Drug Development Research最新文献

Although the incidence of Alzheimer's disease increases with age, the number of effective drugs in the fight against this disease remains insufficient. In this regard, a new series of hydrazide-hydrazone derivative compounds (3a-3n) was synthesized and their structures were elucidated using spectral techniques. Then, all compounds were tested for their in vitro antioxidant and anticholinesterase activities. Compound 3i was found to have the highest antioxidant activity in the series with 63.750 ± 0.033 µM and 44.210 ± 0.058 µM SC₅₀ values in the DPPH and ABTS methods, respectively. Compound 3i exhibited significantly higher inhibitory properties than the reference standard donepezil with IC₅₀ values of 1.850 ± 0.013 µM and 3.680 ± 0.034 µM against AChE and BChE enzymes, respectively. The cytotoxicity and AChE inhibition potential of the compounds on the SH-SY5Y cell line were also evaluated. Compounds 3i and 3l were found to have the highest AChE inhibition (81.03 ± 2.05% and 83.84 ± 2.46%) in SH-SY5Y cells, respectively. Compound 3l also maintained cell viability at 100 µM concentration. The most active compounds in the series were investigated as competitive or noncompetitive inhibitors against AChE and BChE by enzyme kinetic studies. Moreover, molecular docking and MD simulation studies were used to describe the enzyme-ligand interactions and their stability.

Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains unclear. In this study, we investigated the protective effects and mechanisms of baicalin in ICH using an ICH mouse model. ICH mouse model was established by injection of collagenase type IV into intracranial in C57BL/6 mice. Neurological function was evaluated by neurological severity scores and the rotarod test. Hemorrhagic foci of brain was evaluated by TTC and hematoxylin−eosin staining. Iron ion deposition in brain was detected by Prussian blue staining. Ferroptosis was evaluated by measuring expression of FTH-1, SLC7A11, GPX4, and TFRC, as well as detecting iron content and levels of glutathione (GSH) and malondialdehyde (MDA). GPX4 expression and apoptosis of brain were detected by immunofluorescence staining and TUNEL assay. Results showed that baicalin improved neurological function and reduced the area of hemorrhagic foci of brain in ICH mouse model. Baicalin decreased iron ion deposition, inhibited ferroptosis and apoptosis, and upregulated GPX4 in brain of ICH mouse model. Moreover, baicalin increased AKT1 phosphorylation and the protein level of Nrf2 in brain of ICH mouse model. Notably, AKT1 inhibitor LY294002 and Nrf2 inhibitor reversed the effects of baicalin on the activation of AKT1/Nrf2/GPX4 axis and the inhibition of ferroptosis in brain of ICH mouse model. Collectively, we demonstrated that baicalin promotes ICH recovery by inhibiting ferroptosis in brain tissue through activation of AKT/Nrf2/GPX4 axis. These results may provide new insights for the study of baicalin in the treatment of ICH.

Alzheimer's disease (AD) remains a major neurodegenerative disorder with limited therapeutic medication. Despite intensive efforts, the clinical development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors has been hindered by off-target effects, poor brain penetration, and toxicity, which is often due to a lack of selectivity over BACE2. In this study, we conducted a comprehensive analysis of over 9,000 reported BACE1 inhibitors to identify key physicochemical properties and interaction fingerprints associated with effective binding. These criteria were used to filter a library of 1.4 million commercially available compounds, prioritizing candidates with better safety and blood-brain barrier (BBB) permeability properties. The top-ranked molecules were evaluated through molecular docking and molecular dynamics (MD) simulations, followed by selectivity assessments against BACE2 and additional off-targets. Among these, two compounds, MCULE-5138978734 and MCULE-2333131051, exhibited strong and stable binding to BACE1 with markedly reduced affinity for BACE2, suggesting improved selectivity. This integrative in silico framework demonstrates a rational strategy for the discovery of selective BACE1 inhibitors and highlights promising lead candidates for further experimental validation in the development of AD therapeutics.

Bladder and ovarian cancers impose a significant burden on healthcare systems due to their high incidence, mortality rates, and the challenges associated with early diagnosis. Current chemotherapy regimens, which typically involve combinations of drugs, often cause severe side effects that negatively impact patient adherence and treatment efficacy. Recently, studies have explored the use of herbal medicines to mitigate the adverse effects of chemotherapy. One such herbal compound is ursolic acid (UA), a triterpene known for its anti-inflammatory, antioxidant, and antitumor properties. This study aimed to evaluate the effects of UA on bladder and ovarian cancer cells harboring TP53 mutations through various assays, including cytotoxicity, clonogenic survival, cell migration, morphological changes, apoptosis, cell cycle analysis, JHDM1D expression and selectivity using MRC-5 cells, along with in silico evaluation. The treatment demonstrated selectivity for tumoral cells and significant antiproliferative effects in both cell types, leading to decreased cell viability, reduced colony-forming ability, inhibited cell migration, morphological changes characteristic of cell death, and increased expression of JHDM1D. In conclusion, UA exhibited antiproliferative activity against bladder and ovarian cancer cell lines with different TP53 mutation sites, suggesting its potential as a promising therapeutic alternative. Moreover, our study demonstrated for the first time the presence of UA in the species F. formosa.

‌Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress and regulating mitochondrial quality control via the PINK1/Parkin pathway. In vitro, H9C2 cardiomyocytes exposed to H₂O₂-induced oxidative stress were treated with OLEU (0–200 μM), and analyses included cell viability, ROS, SOD, MDA, ΔΨm, ATP, PINK1/Parkin expression and detection of Mitophagic Flux. In vivo, myocardial infarction (MI) was induced in SD rats via coronary ligation, followed by OLEU administration, with assessments of cardiac function, histopathology, and mitophagy using echocardiography, electron microscopy, immunohistochemistry and immunofluorescence. Results showed that OLEU (≤200 μM) dose-dependently restored cell viability, reduced ROS, and normalized SOD/MDA (p < 0.05), while mitigating ΔΨm collapse and ATP depletion, indicating enhanced mitochondrial bioenergetics. OLEU upregulated PINK1/Parkin, promoting mitophagic clearance of damaged mitochondria, and metabolomic analysis revealed modulation of arginine/proline and lipid pathways. In MI rats, OLEU attenuated ROS, preserved myocardial structure, and improved cardiac function, supported by elevated mitophagy in electron microscopy. These findings demonstrate that OLEU protects cardiomyocytes by suppressing oxidative stress, stabilizing mitochondrial integrity, and activating PINK1/Parkin-mediated mitophagy, highlighting its therapeutic potential for myocardial injury and mitochondrial dysfunction.

This study evaluated the neuroprotective potential of a combination therapy using liraglutide (LIRA), an antidiabetic agent, and rivastigmine (RIVA), a standard treatment for Alzheimer's disease (AD), in a rat model of aluminum chloride (AlCl₃)-induced AD. Male rats were divided into five groups: control, AD (AlCl₃,75 mg/kg for 60 days), RIVA-treated (1 mg/kg daily for 6 weeks), LIRA-treated (300 µg/kg daily for 6 weeks), and combination-treated (LIRA + RIVA). Cognitive function was assessed behaviorally, and hippocampal biomarkers related to AD—such as microtubule-associated protein Tau (MAPt), Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), Sequestosome 1 (SQSTM1/p62), and acetylcholinesterase (AChE) activity—were evaluated. Histopathological changes, immunohistochemistry, and transmission electron microscopy were also assessed. The levels of MAPt, BACE1, SQSTM1/p62, and AChE in the LIRA + RIVA group were 11.32 ± 0.467 ng/mL, 1069 ± 80.1 pg/mL, 408.7 ± 19.41 pg/mL, and 0.805 ± 0.342 µmol of acetylthiocholine iodide hydrolyzed/min/g of tissue, respectively. These levels were significant (p < 0.01) when compared with the AlCl₃ group. Histological findings supported these biochemical data, indicating enhanced neuroprotection. LIRA may have a potential neuroprotective effect due to the rise in AChE, BACE1, (SQSTM1/p62) amyloid beta (Aβ), and caspase-3 levels induced by AlCl₃. Co-administration of LIRA and RIVA provided superior neuroprotective effects compared with RIVA alone, suggesting a promising therapeutic strategy for preserving cognitive function in AD.

A series of pyrrolidine-2-carbonitrile derivatives was designed, synthesized, and evaluated for their antidiabetic potential. The synthesized compounds exhibited notable inhibitory activity, with IC₅₀ values ranging from 9.36 to 21.54 µg/mL for α-amylase, 13.32 to 46.14 µg/mL for α-glucosidase, and 22.87 to 42.12 µg/mL for DPP-IV. Among the evaluated derivatives, compounds bearing para-methyl (6b) and para-chloro (6c) substituents demonstrated the most potent inhibitory activity across all three enzymatic targets. To elucidate the underlying trends, a SAR analysis was conducted, revealing that both electronic properties and steric effects of the substituents significantly influenced enzyme inhibition potency. The molecular docking studies showed strong and specific interactions between the active compounds and key residues within the catalytic sites of the target enzymes. In addition, UV-visible absorption and fluorescence spectroscopy studies demonstrated high binding affinities for both 6b and 6c with HSA, having binding constant (K_a) values of 7.31 × 10⁵ M⁻¹ and 7.43 × 10⁵ M⁻¹, respectively. Taken together, these findings highlight compounds 6b and 6c as promising lead candidates for the development of multitarget antidiabetic agents.

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by persistent mucosal inflammation and epithelial barrier disruption. This study investigated the therapeutic efficacy of Scopoletin, a natural coumarin derivative with established anti-inflammatory and antioxidant properties, in a DSS-induced colitis model in Balb/c mice. A total of five experimental groups were established: a normal control, a DSS+ vehicle group, two Scopoletin-treated groups (10 and 30 mg/kg), and a reference group treated with Sulfasalazine (200 mg/kg). Network pharmacology analyses identified key inflammatory and immune-regulatory pathways potentially modulated by Scopoletin. In vivo assessments encompassed body weight monitoring, DAI scoring, colon length measurement, and histopathological evaluation using H&E, PAS, and Alcian blue staining. Scopoletin (30 mg/kg) treatment significantly ameliorated clinical and histological manifestations of colitis, including body weight loss and colonic shortening. Mechanistically, Scopoletin (30 mg/kg) attenuated the expression of pro-inflammatory cytokines such as TNF-α and IL-1β, suppressed NF-κB activation, MMP-9, COX-2 and enhanced the Nrf2 expression, leading to upregulation of antioxidant enzymes HO-1 and NQO1. Notably, Scopoletin (30 mg/kg) restored the expression of tight junction proteins such as Occludin and ZO-1, indicating reinforcement of epithelial barrier integrity. These findings demonstrated that Scopoletin protects against UC by suppressing inflammation, enhancing antioxidant defenses, and preserving mucosal barrier integrity, highlighting its potential as a therapeutic candidate for UC.

Nanoparticle-mediated transdermal systems can bypass the skin's natural outer barrier (stratum corneum), allowing drugs to enter the body more effectively. This technology improves how much drug reaches the bloodstream and how long it acts, which can make drug delivery noninvasive and more comfortable for patients. These technologies are engineered to markedly enhance drug permeability and bioavailability, while improving patient adherence and reducing systemic side effects. The incorporation of nanocarriers into transdermal systems can augment drug permeability across the skin by 2- to 10-fold, contingent upon the physicochemical characteristics of both the drug and the nanocarrier type, as demonstrated in multiple preclinical investigations. This review rigorously analyzes various nanocarriers, including liposomes, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), polymeric nanoparticles, and inorganic nanostructures, and their effects on cutaneous and transdermal drug delivery. Improvements in entrapment efficiency of up to 90% and a three- to fivefold enhancement in drug retention within the epidermis have been recorded. Optimized nanoparticle-based formulations have also demonstrated sustained release characteristics lasting up to 72 h. Additionally, innovative technologies such as dissolving microneedles, nanoneedle arrays, luminous patches, and 3D-printed transdermal systems are examined regarding their capacity to enhance dosage accuracy, bioadhesion, and therapeutic efficacy. The study examines formulation characteristics such as polymer matrices, rate-controlling membranes, excipient compatibility, and penetration enhancers that affect the clinical efficacy and stability of nanoparticle-integrated patches. Significant attention is directed towards the impact of formulation choices on drug loading, release kinetics, and skin interaction patterns. Notwithstanding advancements, no nanoparticle-encapsulated transdermal patch has attained FDA approval to yet. The review delineates the principal translational obstacles—regulatory ambiguity, safety assessment, and GMP-scale production—and emphasizes the necessity for cohesive pharmacokinetic modeling, human skin correlation investigations, and real-time stability data to enhance clinical translation.

In the current study, new pyrazolo [1,5-a]pyrimidine-3-carbonitriles were synthesized and evaluated for their inhibitory activity against Pim-1 kinase. The most potent inhibitors were 4d, 5d, and 9a with IC₅₀ values (0.61, 0.54 and 0.68 μM) compared to quercetin (IC₅₀ = 0.91 μM), with some selectivity towards Pim-1 and Pim-3 over Pim-2. Compound 4d exhibited a 1.5-fold increased cytotoxic activity compared to doxorubicin against the MCF-7 cell line, whereas compound 9a showed an analogous activity to doxorubicin. Furthermore, compounds 4d, 5d, and 9a arrested the cell cycle at G2-M phase with a decrease in the G1-phase population. Compounds 4d, 5d, and 9a induced apoptosis in MCF-7 cells by a 94-, 64-, and 78-fold increase in the entire apoptotic and necrotic cells compared to the untreated control cells and increased the levels of wild p53 in MCF-7 cells by 6.5, 6, and 5.7-fold indicating that these compounds may induce apoptosis via increasing the expression level of p53. Moreover, a promising safety profile was shown for compound 4d on MCF-10A normal breast cells. Besides, docking of the desired compounds into Pim-1 ATP binding site showed a noteworthy binding mode for the enzyme inhibition. Additionally, a 2D QSAR identified the potential structural features controlling the Pim-1 inhibitory activity attained via the targeted pyrazolo[1,5-a]pyrimidines.