Mini Reviews in Medicinal Chemistry - Online First

Luteolin is a naturally occurring flavonoid that exhibits significant potential in mitigating organ fibrosis. This review consolidates evidence from studies demonstrating the antifibrotic effects of luteolin in hepatic, renal, cardiac, pulmonary, dermal, subretinal, and pancreatic fibrosis. Mechanistically, luteolin targets key pathways that drive fibrosis, including the TGF-β/Smad, STAT3, NF-κB, and AMPK signaling pathways, while suppressing oxidative stress, inflammation, and fibroblast activation. In hepatic fibrosis, luteolin inhibits hepatic stellate cell activation, reduces collagen synthesis, and counteracts ferroptosis by modulating the SLC7A11 and GPX4 pathways. Renal fibrosis is alleviated through the regulation of the SIRT1/FOXO3 and AMPK/NLRP3/TGF-β pathways, thereby attenuating ECM accumulation and inflammation. Cardiac benefits arise from luteolin’s modulation of NO-cGMP, AKT/GSK-3, and Nrf2/NF-κB axes, improving myocardial function. Pulmonary fibrosis models highlight the ability of luteolin to inhibit TGF-β1-induced Smad3 phosphorylation and inflammatory cytokine release. Additionally, luteolin demonstrates efficacy in skin and subretinal fibrosis by targeting TGF-β/Smad and YAP/TAZ pathways. Toxicology and pharmacokinetic studies indicate favorable safety profiles. Despite promising preclinical outcomes, clinical data remain scarce. The multi-target engagement, low toxicity, and broad bioactivity of luteolin position it as a compelling candidate for antifibrotic therapy. Further clinical research is warranted to translate these findings into therapeutic applications for fibrotic disorders.

Inflammation is a fundamental biological reaction to harmful stimuli, which is crucial in the initiation and advancement of different diseases, including rheumatoid arthritis, cardiovascular conditions, neurological disorders such as Alzheimer's and Parkinson’s, and multiple cancer types. Chronic inflammation, in particular, contributes to irreversible tissue damage and the progression of disease. Thus, the suppression of key inflammatory mediators has become a promising therapeutic approach. Thromboxane A2 (TxA2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) are among the mediators that have been thoroughly investigated for their roles in regulating immune responses and sustaining inflammation; therefore, targeting these mediators offers substantial therapeutic potential. In recent years, significant attention has been focused on heterocyclic compounds, especially pyridazine and pyridazinone derivatives, owing to their structural diversity and extensive biological activity. These scaffolds have shown significant effectiveness in regulating inflammatory pathways by limiting TxA2 production, reducing TNF-α release, and disrupting IL-6 signaling. This review presents a comprehensive overview of pyridazine and pyridazinone-based compounds as potential anti-inflammatory agents. It highlights both traditional and current synthetic strategies used in their development and explores their mechanisms of action with respect to key inflammatory targets. Additionally, the study examines recent pharmacological assessments and preclinical results, offering insights into the medicinal uses of these substances. A brief perspective on future research directions is also included, emphasizing the need for further structural optimization, in vivo validation, and clinical translation. Collectively, these results highlight the potential of pyridazine and pyridazinone derivatives in the development of advanced anti-inflammatory pharmaceuticals.

Sigma receptors (σRs), comprising σ1 and σ2 subtypes, are versatile pharmacological targets with significant roles in cancer, neurodegeneration, and psychiatric disorders. The tetrahydroisoquinoline (THIQ) scaffold, a core structure in many biologically active compounds, has garnered attention as a versatile platform for designing σRs ligands. THIQ-based compounds exhibit potent σRs binding affinity, leading to therapeutic effects ranging from neuroprotection to antitumor activity. This mini-review explores the structural features of THIQ ligands, their interaction with σRs, and their therapeutic implications. Challenges and future prospects for THIQ derivatives in σRs research are also discussed.

Millions of people worldwide are affected by neurodegenerative disorders (NDs), which include a broad range of clinical ailments that affect the brain or peripheral nervous system, including Alzheimer’s disease (AD), Parkinson's disease (PD), Huntington's disease, etc. Neuronal cell death in NDs is often linked to oxidative stress; thus, antioxidant treatment can combat oxidative cell damage, and this strategy has been studied in neurodegenerative processes. Over the past 10 years, we have witnessed intense research activity on the biological potential of human monoamine oxidase (hMAO) inhibitors that have been associated with the prevention of oxidative stress and inflammation. These inhibitors have emerged as promising therapeutic agents, especially in the treatment of neurodegenerative diseases (NDs), where their core activity may help mitigate disease progression. An overview of the current state of numerous scaffolds, such as chromones, coumarins, chalcones, propargylamines, benzothiazoles, aminoisoquinolines, and the natural compounds, including ferulic acid, resveratrol, and chrysin, which combine antioxidant capability and hMAO inhibition is given in this review, with particular attention given to each scaffold's mechanism of action and structure-activity relationships (SARs), which are thoroughly discussed. Focusing on the dual mechanism of action, combining inhibition and antioxidant properties, as a potential therapy for neurodegenerative diseases, we have reviewed the different chemical classes of multi-target-directed ligand (MTDL) inhibitors developed within this framework. Other central nervous system (CNS)-related enzymes, such as cholinesterases, carbonic anhydrases, and BACE-1, have also been explored as targets in the MTDL strategy. By understanding their biological activity, medicinal chemists can better comprehend biological activity and recommend more effective and specific ND treatments.

O-GlcNAcylation is a non-canonical form of protein glycosylation that occurs in nuclear, cytoplasmic, and mitochondrial proteins among all multicellular eukaryotes. There are only two enzymes that regulate this post-translational modification, one of which is O-GlcNAcase, a glycoside hydrolase that catalyzes the hydrolytic cleavage of O-GlcNAc from protein substrates. Related studies have shown that the reduction of O-GlcNAc levels is closely related to Alzheimer's disease, which is maintained by reducing the aggregation of tau via inhibiting O-GlcNAcase. Various small-molecule O-GlcNAcase inhibitors with different chemical structures have been developed and used as chemical probes to explore the O-GlcNAc pathway. Although many reported inhibitors have shown that O-GlcNAcase activity has single-digit nmol IC50 values in binding assays, and molecules, such as LY-3372689, have entered phase II clinical studies, further exploration of novel O-GlcNAcase inhibitors with higher inhibitory activity and specificity is still worthy of attention. This article reviews the pathogenesis and therapeutic role of O-GlcNAcase in Alzheimer's disease, as well as the recent progress of O-GlcNAcase small molecule inhibitors, including sugar-derived or non-sugar scaffolds, and summarizes the clinical progress and potential prospects of O-GlcNAcase inhibitors.

This review delves into the potential of nanotechnology for improved lung cancer diagnosis and treatment. A critical focus is placed on various overexpressed biomarkers within lung tumors. These biomarkers serve as potential targets for nanoparticle-based drug delivery strategies. The review explores two main targeting approaches: passive and active (receptor-based) targeting. Active targeting mechanisms like EGFR, folic acid, and CD44 receptor targeting are specifically discussed. Additionally, the review examines stimuli-responsive systems for targeted drug delivery, including pH, temperature, ligand-attached, and multi-stimuli-responsive systems. Moreover, the role of nanotechnology in theranostics, which combines therapeutic and diagnostic capabilities, is explored and different types of nanocarriers, including lipid-based, polymer-based, metal-based, and magnetic nanoparticles, are examined for their potential applications. The review also highlights advancements in lung cancer diagnostic techniques beyond nanotechnology. This includes emerging tools like biomarkers, biosensors, and artificial intelligence, alongside improvements to established methods. Finally, the review provides a glimpse into ongoing clinical trials and concludes by emphasizing the transformative potential of nanotechnology in improving lung cancer patient outcomes.

Carbamate has been extensively used as a scaffold in the recent era of drug discovery and is a common structural motif of many approved drugs. The carbamate moiety's unique amide-ester hybrid (-O-CO-NH-) feature offers the designing of specific drug-target interactions. Despite the discovery of numerous carbamate derivatives that act on the endocannabinoid system (ECS), the development of clinically effective carbamates remains a challenge. In this review, we highlight the therapeutic potential of carbamate inhibitors of endocannabinoid degrading enzymes as a breakthrough in discovering neurotherapeutic drugs. We discuss the design strategies and medicinal chemistry aspects involved in developing carbamate-based molecular architectures that modulate the endocannabinoid signaling pathway by interfering with fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and α/β-Hydrolase domain-containing 6 (ABHD6). Additionally, we highlight the dual activity profile of carbamates against FAAH and MAGL, FAAH and cholinesterase, and FAAH and TRPV1 channels. Furthermore, we illustrate the pharmacophores of O-functionalized carbamates and N-cyclic carbamates that are crucial for FAAH and MAGL inhibitory activities, respectively.