with MIC 3.4 nM against Ciprofloxacin with MIC 4.7 nM. The review also highlights advancements in green synthesis, QSAR modeling, and molecular docking, which collectively facilitate the rational design of next-generation chalcone-based antibacterials. Altogether, chalcones represent a structurally simple yet biologically robust class of compounds, offering significant promise as adaptable and effective agents in the evolving landscape of antimicrobial therapy.

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