Future Journal of Pharmaceutical Sciences最新文献

Background

Since its first synthesis in the nineteenth century, hydantoin has emerged as a vital scaffold in drug development, especially for anticonvulsant, antimicrobial, antitumor, and anti-inflammatory agents. Phenytoin, a well-known hydantoin derivative, remains a cornerstone in epilepsy treatment due to its modulation of voltage-gated sodium channels. Beyond this, hydantoin derivatives exhibit diverse biological activities, including anticancer, immunomodulatory, and antimicrobial properties. Synthetic versatility and a broad bioactive profile enhance their pharmaceutical significance.

Objective

The objective of this review is to provide a comprehensive insights on hydantoin derivatives, highlighting their pharmacological potential, structural diversity, and synthetic approaches. It also explores how substitution patterns and stereochemistry influence their biological activity.

Materials and Methods

Hydantoin derivatives can be synthesized through conventional methods and advanced techniques, such as microwave-assisted synthesis. Their anticonvulsant properties are typically evaluated using both in vitro and in vivo models. Common in vivo screening includes intraperitoneal administration in maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ)-induced seizure models.

Results

Studies show that substitution at key positions on the hydantoin ring significantly affects biological activity. Microwave-assisted synthesis often yields more potent derivatives. Some compounds also exhibit anti-inflammatory and anticancer activities, broadening their therapeutic potential.

Conclusion

Hydantoin derivatives exhibit significant pharmacological potential, driven by their structural versatility and diverse substitution patterns. Enhanced synthetic approaches, such as microwave-assisted methods, improve yield and bioactivity. Their broad spectrum of action, particularly in anticonvulsant, anti-inflammatory, and anticancer domains, underscores their continued relevance in drug development.

Graphical Abstract

Background

Chalcones are versatile intermediates widely used in synthesizing heterocyclic compounds due to their diverse pharmacological potential. ß-amino ketones, derived from chalcones, are valuable in medicinal chemistry as intermediates for bioactive molecules. This study focuses on the synthesis of substituted N'-(3-oxo-1,3-diphenylpropyl)isonicotinohydrazides via an Aza-Michael reaction, using substituted chalcones and isoniazid.

Results

The synthesized compounds were characterized by spectral data (UV–visible, FTIR, 1H NMR, 13C NMR, and elemental analysis). Antimicrobial activities were evaluated against Gram-positive and Gram-negative bacteria and fungal strains using the standard disk diffusion method. Specifically, compound 5a exhibited a 32 mm zone of inhibition against Panysallium notatum and a 15 mm zone of inhibition against Trichoderma harzianum, which were superior to the standard commercial antifungal agent miconazole (15 mm and 10 mm, respectively).

Conclusion

The study successfully synthesized and characterized ß-amino ketones derived from substituted chalcones and isoniazid. Among the synthesized compounds, 5a displayed remarkable antifungal activity, compared with the standard antifungal agent, miconazole. This highlights its potential as a lead compound for developing new antifungal agents.

Background

Genus Penicillium represents one of the most prolific fungi in terms of biosynthesis of bioactive secondary metabolites. This review aims to survey the reported terpenoids isolated from different species of genus Penicillium and virtually screen their potential as xanthine oxidoreductase (XORs) inhibitors via in silico molecular modeling studies.

Results

More than 140 terpenoidal compounds were included in this study and evaluated for their in silico XOR inhibitory activity. The in silico study revealed that compounds 3-hydroxy-agathic acid (27), agathic acid (28), isopenicin A (86), decaturenol A (108), chermebilaene A (137), and 6-[(2E,6E)-10,11-dihydro-11-hydroxy-farnesyl]- 5,7-dihydroxy-4-methylphthalide (142) exhibit considerable inhibition of XOR potential.

Conclusion

The in silico XORs inhibition screening study revealed promising candidates from the terpenoidal pool reported from different Penicillium sp., and these candidates can be promoted for further in vitro, in vivo, and preclinical studies to validate the in silico results to support the anti-gout drug pipelines with potential natural products candidates.

Breast cancer is the most prevalent cause of cancer-related deaths among women worldwide. Patients that get chemotherapy endure severe side effects and develop drug resistance. To optimize the immune system's ability to destroy breast cancer, several strategies have been developed. Natural product-based breast cancer treatments are also getting plenty of attention because of their low toxicity as well as their high efficacy and selectivity. From marine cyanobacteria Moorena producens, about 231 chemicals were discovered and categorized into 66 types. The role of M. producens constituents such as malyngamides, microcolins, dolastatins, apratoxins, apramides, lyngbyatoxins, guineamides, oscillatoxins, and majusculamides in the treatment of breast cancer is thoroughly reviewed in this article, which also highlights related mechanisms of action and potential difficulties. Additionally, it provides recommendations for future research directions.

This study examined the protective effects of the central nervous system stimulant modafinil (MODA) in a mouse model of cholestatic hepatitis caused by α-naphthylisothiocyanate (ANT). Cholestatic hepatitis is a liver disease that is characterized by liver damage, discomfort, and jaundice. MODA was selected because of its known anti-inflammatory, anti-apoptotic, and protective qualities. For the study, mice received ANT (50 mg/kg) to induce liver injury, while MODA (60 mg/kg) was administered daily for five days. Liver function was assessed by measuring plasma levels of ALT, AST, and total bilirubin, alongside markers of oxidative stress. Apoptotic and inflammatory indicators, including p53, Bax, Bcl-2, caspase-3, and NF-κB, were quantified using immunohistochemistry and ELISA. Caspase-1, -3, and -9 activities were also measured. Results showed that ANT caused hepatomegaly, increased oxidative stress, inflammation, and apoptosis in the liver. However, MODA treatment significantly reduced these adverse effects. Specifically, MODA decreased liver enlargement, improved histological damage, lowered ALT and AST levels, and enhanced oxidative balance by reducing MDA and increasing GSH and SOD. Inflammatory mediators like NF-κB, IL-6, TNF-α, and caspase-1 were also suppressed. Moreover, MODA modulated apoptotic pathways, leading to decreased Bax and caspase-3/9 expression and increased Bcl-2 expression. In conclusion, MODA offers protective benefits against ANT-induced cholestatic liver injury by mitigating oxidative stress, inflammation, and mitochondria-mediated apoptosis. These findings highlight MODA's therapeutic potential for cholestatic hepatitis, suggesting a quicker path to clinical application given its existing approval for other uses. However, MODA retained only mild ability to restore normal bilirubin clearance. Due to the acute nature of the model, the anti-fibrotic potential in a chronic disease model should be evaluated in future, thereby facilitating advancement in clinical translation.

Background

Allium genus encompasses widely consumed vegetables including onion, Welsh onion, garlic, and leek which are known for their rich bioactive compound content.

Methods

In the present study, the total phenolic and flavonoid contents, vitamin composition, in addition antioxidant capacities of alcoholic extracts from four Egyptian Allium species: A. cepa (red onion), A. fistulosum (Welsh onion), A. sativum (garlic), and A. porrum (leek), were investigated. Standard spectrophotometric assays (Folin–Ciocalteu, aluminum chloride) and antioxidant assays (DPPH, ABTS, and FRAP) were employed.

Results

A. cepa exhibited the greatest total phenolic content (135.69 ± 1.89 mg GAE/g), while A. porrum showed the greatest flavonoid content (25.15 ± 0.52 mg RE/g). Vitamin profiling revealed A. fistulosum contained the highest levels of vitamin B6 and was the only species to contain vitamin C. Antioxidant activity varied by assay: A. fistulosum demonstrated the strongest DPPH and ABTS radical scavenging activities (4.37 ± 0.09 µg Eq/mg and 62.27 ± 2.86 µg Eq/mg, respectively), while A. porrum exhibited the highest reducing power in the FRAP assay (49.98 ± 1.76 µg Eq/mg).

Conclusion

These findings highlight the health-promoting potential of four Egyptian Allium species, supporting their inclusion into functional foods and nutraceuticals. Their high content of bioactive substances, particularly natural antioxidants and critical vitamins, makes them interesting candidates for dietary therapies to prevent oxidative stress-related illnesses. This study provides the first comprehensive comparative analysis of these four Allium species collected from Egypt, conducted under standardized extraction and analytical conditions, thereby offering new insights into their unique phytochemical composition and antioxidant profiles.

Background

Non-ischemic reactive myocardial fibrosis (MF) is a significant global cause of chronic heart failure (CHF) related to fatalities and morbidity. Punicalagin (PUN), a primary phenolic component in pomegranate, has been acknowledged as cardioprotective agent in isoproterenol (ISO)-induced ischemic MF. However, the therapeutic roles of PUN individually and in combination with captopril in ameliorating the progression of reactive myocardial fibrosis were not previously explored.

Aim of the study

Our study was designed to explore the potential therapeutic benefits of PUN alone and in combination with captopril (CAP) in ISO-induced reactive MF.

Material and methods

Thirty-five male rats of the Sprague–Dawley species, 220–240 g, were randomly allocated across the 5 groups. Group1: Normal control; ISO Group2: received single daily subcutaneous injections of isoprenaline (5 mg/kg/day) for 10 days Captopril (CAP) group3: orally administered in a dose of 15 mg/kg/day for 60 days; PUN group4: orally administered in a dose of 200 mg/kg/day60 days, and CAP/PUN group5: rats were administered both CAP and PUN in the aforementioned doses and duration.

Results

Bioinformatically, CD68 protein showed co-expressional associations with TGF-β1, PPAR-γ, and Akt proteins, for which PUN displayed significant affinities via molecular docking. In ISO-injected rats, PUN and/or CAP lowered abnormally elevated parameters, but the combination therapy demonstrated superior effects in near normalizing most parameters including cardiac hemodynamics (in contrast to ISO group, HR, SBP, DBP, and DBP were by 53%, 21%, and 39%, respectively, with concomitant increase in EF by 70% and decrease in IVSD and LVDD by 43% and 66%, respectively, alongside with amelioration of the ISO-driven higher cardiac TGF-β1, Smad2/3, PTEN, and Wnt/β-catenin levels by 57%, 74%, 69%, 70% and 67%, respectively, in addition to considerable 1.6-, 1.2-, onefold, 1.45-fold increases in cardiac PPAR-γ, PI3K, pAKT, and Smad7 expression levels, respectively). Histopathological MF generated by ISO was reversed after PUN and/or CAP administration. The immunohistochemical study of fibrotic heart tissues revealed a noticeable increase in CD68⁺ macrophages and TGF-β1, which were reduced after PUN and/or CAP.

Conclusion

Phenotypical CD68⁺ macrophages have a pathophysiological role in ISO-induced reactive MF. Besides, punicalagin alone or in combination with captopril plays complementary therapeutic functions in experimentally reactive MF, suggesting their combination as a potential novel therapeutic approach for MF.

Graphical abstract

Background

β-lactam antibiotics are the greatest pharmaceutical development in modern medicine and are employed to treat numerous bacterial infections. Nonetheless, an alarming increase in antimicrobial resistance to β-lactam antibiotics has emerged primarily as a result of the extensive spread of β-lactamase enzymes such as extended-spectrum β-lactamases and carbapenemases, undermining the efficacy of available therapy, creating a global health problem through the rise in morbidity, mortality, and healthcare expenditure. Despite the development of β-lactamase inhibitors, the emergence of resistant β-lactamases necessitates the rapid discovery of new inhibitors or potentiators of existing antibiotics. Therefore, finding novel inhibitory compounds or a potentiator from alternative natural sources, such as medicinal plants, is imperative. Thus, this study aims to evaluate the potentiating effect of the crude extract of Melastoma malabathricum and other medicinal plants in combination with β-lactam antibiotics against resistant bacterial strains using in vitro as well as in silico study.

Results

The crude extract of Melastoma malabathricum was found to exhibit synergism against a CTX-M-producing E. coli when combined with cefotaxime, whose association of synergy with β-lactamase inhibition was confirmed using micro-iodometric assay and agar-based diffusion bioassay. It was further validated by molecular docking of the phytocompounds from the GC–MS study, in which 1,2-benzenedicarboxylic acid/NSC5348 exhibited the best binding energy with potential interactions with the active amino acid sites of the CTX-M. Thus, this compound was further chosen for a molecular dynamics simulation study with CTX-M-14, in which the complex was found to have good stability with consistent conformation throughout the simulation. Moreover, NSC5348 cleared drug-likeness filters.

Conclusion

This finding highlights the β-lactamase inhibitory potential of Melastoma malabathricum, which may also act as a potentiator of β-lactams against the CTX-M producers. Thus, Melastoma malabathricum shows promise for use in combination therapy to combat drug resistance.

Background

Breast cancer (BC) is a complex malignancy, impacting a considerable number of women worldwide. Devastating evidence annotated the contribution of dysregulated non-coding RNAs in the evolution and diagnosis of BC. Bioinformatics analyses were employed to select the markers; long non-coding RNA tumor suppressor candidate 7 (TUSC7), its target miR-616, and the associated tumor suppressor Sex Determining Region Y-Box 7 (SOX7) as potential therapeutic targets in BC pathogenesis and metastasis, pertaining to their predictive and discriminating capacities. Herein, 100 subjects were enrolled; 60 BC patients (40 non-metastatic, 20 metastatic), along with 20 fibroadenoma patients, and 20 healthy volunteers.

Results

Serum TUSC7 and SOX7 were significantly downregulated, whereas miR-616 was significantly upregulated in BC patients versus both controls and fibroadenoma patients. As well, these alterations were more prominent in metastatic versus non-metastatic BC patients. ROC analysis identified SOX7 as an excellent discriminator between BC patients and controls (AUC = 0.91, p < 0.0001) and between metastatic and non-metastatic cases (AUC = 0.766, p = 0.0009). Meanwhile, TUSC7 demonstrated an outstanding discriminative power between BC and fibroadenoma (AUC = 0.933, p < 0.0001). Furthermore, univariate and multivariate logistic analyses revealed the capabilities of TUSC7, miR-616, and SOX7 as significant predictors of BC risk; meanwhile, only SOX7 was identified as a significant predictor of BC metastasis. Combining TUSC7, miR-616, and SOX7 in a predictive panel showed substantial diagnostic accuracy for BC (AUC = 0.978, 95% CI = 0.9567–1.000, p < 0.0001).

Conclusion

Collectively, this study configures TUSC7/miR-616/SOX7 panel as a novel prospective biomarker and therapeutic target for BC and accentuates SOX7 as a potential predictor of tumor aggressiveness and metastatic behavior.

Graphical abstract