Archiv der Pharmazie最新文献

The aim of this study is to design, synthesize, and characterize novel benzo[f]chromene-substituted thiosemicarbazone derivatives as potential anticancer agents, based on the rationale of simultaneously targeting key cancer-related enzymes and signaling pathways to improve therapeutic efficacy against lung cancer. For these purposes, 18 novel thiosemicarbazone derivatives 4a–r were synthesized. Among them, compound 4p exhibited the most promising anticancer effects against A549 cells, with an IC₅₀ value of 5.11 µM and a selectivity index (SI) of 10.55, surpassing the reference drug sorafenib. Compound 4p also demonstrated potent enzyme inhibitory activity, particularly against hCA I (IC₅₀ = 104.26 nM) and hCA II (IC₅₀ = 95.18 nM), outperforming acetazolamide. In anticancer assays, compound 4p (SI = 10.55) was about twice as effective as sorafenib (SI = 5.34), and in enzyme inhibition, it showed ~1.5-fold greater potency than acetazolamide. Molecular docking studies show strong binding interactions of 4p with hCA I, hCA II, and BRAF, with favorable docking scores and stable protein–ligand complexes confirmed by 100-ns and 250-ns triplicate random seed MD simulations. Additionally, pharmacokinetic predictions indicated excellent drug-like properties for 4p, including high permeability, oral absorption, and adherence to Lipinski's rule. These findings highlight compound 4p as a promising candidate for an anticancer agent targeting key enzymes involved in lung cancer progression.

A series of novel phthalimidoalkyl-arylidene thiazolidinedione hybrids (10a–e and 11a–e) were designed and synthesized by the combination of the bioactive phthalimide and thiazolidinedione pharmacophores and connected via an ethyl or propyl linker. Additionally, selenocyanates (12 and 13) were synthesized via nucleophilic substitution using KSeCN in DMF. The novel phthalimide benzylidene thiazolidinedione hybrids (10a–e and 11a–e) and phthalimide selenocyanates (12 and 13) were examined as apoptotic inducers against 15 cancer cell lines. Compound 10e showed the best mean growth inhibition percentage (GI%) of 64.60% compared with the FDA-approved doxorubicin (Dox). Moreover, the synthesized compounds showed higher therapeutic efficacy against the A549 and MDA-MB-468 cell lines compared with HeLa and FaDu cells. Analogs 10e, 11b, 11d, and 13 displayed the highest cytotoxic potential at the MDA-MB-468 cancer cells with IC₅₀ values of 12.52, 13.16, 12.00, and 14.78 µM, respectively, in comparison to Dox (IC₅₀ = 11.39 µM). Evaluation of the apoptotic and proinflammatory markers after treatment with analog 13 revealed upregulation of the proapoptotic Caspases 3, 8, and 9 and downregulation of the prosurvival proteins BCL-2, MMP2, and MMP9 by 1.27-, 6.71-, 2.00-, 2.26-, 2.31-, and 2.12-fold change, respectively. Furthermore, analog 13 showed the most significant downregulation of COX-2 and IL-1β protein expression, showing 2.08- and 2.34-fold changes, respectively. Finally, the molecular docking study against Caspase 6 demonstrated eligible binding affinities of the examined analogs. Overall, this study demonstrated that the synthesized compounds are promising apoptotic inducers and possess great potential as anticancer drugs.

A new series of pyrazole–thiazole–oxadiazole hybrid compounds targeting the EGFR and VEGFR2 enzymes was designed and synthesized using innovative approaches. The compounds were characterized through spectral methods, and their cytotoxic activities were evaluated against the A549 lung and HT-29 colon cancer cell line using the MTT assay. Among them, compounds 17i and 17m exhibited notable cytotoxicity, with 17i demonstrating approximately threefold greater activity compared to the reference drug sorafenib for A549 cells. Flow cytometry analysis revealed that 17i induced extensive necrotic cell death, while 17m triggered a more targeted and controlled apoptotic mechanism. In vitro enzyme inhibition assays demonstrated that 17i inhibited EGFR and VEGFR2 with IC₅₀ values of 0.158 and 0.128 µM, respectively. In contrast, 17m exhibited more potent inhibition of EGFR (IC₅₀ = 0.012 µM) and moderate activity against VEGFR2 (IC₅₀ = 0.309 µM). Molecular docking and molecular dynamics simulations further supported the structural stability of the complexes formed by these compounds with their target enzymes, highlighting their potential as effective enzyme inhibitors. Collectively, these findings suggest that pyrazole–thiazole–oxadiazole hybrids represent promising candidates for targeted cancer therapy at the cellular level.

Two multivariate calibration models were created for the concurrent estimation of methocarbamol and paracetamol in their co-formulated pharmaceutical dosage form. These methods also enabled the detection of their impurities, p-aminophenol and guaifenesin. The calibration paradigms, based on principal component regression (PCR) and partial least squares (PLS), were employed to assess the drugs and their impurities. The methods demonstrated accurate simultaneous determination of methocarbamol, paracetamol, p-aminophenol, and guaifenesin within the concentration ranges of 20.00–80.00 µg mL⁻¹ for methocarbamol, 20.00–60.00 µg mL⁻¹ for paracetamol, 0.06–4.00 µg mL⁻¹ for p-aminophenol, and 0.08–10.00 µg mL⁻¹ for guaifenesin. The techniques were evaluated in accordance with ICH directions, and the outcomes confirmed the reliability and validity of the developed methods. The suggested approaches were successfully applied to analyze methocarbamol and paracetamol in their combined tablets and to quantify their related impurities. Furthermore, the environmental impact of these techniques was evaluated using a variety of metrics, assessing their greenness and whiteness alongside their practical effectiveness (blueness), with the results highlighting their superior environmental performance. Additionally, the suggested techniques' sustainability was appraised using the recently introduced NQS index, yielding a score of 67.70%, demonstrating strong alignment with sustainable analytical practices.

Oxidative stress is responsible for the functional loss and sensory impairment of neurons, which leads to progressive loss of brain and spinal cord cells and contributes significantly to several neurological disorders, thus eventually resulting in brain atrophy and death. This study involves the isolation of lignans, including phyllanthin, hypophyllanthin, and nirtetraline, from Phyllanthus amarus. Furthermore, the phyllanhtin was semi-synthetically modified to give phyllanthin oxadiazole derivatives and was evaluated for neuroprotective activity in scopolamine-injured neuroblastoma-2a (N2A) cells. The biochemical assay for reactive oxygen generation (ROS) production in N2A cells was carried out using 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) dye, and the mitochondrial membrane potential (MMP) was determined in N2A cells by using JC-1 dye. Furthermore, the N2A neuronal deaths were evaluated using acridine orange (AO), ethidium bromide (EtBr), and propidium iodide dyes. Among them, nirtetraline, hypophyllanthin, phyllanthin, and compounds 21 and 31 showed potential neuroprotective effects in N2A cells against scopolamine-induced neurotoxicity by inhibiting ROS production and improving MMP. Moreover, the synthesized compounds were nontoxic to the N2A cell line. Furthermore, in silico docking studies predicted phyllanthin derivatives 21 and 31 exhibit neuroprotective activity by binding to the human NADPH-oxidase 5 enzyme. Thus, compounds 21 and 31 can be considered potential neuroprotective leads.

Ovarian cancer remains one of the most lethal gynecological malignancies, underscoring the need for novel therapeutic strategies. In this study, a series of pyrimidine-based nucleobase (7–14) and nucleoside (21–24) analogs were synthesized and evaluated for their potential anticancer activity through poly(ADP-ribose) polymerase (PARP) inhibition. These compounds were tested for in vitro cytotoxicity on ovarian cancer cell lines OVCAR-3 and KURAMOCHI. Among the synthesized derivatives—namely, 4-(4-substituted phenylamino)-1-cyclopentyl-5-(H/methyl)pyrimidine-2(1H)-ones (7–14) and 4-(4-substituted phenylamino)-1-(β-d-ribofuranosyl)-5-methylpyrimidine-2(1H)-ones (21–24)—compound 8 exhibited the most potent cytotoxic activity. It significantly reduced cell viability in OVCAR-3 (IC₅₀ = 27.1 ± 4.56 µM) and KURAMOCHI (IC₅₀ = 46.2 ± 4.87 µM) cells, outperforming the reference PARP inhibitor olaparib (IC₅₀ = 75.8 ± 6.1 µM for OVCAR-3, IC₅₀ = 84.5 ± 11.4 µM for KURAMOCHI). These results suggest that compound 8 is a promising lead candidate for further development as an anticancer agent targeting PARP in ovarian cancer.

Recent research has shown that heterocyclic compounds and their derivatives have garnered a great deal of attention in medicinal chemistry due to their noteworthy biological and pharmacological characteristics. A characteristic of both natural products and pharmaceutical drugs is the triazole nucleus which is one of the most significant heterocycles. Most pharmaceuticals include large amounts of heterocyclic nitrogen. One of the preferred structural motifs of triazoles, among nitrogen-containing heterocyclic compounds, has drawn a lot of interest from both academia and industry. Triazoles are widely used in organic synthesis, supramolecular chemistry, polymer chemistry, drug discovery, chemical biology, bioconjugation, fluorescence imaging, and materials research. Additionally, this intriguing heterocycle's many biological functions will be covered. Researchers, particularly those paying attention to the development of triazole derivatives with a number of synthetic methods—particularly the well-liked click chemistry approach—and their pharmacological outcomes such as antifungal, antitubercular, antibacterial, antiviral, and anticancer properties will find this review highly significant.

Mogroside V (MOG-V), a natural triterpene glycoside predominantly derived from the fruit pulp of Siraitia grosvenorii, is widely recognized as a high-intensity non-caloric sweetener. In recent years, it has attracted considerable research interest due to its broad pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and neuroprotective effects. Notably, MOG-V exhibits a remarkable capacity to scavenge intracellular reactive oxygen species (ROS), thereby supporting mitochondrial function and promoting cellular homeostasis. It has also shown promising efficacy in alleviating pneumonia. Mechanistic studies indicate that MOG-V modulates glucose and lipid metabolism through activation of the AMPK signaling pathway. Furthermore, it confers neuroprotective benefits in models of Parkinson's disease via regulation of critical metabolic pathways. Despite these advances, a comprehensive and critical outlook on the synthesis, pharmacological mechanisms, and therapeutic applications of MOG-V remains lacking. Based on the current research status and existing limitations, this review provides a comprehensive analysis of MOG-V, including its structural characteristics, novel synthetic approaches, and pharmacological investigations. Furthermore, it critically evaluates the therapeutic potential of MOG-V and identifies promising directions for future research. This study systematically consolidates and assesses the available knowledge of MOG-V, with the aim of clarifying its mechanistic foundations and proposing novel insights for subsequent studies.