Archiv der Pharmazie最新文献

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is mainly treated with cytotoxic chemotherapy. However, this treatment is not always effective, and an important percentage of patients develop recurrence. Nanomaterials are emerging as alternative treatment options for various diseases, including cancer. This work reports the synthesis, characterization, antitumor activity evaluation, and sub-acute toxicity studies of two formulations based on amorphous silica nanoparticles (SiNPs). They are functionalized with 3-aminopropyltriethoxisilane (Si@NH₂) and folic acid (FA; Si@FA). The results show that SiNPs reduce the viability and migration of TNBC MDA-MB-231 and 4T1 cell lines and Si@FA do not affect the growth of the mammary nonmalignant HC11 cells. In addition, Si@FA induces reactive oxygen species (ROS) generation and displays antiproliferative and subsequently proapoptotic effects in MDA-MB-231 cells. Moreover, none of the SiNPs cause signs of sub-acute toxicity in mice when administered at 30 mg/kg over a month. In conclusion, these nanosystems display intrinsic antitumor activity without causing toxic in vivo effects, being a promising therapeutic alternative for TNBC.

In the late 19th century, progress in dye chemistry led to advances in industrial organic chemistry in Germany. Over the next few decades, this revealed dyes not just as color agents but as promising lead compounds for drug development. Collaborations between dye chemists and medical researchers were crucial in turning these unexpected discoveries into structured medicinal chemistry efforts. The outcomes included major drug classes like sulfa antibiotics, antifungal azoles, and others, resulting in a legacy where dyes served not only as biological stains but as crucial tools for understanding complex natural products and drug interactions. Today, the impact of dye molecules persists in clinical therapies, molecular probing, pharmacokinetic tracing, and high-throughput screening. This review underscores the historical contributions shaping contemporary pharmaceutical sciences, highlighting the role of dyes as indispensable tools propelling drug discovery across generations.

The flavonoid chrysin is an effective vascular Ca_V1.2 channel blocker. The aim of this study was to explore the chemical space around chrysin to identify the structural features that can be modified to develop novel and more effective blockers. Four derivatives (Chrysin 1–4) were synthesised and a functional, electrophysiology and molecular docking approach was pursued to assess their binding mode to Ca_V1.2 channels and their activity in vascular preparations. Methylation of the 5- and 7-OH of the chrysin backbone caused a marked reduction of the Ca²⁺ antagonistic potency and efficacy. However, C-8 derivatives showed biophysical features similar to those of the parent compound and, like nicardipine, bound with high affinity to and stabilised the Ca_V1.2 channel in its inactivated state. The vasorelaxant effects of the four derivatives appeared vessel-specific, addressing the molecules' derivatization towards different targets. In conclusion, the scaffold of chrysin may be considered a valuable starting point for the development of innovative vascular Ca_V1.2 channel blockers.

Hibiscus species (Malvaceae) possess a plethora of appealing pharmacological activities with an extended history of customary use in diverse medical conditions. The present study aimed at comparing the metabolomic analyses of three Hibiscus species native to Egypt, namely H. tiliaceus, H. schizopetalus extract (HSE), and H. rosa-sinensis, alongside identifying a promising natural wound healing candidate. Chemical profiling of the leaf extracts was achieved via UPLC-ESI/MS/MS-guided analysis that resulted in the tentative identification of a total of 48 secondary metabolites pertaining to phenolic acids, flavonoids, anthocyanins, fatty acids, and fatty amides. Remarkably, in vitro studies revealed that HSE exhibited the topmost wound healing activity. Subsequently, HSE was formulated into hydro- and nanogel (1% w/v) formulations for further assessing its efficacy in the wound excision model. HSE-nanogel demonstrated a significant in vivo wound contraction activity alongside improving histopathological abnormalities. Mechanistically, HSE-nanogel upregulated the wound antioxidant status through increasing the levels of reduced glutathione (GSH) and catalase activity. Moreover, HSE-nanogel suppressed the wound inflammatory responses by diminishing the expressions of NF-ĸB, TNF-α, and IL-6. Molecular docking studies were performed on HSE's major constituents using CDOCKER, which further supported the in vivo findings. Collectively, HSE nanogel exhibits notable aptitude as a wound-healing agent, warranting further clinical appraisal.

Sulfonamides are promising classical carbonic anhydrase (CA; EC 4.2.1.1) inhibitors, being used for several medical purposes such as diuretics, anticonvulsants, topically acting antiglaucoma agents, for antiobesity and anticancer therapies. Herein, a series of chalcone-based benzenesulfonamides (3a‒m) was synthesized and assessed for its inhibitory activity against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX, and XII). Most compounds displayed single- to double-digit nanomolar inhibition constants (K_is), with some derivatives being more potent and/or selective than the standard drug acetazolamide (AAZ). Among the synthesized compounds, 3g compound demonstrated the highest inhibitory activity against the hCA II isoform (K_i = 2.5 nM) with 30-, 9-, and 11-fold selectivity for hCA II over the I, IX, and XII isoforms, respectively. Structure–activity relationships for different substitution patterns were analyzed. Additionally, a molecular docking study showed that compound 3g bound to hCA II by coordinating with the zinc ion through the deprotonated benzenesulfonamide moiety, in addition to a hydrogen bond formed between an oxygen of the sulfonamide moiety and Thr199. Moreover, the chalcone core participated in van der Waals interactions with some active site residues, such as Ile91, Val121, and Leu198. Consequently, this report introduces a successful approach toward identifying compound 3g as a highly potent and selective chalcone-based benzenesulfonamide inhibitor of hCA II worthy of further investigation.

Cancer ranks among the most life-threatening diseases worldwide and is continuously affecting all age groups. Consequently, many research studies are being carried out to develop new cancer treatments, but many of them experience resistance and cause severe toxicity to the patients. Therefore, there is a continuous need to design novel anticancer agents that are target-based, have a higher potency, and have minimal toxicity. The imidazo[1,2-a]pyridine (IP) pharmacophore has been found to be a prominent moiety in the field of medicinal chemistry due to its vast biological properties. Also, it holds immense potential for combating cancer with minimal side effects, depending on the substitution patterns of the core structure. IPs exhibit significant capability in regulating various cellular pathways, offering possibilities for targeted anticancer effects. The present review summarizes the anticancer profile of numerous IP derivatives synthesized and developed by various researchers from 2016 till now, as inhibitors of phosphoinositide-3-kinase/mammalian target of rapamycin (PI3K/mTOR), protein kinase B/mammalian target of rapamycin (Akt/mTOR), aldehyde dehydrogenase (ALDH), and tubulin polymerization. This review provides a comprehensive analysis of the anticancer activity afforded by the discussed IP compounds, emphasizing the structure–activity-relationships (SARs). The aim is also to underscore the potential therapeutic future of the IP moiety as a potent partial structure for upcoming cancer drug development and to aid researchers in the field of rational drug design.

The eradication of Helicobacter pylori, the etiologic agent of gastric ulcer and adenocarcinoma, is a big concern in clinics due to the increasing drug resistance phenomena and the limited number of efficacious treatment options. The exploitation of the H. pylori carbonic anhydrases (HpCAs) as promising pharmacological targets has been validated by the antibacterial activity of previously reported CA inhibitors due to the role of these enzymes in the bacterium survival in the gastric mucosa. The development of new HpCA inhibitors seems to be on the way to filling the existing antibiotics gap. Due to the recent evidence on the ability of the coumarin scaffold to inhibit microbial α-CAs, a large library of derivatives has been developed by means of a pH-regulated cyclization reaction of coumarin-bearing acyl thiosemicarbazide intermediates. The obtained 1,3,4-thiadiazoles (10–18a,b) and 1,2,4-triazole-3-thiones (19–26a,b) were found to strongly and selectively inhibit HpαCA and computational studies were fundamental to gaining an understanding of the interaction networks governing the enzyme–inhibitor complex. Antibacterial evaluations on H. pylori ATCC 43504 highlighted some compounds that maintained potency on a resistant clinical isolate. Also, their combinations with metronidazole decreased both the minimal inhibitory concentration and minimal bactericidal concentration values of the antibiotic, with no synergistic effect.

Tetrahydropyrimidine (compound A = methyl 4-[4′-(heptyloxy)-3′-methoxyphenyl]-1,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate) was chosen for in vivo studies after exhibiting noteworthy in vitro activity against the K562 and MDA-MB-231 cell lines, with IC₅₀ values of 9.20 ± 0.14 µM and 12.76 ± 1.93 µM, respectively. According to experimental (fluorescence titration, viscosity, and differential scanning calorimetry) results, A interacts with DNA via the minor groove. In vivo, acute oral toxicity studies in Wistar albino rats proved no noticeable symptoms of either toxicity or death during the follow-up period. Genotoxic and antigenotoxic studies at three different concentrations of A (5, 10, and 20 mg/kg of body weight) in Wistar albino rats showed that the dose of 5 mg/kg body weight did not cause DNA damage and had a remarkable DNA protective activity against CCl₄-induced DNA damage, with a percentage reduction of 78.7%. It is also important to note that, under the investigated concentrations of A, liver damage is not observed. Considering all experimental outcomes realized under various in vivo investigations (acute oral toxicity, genotoxicity, antigenotoxicity, and biochemical tests), compound A could be a promising candidate for further clinical testing.

Psoriasis is a skin disorder characterized by impaired epidermal differentiation that is regularly treated by systemic drugs with undesirable side effects. Based on its anti-inflammatory, antiproliferative and anti-melanoma attributes, the fungal metabolite kojic acid represents an attractive candidate for anti-psoriatic research. The present work aims to investigate an efficient topical bio-friendly vesicular system loaded with kojic acid isolated from Aspergillus oryzae as an alternative way for the management of psoriasis to avoid systemic toxicity. Kojic acid-loaded spanlastics were prepared by ethanol injection technique, employing span 60 along with brij 35 and cremophor rh40 as edge activators, with the complete in vitro characterization of the developed nanoplatform. The selected formulation displayed a spherical morphology, an optimum particle size of 234.2 ± 1.65 nm, high entrapment efficiency (87.4% ± 0.84%) and significant sustained drug release compared with the drug solution. In vivo studies highlighted the superior relief of psoriasis symptoms and the ability to maintain healthy skin with the least changes in mRNA expression of inflammatory cytokines, achieved by the developed nanoplatform compared to kojic acid solution. Moreover, the in vivo histopathological studies confirmed the safety of the topically applied spanlastics. In addition, the molecular mechanism was approached through in vitro assessment of cathepsin S and PDE-4 inhibitory activities and in silico investigation of kojic acid docking in several anti-psoriatic drug targets. Our results suggest that a topically applied vesicular system loaded with kojic acid could lead to an expansion in the dermo-cosmetic use of kojic acid as a natural bio-friendly alternative for systemic anti-psoriatic drugs.