Drug Development Research最新文献

Although topical minoxidil is the most common drug for alopecia areata (AA), it has limited therapeutic effect in the treatment of patients with moderate and severe AA because it can only promote hair follicle growth and improve the characteristics of hair follicle degeneration in AA and cannot alleviate local inflammatory response. Therefore, we designed a novel topical compound gel loading minoxidil and Janus kinases (JAK) inhibitors tofacitinib. The compound gel not only had good semi-solid properties and the effect of permeation but also maintained stability for up to 3 months under accelerated conditions, ensuring the long-term quality of the formulation. This compound gel can effectively improve hair follicle growth and significantly alleviate local inflammatory response by downregulation of the ratio of inflammatory factor interferon-γ to anti-inflammatory factor interleukin-4 in C3H/HeN mice bearing AA, achieving the purpose of synergistic treatment of AA. The first combination of minoxidil and tofacitinib in a topical formulation gives a new idea for the clinical treatment of AA.

Herein, we report the design, synthesis, and characterization of novel organoselenium (OSe) hybrids (5–19) via modifications of the lead, N-(4-selaneylphenyl)-2-selaneylacetamide. The OSe-based thiazol 9 showed the highest growth inhibition % (GI%) of 64.72% relative to the positive reference doxorubicin (DOX), with a GI% of 79.5%. Furthermore, the novel OSe derivatives showed low GI% values compared to the normal cell lines employed, demonstrating their selectivity. The OSe tethered N-chloroacetamide 5 and Schiff base 19 showed a cytotoxic effect with an IC₅₀ of (25.07 and 11.61 µM), respectively, against the A549 tumor cell line and IC₅₀ of (34.22 and 20.12 µM), respectively, against the HELA cancer cell line. Enzyme-linked immunosorbent assay to study the JAK1 and the STAT3 inhibitory potentials of OSe compounds 5 and 19 in the A549 cancer cells both showed promising inhibitory activities with IC₅₀ values of 25.07 and 11.61 µM, respectively. Protein expression analysis on the A549 cancer cell line on OSe compounds 5 and 19 showed upregulation of P53, BAX, and Caspases 3, 6, 8, and 9 as apoptotic proteins. However, both candidates expressed downregulation of the antiapoptotic proteins (BCL2, MMP2, and MMP9). Moreover, OSe compounds 5 and 19 described the downregulation of the examined inflammatory proteins: COX2, IL-6, and IL-1β. In addition, OSe compound 19 showed potential cell cycle arrest at the G0, S, and G2-M layers, with an increase in cellular levels. Finally, molecular docking studies of OSe compound 19 showed the most promising inhibitory potential toward the JAK1 and STAT3 target receptors, with binding scores and interactions exceeding that of the cocrystallized inhibitor of JAK1.

Tissue plasminogen activators (tPAs) are critical in fibrinolysis and have become central to treating thrombotic disorders, including heart attacks, strokes, and pulmonary embolisms. Despite their efficacy, challenges such as bleeding complications, limited fibrin specificity, and rapid clearance necessitate the discovery of novel tPAs and the engineering of improved variants. This review highlights strategies for the discovery of tPAs from natural sources, including human, bacterial, venom-derived, and bat saliva-derived agents, as well as enzyme engineering approaches that enhance functional characteristics such as half-life, fibrin specificity, resistance to inhibitors, and clot penetration. Furthermore, this review explores alternative therapeutic approaches independent of tPAs, focusing on nonplasminogen activator agents and strategies that target platelets. By addressing current challenges and identifying future opportunities, this review provides a comprehensive perspective on advancing thrombolytic therapies through innovative discovery and design strategies.

Palmatine (PAL), as an active ingredient in traditional Chinese medicine, had been demonstrated efficacy in ameliorating the manifestations of AD. Our research group has previously designed and synthesized the novel oxo-PAL derivative 2q and found that it has exhibited notable neuroprotective properties. However, compound 2q therapeutic impact on AD remains uncertain. In the current investigation, our findings demonstrated that compound 2q displayed significant anti-AβOs activity in vitro by using xCELLigence analysis, and showed a high likelihood of crossing the blood-brain barrier. Furthermore, administration of compound 2q yielded a notable amelioration in Aβ accumulation and hyperphosphorylation of Tau in 3×Tg mice. Additionally, it was observed that compound 2q potentially enhanced the pathological characteristics of AD by targeting Potassium/Sodium Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 (HCN2). In conclusion, compound 2q emerged as a promising candidate for AD treatment, as it effectively restored AD-associated pathological impairments. Furthermore, it has been identified as a potential target of HCN2, thereby offering novel avenues for the development of treatments for AD.

The headway for the management of emerging resistant microbial strains has become a demanding task. Over the years, antimicrobial peptides (AMP), have been recognized and explored for their highly systematized SAR and antibacterial properties. With this background, we have reported a new class of AMPs. These peptides incorporate an unnatural amino acid, with a motivation from cruciferous bioactive phytochemical bisindoles methane derivatives with highly selective antimicrobial action. These peptides may also be considered as linear derivatives of hirsutide isolated from entomopathogenic fungus. The synthesized peptides were tested for their antimicrobial activity against an ESKAPE pathogen panel, where peptide 3 exhibited equipotent MIC and potent synergistic action along with gentamicin against Staphylococcus aureus and Enterococcus clinical isolates. This combination was also able to repotentiate gentamicin against NRS119, a gentamicin-resistant MRSA. Molecular dynamics study and free energy calculations provided insights to membrane disruptive properties of AMP action, which assisted gentamicin pass through the lipid–water interface.

MAPKAPK2/MK2 is well implicated in the progression of Head and Neck Squamous Cell Carcinoma (HNSCC), and potent MK2-inhibitors are required to suppress its activity. Several MK2-inhibitors have been developed in recent years to combat its effects on cancer. However, inadequate solubility, insufficient cellular permeability, systemic toxicity-mediated side effects, and low bioavailability have severely impeded the advancement of MK2-inhibitors to clinical trials. This void necessitates research to develop less toxic and more bioavailable potent MK2-inhibitors in HNSCC. In the present article, we have evaluated the in-vitro efficacy, in-vivo single-dose acute toxicity, and in-vivo pharmacokinetic profiling of recently developed PfBS (pyrrolone-fused benzosuberene) MK2-inhibitor analogues against HNSCC. The PfBS MK2 inhibitor analogues impeded HPV+ and HPV- HNSCC cell proliferation and two-dimensional migration. Moreover, MK2-inhibitors lowered HNSCC cell clonogenic survival in a dose-dependent manner, significantly enhancing radiation-induced cell death via exerting radio-sensitization effects. Furthermore, γ-H2AX immunostaining revealed that PfBS analogues impaired DNA damage repair in HNSCC cells exposed to gamma radiation. In mice, PfBS MK2 inhibitors at 300 mg/kg were well-tolerated without any lethal effects. Pharmacokinetic studies showed that PfBS analogues exhibited rapid absorption (Tmax), adequate plasma concentration above the micromolar level (C0 or Cmax), limited tissue distribution (Vd), and faster elimination from the body (Cl). Overall, this study summarizes in-vitro efficacy, safety, and pharmacokinetics of developed MK2-inhibitors and opens doors for pharmacodynamics and mechanism of action study of most effective leads in HNSCC.

Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of clear therapeutic targets. Paclitaxel (PTX) is commonly used to treat TNBC, but drug resistance limits its effectiveness. Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are involved in various diseases, including infections, inflammatory diseases, and cancer. We investigated their role in PTX resistance to identify potential anti-TNBC drugs. In this study, we investigated the changes of SAA1 in TNBC tissues and its role in PTX-induced TNBC cells. Our study revealed SAA1 expressed in the human TNBC subtype and TNBC cells. PTX and CIS induce SAA1 in TNBC cells, and PTX induces inflammatory response via SAA1 in TNBC cells. MD2 blockade increased the sensitivity of TNBC cells to PTX, which was related to the expression of SAA1 during PTX-caused damage of TNBC cells. In further research, SAA1 binds to MD2, promotes the combination of TLR4/MD2 and TLR4/MyD88, activates the NF-κB signaling pathway, and creates the inflammatory microenvironment for cancer cells. Our study reports for the first time that the PTX/SAA1/MD2 axis exists in the PTX-resistance process, which could be a potential treatment target of PTX-resistance.

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality. Ginsenosides have been shown to have strong antitumor activity, inhibiting tumor cell growth and promoting apoptosis. In this paper, the effects of ginsenoside CK on the proliferation and apoptosis of NSCLC 95D and NCI-H460 cells were investigated by CCK8, colony formation assay, flow cytometry, fluorescence staining assay, and Western Blot, and it was found that ginsenoside CK could significantly inhibit the growth and proliferation of non-small cell lung cancer, and it was also clarified that the mechanism of its action was realized by the mitochondrial apoptosis pathway. It provides new therapeutic ideas for lung cancer and other major tumor diseases.

Biofilm is a “growing” problem and needs effective remedial agents. Here we report novel methyl 4-((4-(4-chlorophenyl)-2,5-dioxoimidazolidin-1-yl) methyl) benzoate derivatives (5a-l) as antibiofilm and antimicrobial agents evaluated with both in silico and in vitro techniques. When it comes to Gram-positive bacterial strains like Staphylococcus aureus (MTCC 737), MRSA and Streptococcus pneumoniae (MTCC 1936), and Gram-negative bacterial strains like Pseudomonas aeruginosa (MTCC 424) and Escherichia coli (MTCC 443), the minimum inhibitory concentration (MIC), minimum biofilm inhibition concentration (MBIC), and anti-biofilm activity were measured. Out of all the compounds (5a-l), 5b and 5d showed no toxicity to mammalian cells and were equally active against various Gram-positive and Gram-negative bacteria at low concentrations (MIC: 0.1–9.5 µg/mL). Compounds 5b and 5d were also validated for the DNA gyrase inhibition potential as an antimicrobial mechanism of action in vitro. These compounds showed high level DNA gyrase inhibition potentials (IC₅₀ 0.025 µM, ≥ 98 relative % activity and 0.24 µM, ≥ 94 relative % activity respectively. In the end, we have identified 5b and 5d as most effective among 5a-l and are considered for further preclinical studies.