Current Topics in Medicinal Chemistry - Volume 25, Issue 28, 2025

Nanomedicine is a rapidly growing field in pharmaceutical science, driven by the enhanced quality of nano-formulations that improve the treatment of various diseases. Nano-sized novel drug delivery techniques for herbal pharmaceuticals have the potential to enhance activity and address concerns related to medicinal plants in the future. Natural chemicals show promise in various neurodegenerative diseases, but their permeability across the blood-brain barrier prevents them from reaching the nervous system. By improving molecular monitoring, synthesis, and diagnostics, pharmaceutical nanotechnology provides improved controlled drug delivery for the treatment of neurodegeneration.

The evaluated and investigated data from recent studies were gathered using Google Scholar as a search engine. We reviewed and analysed research publications from databases like Bentham Science, Elsevier, PubMed, and ScienceDirect, among others, to summarize the findings.

Curcumin, Centella asiatica, thymoquinone, Hypericum perforatum, Panax ginseng, quercetin, piperine, and a variety of other herbs and herbal medicines have all been examined for their potential to aid in the treatment of brain disorders like Alzheimer's disease. To enhance drug bioavailability in the brain, nanoformulations, including phytosomes, transferosomes, ethosomes, and niosomes, have been utilized as pharmaceuticals.

Herbs and herbal medicines have been synthesized into nanoparticle form to enhance tissue distribution, achieve sustained delivery, and protect against physicochemical degradation while also increasing the solubility and bioavailability of poorly soluble herbal products. To overcome physiological complications, researchers must develop lab-scale approaches, characterization methodologies, and targeting tactics for nanoformulations with high translational potential early in product development.

Mitochondria are dynamic organelles essential for energy metabolism and cellular homeostasis, playing critical roles in ATP production, calcium regulation, redox balance, and apoptosis. However, mitochondrial dysfunction is a central factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Given the essential role of mitochondria in neuronal survival, targeted therapeutic strategies that restore mitochondrial function have gained significant attention. This review explores the latest advances in mitochondrial-targeted therapies and their potential applications in neurodegenerative diseases.

A comprehensive literature review was conducted on mitochondrial-targeted therapeutic strategies, with a focus on nanotechnology-based drug delivery systems. The analysis includes various nanoparticle-based approaches, such as liposomes, DQAsomes, and polymeric nanoparticles, which have demonstrated high biocompatibility, controlled drug release, and enhanced mitochondrial targeting efficiency. Additionally, mitochondria-penetrating peptides and delocalized lipophilic cations (DLCs) are discussed for their role in improving drug localization within mitochondria and overcoming biological barriers, including the blood-brain barrier (BBB).

Recent research shows the potential of mitochondrial-targeted antioxidants, peptides, and biocompatible nanocarriers in arranging mitochondrial dysfunction and protecting neurons from oxidative damage. Various nanoparticle-based drug delivery systems have demonstrated the ability to selectively target mitochondria, improving drug bioavailability, therapeutic efficacy, and neuroprotective outcomes in neurodegenerative diseases.

Mitochondria-targeted therapies provide promising avenues for disease-modifying treatments aimed at preserving neuronal integrity and delaying disease progression. The unique properties of nanoparticles, such as their ability to enhance drug stability, facilitate controlled release, and achieve precise mitochondrial localization, make them valuable tools for neurodegenerative disease therapy. Future research should focus on optimizing delivery systems, validating clinical applicability, and exploring interdisciplinary approaches to accelerate translation into effective treatments.

In this study, we report on the synthesis and characterization of new silicon (IV) phthalocyanine compounds (SiPcs) axially substituted with coumarin-linked derivatives, designed for potential application in photodynamic therapy (PDT) due to their photophysical properties.

Characterization was carried out using FT-IR, UV-Vis, MALDI-TOF-MS, and ¹H NMR spectroscopy. In dimethyl sulfoxide (DMSO), the SiPcs produced singlet oxygen with quantum yields of 0.17 to 0.19, assessed by the DPBF quenching method. DNA binding studies via UV-Vis spectroscopy and molecular docking suggested high binding affinities (ΔG⁰ values between -9.90 to -10.4 kcal/mol) and stable interactions with calf thymus DNA (ct-DNA).

The compounds showed promising inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with IC50 values indicating higher potency and selectivity compared to galantamine, a known cholinesterase inhibitor.

The combined singlet oxygen generation, DNA binding, and enzyme inhibition data underscore the potential of these SiPc-coumarin derivatives as multifunctional agents for PDT and neuroprotective applications such as Alzheimer's disease (AD).

CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms.

A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4-arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity.

The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy.

Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders.

The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.

Cellular aging is a complicated event known for gradually reducing homeostasis, leading to a higher susceptibility to diseases and mortality. Since the behavior of Hematopoietic Stem Cells (HSCs) is potentially affected by plasma-derived exosomes, this study aimed to investigate whether the plasma-derived exosome of young and elderly human donors can deliver “youth” or “aging” signals into human umbilical cord blood-derived HSCs in vitro.

Exosomes were isolated from four young (Y-exo) and four old (O-exo) donors. Umbilical cord blood-derived HSCs were exposed to two concentrations of exosomes (5 and 10 μg/mL). Then, lineage differentiation (CD41 and CD38), the mRNA and protein expression of IL-1β and IL-6, and NFκB activity were evaluated using flow cytometry, qRT-PCR Enzyme-Linked Immunosorbent Assay (ELISA) methods, and western blot techniques, respectively.

The lineage-specific markers CD41 and CD38 expression were increased after exposure to O-exo compared to Y-exo at the concentration of 10 μg/mL (P<0.001). The HSCs treated with 10 μg/mL O-exo increased protein and mRNA expression of IL-1β and IL-6 compared to Y-exo at 10 μg/mL concentration (P<0.01). Furthermore, a significant difference was seen in p-NF-κB levels between O-exo and Y-exo at the concentration of 10 μg/mL (P=0.0014).

Our findings advocated the concept that circulating exosomes of old and young individuals may differently affect the pathways involved in the aging process in HSCs.Therefore, exosomes may be applied as therapeutic agents for regenerative medicine.