Drug Development Research最新文献

Lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist, which is approved for treatment of dry eye disease. In this work we explored the effect of lifitegrast in imiquimod induced psoriasis model in mice. Lifitegrast (5% solution) was tested in imiquimod-induced psoriasis model in C57 mice. Lifitegrast was topically administered twice a day to the psoriatic skin for 6 days and epidermal skin thickness, psoriasis area and severity index (PASI) score and inflammation markers were assessed. Lifitegrast inhibited the imiquimod-induced increase in the epidermal thickness, histopathological changes and PASI score. This decrease in psoriasis inflammation was accompanied by decrease in TNF-α, IL-6, IL-22 and IL-17/IL-23 axis gene expression in the skin, and the effect is comparable to the oral cyclosporine A(5 mg/kg, twice a day) treatment. Lifitegrast demonstrated significant anti-inflammatory activity, mainly through reduction in cytokine gene expression related to psoriasis and decreased the severity of psoriasis in vivo. The significant effect shown by this LFA-1 and ICAM-1 antagonist indicates a novel topical treatment for psoriasis.

The design and synthesis of unique two series of fluorinated sulfonamides 3a-f and 5a-g utilizing nucleophilic aromatic substitution reactions of tetrafluorophthalonitrile 1 with various sulfonamides 2 under a variety of different reactions conditions were the key goals of the current research. The chemical composition of the generated products has been investigated via mass spectroscopy, ¹HNMR, ¹³CNMR, infrared, and elemental analyzes. Antimicrobial studies were conducted in vitro to evaluate the activity of all new synthesized compounds against resistant strains. The first series showed high potency in very low concentrations. All compounds were studied against DPPH Radical Scavenging Activity and the other series showed high activity even in low molar ratio. In silico molecular docking was used to investigate the potential binding pathways for different receptors: dihydroprotien synthase protein (ID Code: 1AJ0) as an antibacterial and EGFR^WT co-crystallized with erlotinib [PDB ID code 1m17]. Furthermore, synthesized compounds with good ADME predictions to the Lipinski rule of five demonstrated that the recently synthesized compounds had high drug-likeness qualities when the physicochemical parameter for the most powerful novel candidates was determined. Moreover, the DFT/B3LYP method functionalized with a 6-31G (d, p) basis set was employed to calculate quantum parameters, MEP analysis, HUMO, and LUMO.

Cerebral ischemia/reperfusion injury is one of the main causes of neuronal damage. Neuron ferroptosis and microglia polarization are considered as critical processes during cerebral ischemia/reperfusion. Adipocyte enhancer-binding protein 1 (AEBP1) usually acts as a transcriptional repressor which is involved in various diseases. However, it is still remains unknown whether AEBP1 could have important roles in regulating the neuron ferroptosis and microglia polarization in cerebral ischemia/reperfusion injury. The oxygen-glucose deprivation and reperfusion (OGD/R)-treated cells and middle cerebral artery occlusion (MCAO)-treated mice were used as in vitro and in vivo models. The differentially expressed factors were analyzed according to GEO datasets. Relative mRNA and protein expression levels were detected by qRT-PCR and western blot analysis. Cell viability was measured by CCK-8 assay. ROS, GSH and iron contents were detected using specifical assay kits. CD26 and CD206 levels were measured by immunofluorescence assay. Inflammatory cytokines were detected by ELISA. The association between AEBP1 and PRKCA was assessed by luciferase reporter and ChIP analyses. The neuron damage in mice was analyzed by TTC staining and neurological deficit score. Transcription factor AEBP1 was increased in OGD/R-treated HT22 and BV2 cells. AEBP1 silencing attenuated OGD/R-induced HT22 cell ferroptosis through increasing cell viability, GSH and GPX4 levels, and decreasing ROS, iron and ACSL4 levels. AEBP1 knockdown promoted microglia M2 polarization by increasing CD206-positive cells and Arg-1 level, and reducing iNOS, TNF-α, IL-1β and IL-6 levels in BV2 cells. AEBP1 transcriptionally repressed PRKCA expression, and further regulated PI3K/Akt signaling activation. Inhibition of PRKCA or PI3K/Akt reversed the effects of AEBP1 silencing on neuron ferroptosis and microglia M2 polarization. AEBP1 downregulation attenuated neuronal damage by decreasing infarct size and deficit scores in MCAO-treated mice. AEBP1 silencing mitigated neuron ferroptosis and promoted microglia M2 polarization through increasing PRKCA and activating PI3K/Akt signaling, indicating the potentially protective action of AEBP1 knockdown in cerebral ischemia/reperfusion injury.

Dual-targeting drug design has become a popular approach in investigating and developing potent anticancer agents. In this regard, carbonic anhydrase (CAIX) and vascular endothelial growth factor receptor (VEGFR-2) are emerging as highly effective targets in the battle against cancer. In the present study, two series of 4-thiazolidinones/2,4-thiazolidinediones carrying 2-methylbenzenesulfonamide derivatives were designed and synthesized as potential dual CAIX/VEGFR-2 inhibitors. All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (3a, 3b, 3o, 6d, 6g, and 6i) were selected to evaluate their inhibitory activity against VEGFR-2 using sorafenib as a reference drug. These compounds were also evaluated against MCF-7 breast cancer cells and the murine fibroblast 3T3 cell line. According to the results, 3b (CAIX IC₅₀ = 0.035 µM, VEGFR-2 IC₅₀ = 0.093 µM) and 6i (CAIX IC₅₀ = 0.041 µM, VEGFR-2 IC₅₀ = 0.048 µM) emerged the most potent compounds against CAIX and VEGFR-2. Furthermore, docking studies of selected compounds were performed with the CAIX and the tyrosine kinase domain of VEGFR-2 to comprehend the ligand-binding interactions. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR-2 inhibitors.b

Microglia-mediated neuroinflammatory responses have a critical function in the spinal cord injury (SCI) mechanism, and targeted modulation of microglia activity has emerged as a new therapeutic strategy for SCI. Heme oxygenase 1(HO-1) regulates the close dynamic crosstalk between oxidative stress and inflammatory responses. This investigation aimed to study the molecular pathways by which HO-1 regulates the inflammatory response of microglia. We cultivated primary rat spinal cord microglia and BV2 cell lines and used lipopolysaccharide (LPS) to stimulate microglia to establish an in vitro model. The adeno-associated virus (AAV) was used to induce HO-1 overexpression to observe the effects of HO-1 overexpression on microglia survival, morphological changes, microglia activation, inflammatory cytokines secretion, mitochondrial dynamics, and nucleotide-binding oligomerization domain-like receptor protein (NLRP3) inflammatory complex and nuclear factor-κB (NF-κB) signaling pathways. It was found that HO-1 overexpression was successfully induced using an AAV on microglia in vitro. HO-1 overexpression increased microglia survival and reduced microglia apoptosis in the inflammatory microenvironment. Overexpressed HO-1 inhibited microglia M1-type polarization, downregulated the NF-κB signaling pathway, inhibited NLRP3 inflammatory complex activation, and reduced the secretion of inflammatory factors. Overexpressed HO-1 maintained the stability of mitochondrial dynamics and inhibited excessive mitochondrial cleavage. Further experiments showed that overexpression of HO-1 activated the interferon regulatory factor 1 (IRF1)/dynamin-related protein 1 (DRP1) signaling pathway, thereby promoting microglia M2-type polarization and improving neuronal survival. This study demonstrates that HO-1 activates the IRF1/DRP1 axis, promoting M2 polarization in microglia and attenuating neuroinflammation by suppressing the NF-κB signaling pathway. These outcomes offer new visions and important clues for effectively managing SCI in the clinic.

Protein tyrosine phosphatase 1b (PTP1b) is a member of the protein tyrosine phosphatase (PTP) enzyme group and encoded as PTP1N gene. Studies have evidenced an overexpression of the PTP1b enzyme in metabolic syndrome, anxiety, schizophrenia, neurodegeneration, and neuroinflammation. PTP1b inhibitor negatively regulates insulin and leptin pathways and has been explored as an antidiabetic agent in various clinical trials. Notably, the preclinical studies have shown that recuperating metabolic dysfunction and dyshomeostasis can reverse cognition and could be a possible approach to mitigate multifaceted Alzheimer's disease (AD). PTP1b inhibitor thus has attracted attention in neuroscience, though the development is limited to the preclinical stage, and its exploration in large clinical trials is warranted. This review provides an insight on the development of PTP1b inhibitors from different sources in diabesity. The crosstalk between metabolic dysfunction and insulin insensitivity in AD and type-2 diabetes has also been highlighted. Furthermore, this review presents the significance of PTP1b inhibition in AD based on pathophysiological facets, and recent evidences from preclinical and clinical studies.

Plant-based components have helped generate novel lead molecules and scaffolds for anxiety research in psychopharmacology. The present study examined the anxiolytic properties of sesamol (SES), a phenolic lignan derived from Sesamum indicum, employing both in vivo and computational methods to understand its mechanisms of action. In this experiment, adult Swiss albino mice received various doses of SES (25 and 50 mg/kg, p.o.) orally. Afterward, a series of behavioral assessments, including open field, swing, hole cross, and light–dark testing, were conducted. The impact of the GABAergic agonist diazepam (DZP-1 mg/kg, i.p.) along with the antagonist flumazenil (FLU-0.1 mg/kg, i.p.) has been studied as provided concurrently with the SES-50 group. Computational studies were performed to comprehend the interaction between SES and GABA_A receptor subunits (α₂ and α₃). The results of our investigation revealed that SES dose-dependently and significantly (p < 0.05) reduced the number of square crosses, hole crosses, swings, grooming, and rearing along with a reduction of light residence time in animals. When combined with DZP, SES-50 significantly reduced all these parameters, while altering with FLU-0.1. The molecular docking analysis showed that the SES has a relatively good binding score (−5.03 ± 0.15 and −5.25 ± 0.23 kcal/mol) with GABA_A receptor α₂ and α₃ subunits, respectively. The SES triggers anxiolytic effects via GABA_A receptor α₂ and α₃ subunit interactions. Furthermore, precise and comprehensive preclinical research must be considered to validate potential SES targets for anxiolytic impact, clinical trial efficacy, and safety.

Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor in adults and is known for its rapid proliferation and infiltrative nature. Current therapeutic strategies include surgical resection followed by radio- and chemotherapy. Still, they are hindered by GBM biological characteristics and physical-chemical properties of chemotherapeutic drugs, leading to limited efficacy and poor prognosis. Cannabinoids have emerged as potential anti-GBM agents, exhibiting antiangiogenic, antimetastatic, and antiproliferative effects. However, their hydrophobicity and poor oral bioavailability pose significant challenges for clinical applications. This study evaluates the potential of nanocarriers in enhancing the solubility and targeted delivery of cannabinoids for GBM therapy. The innovative combination of nanotechnology with cannabinoid-based treatment offers a promising strategy to improve therapeutic outcomes. We addressed the application of nanocarriers to deliver cannabinoids, which can enhance passage across the blood-brain barrier and enable targeted therapy. Studies demonstrate the potential of nanocarriers in improving solubility, stability, and controlled release of cannabinoids, highlighting the advancements in nanocarrier design for optimized delivery to glioma cells. Cannabinoids can exert their antitumor effect, including the induction of apoptosis through the ceramide and p8-regulated pathways and the modulation of immune responses. The evidence found in this study supports the potential of cannabinoid-based nanotechnologies in GBM therapeutic regimens as a strategy to enhance its efficacy and patient outcomes.

Leishmaniasis are caused by protozoa of the genus Leishmania and affect millions of people worldwide. They are considered neglected diseases that primarily impact individuals in tropical and subtropical regions. The drugs currently available for treating this infection have limitations, such as high toxicity, adverse reactions, and a long therapeutic intervention period. Numerous studies, using various experimental models, have sought to develop more effective and less toxic chemotherapeutic agents against these protozoa. In this context, the present study aimed to evaluate the antileishmanial activity of two new dichalcogenides, LQ64 and LQ62, as well as their possible mechanism of action in promastigote forms of Leishmania amazonensis. Both substances, LQ64 and LQ62, exhibited activity against promastigote (IC₅₀ = 2.35 and 12.59 µM, respectively), and amastigote forms (IC₅₀ = 3.50 and 6.58 µM, respectively). Furthermore, the substances revealed selectivity for the parasite when analyzing their cytotoxicity in J774A-1 macrophages. Moreover, electron microscopy analysis and mechanisms of action assays investigated in promastigote forms with both substances showed mitochondrial depolarization. This phenomenon possibly promoted changes in intracellular ATP levels, resulting in increased reactive species and lipid peroxidation, leading the parasites to oxidative stress. Additionally, the treatments induced changes in plasma membrane integrity, lipid body accumulation, alterations in the cell cycle, and phosphatidylserine externalization. Thus, the results indicate that LQ64 and LQ62 may induce characteristic changes in the protozoan suggestive of apoptosis cell death.

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure–activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC₅₀ = 2.68 μM) and MOLM-13 (IC₅₀ = 1.03 μM). In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.