Archiv der Pharmazie最新文献

The Amazon rainforest is renowned for its biodiversity and as a reservoir of edible and medicinal plants. The phytochemicals in murici and taperebá fruits serve as natural antioxidants, contributing to cultural preservation, ecosystem protection, and economic opportunities. However, limited scientific research on their composition and health benefits hinders their recognition as functional foods. This study aimed to evaluate the antioxidant activity, carotenoid content, phenolic compounds, and antitumor effects of murici and taperebá fruit pulps. Four antioxidant tests (2,2-Diphenyl-1-picrylhydrazylradical scavenging activity, 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) method, 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) method, oxygen radical absorbance capacity) were conducted, and total phenolics were quantified (Folin-Ciocalteu). Phenolics were identified using UHPLC-HRMS, and carotenoids by high-performance liquid chromatography (HPLC). The impact on breast cancer cell viability (MCF-7, MDA-MB-231) was assessed via water-soluble tetrazolium (WST) assay. Both fruits showed high antioxidant activity and phenolic content, with murici leading. HPLC revealed five carotenoids per fruit, with taperebá showing higher concentrations. UHPLC-HRMS identified 23 phenolic compounds: 16 in murici aqueous extract, 18 in murici ethanolic extract, and 15 in each taperebá extract. WST assay demonstrated that both fruits exerted a significant impact on breast cancer cells, reducing their viability in a dose-dependent manner. These findings underscore the potential of murici and taperebá as sources of phytochemical antioxidants and antiproliferative agents with promising health applications.

2,2′-Thio-bis(4,6-dichlorophenol), namely bithionol, is a small molecule endowed with a multifaceted bioactivity. Its peculiar polychlorinated phenolic structure makes it a suitable candidate to explore its potentialities in establishing interaction patterns with enzymes of MedChem interest, such as the human carbonic anhydrase (hCA) metalloenzymes. Herein, bithionol was tested on a panel of specific hCAs through the stopped-flow technique, showing a promising micromolar inhibitory activity for the hCA II isoform. X-ray crystallographic studies revealed an unprecedented halogen-bond interaction between one chlorine of bithionol and the N3(ε) atom of the hCA II catalytically active histidine residue, His64. Then, quantum mechanics calculations based on the fragment molecular orbital method allowed us to estimate the strength of this bond (~2.9 kcal/mol) and highlighted the contribution of a rich hydrophobic interaction network within the isoenzyme. Interestingly, the compound inactivity against the hCA III isoform, characterized by His64Lys and Leu198Phe mutations, supported the key role played by halogen bonding in the enzyme affinity. This finding might pave the way for the development of a new class of hCA inhibitors characterized by such chemical features, with the halogen bond being a key ligand–receptor interaction.

The P2X4 receptor (P2X4R), a ligand-gated ion channel activated by ATP, plays a critical role in neuroinflammation, chronic pain, and cancer progression, making it a promising therapeutic target. In this study, we explored the design and synthesis of piperazine-based P2X4R antagonists, building on the structural framework of paroxetine. A series of over 35 compounds were synthesized to investigate structure–activity relationships (SARs) in a Ca²⁺-flux assay for P2X4R antagonistic activity. Several compounds outperformed paroxetine in terms of antagonistic P2X4R potency. Further studies on absorption, distribution, metabolism, excretion properties revealed that increased lipophilicity often correlated with high plasma protein binding and decreased metabolic stability, particularly in compounds with a naphthalene-2-yloxy group. Although promising SARs were observed, further optimization is needed to enhance antagonistic P2X4R receptor activity. This work provides important insights into the development of piperazine-based P2X4R antagonists and lays the foundation for future therapeutic advancements targeting P2X4R-related diseases.

Cancer, characterized by uncontrolled growth and spread of abnormal cells potentially influencing almost all tissues in the body, is one of the most devastating and lethal diseases throughout the world. Chemotherapy is one of the principal approaches for cancer treatment, but multidrug resistance and severe side effects represent the main barriers to the success of therapy, creating a vital need to develop novel chemotherapeutic agents. The 1,2,3-triazole moiety can be conveniently constructed by “click chemistry” and could exert diverse noncovalent interactions with various enzymes in cancer cells. Hence, 1,2,3-triazole is one of the most fascinating anticancer pharmacophores. Moreover, 1,2,3-triazole could also serve as a powerful ligation tool for the complex molecular architectures to increase the anticancer efficacy of lead molecules. Notably, 1,2,3-triazole-containing hybrids with intriguing structural variations could target different biological components in cancer cells simultaneously, highlighting their potential in the treatment and eradication of cancer. This review outlines the current landscape of 1,2,3-triazole-(fused) six-membered nitrogen-containing heteroaromatic ring hybrids, inclusive of 1,2,3-triazole-quinazolines, 1,2,3-triazole-quinazolinones, 1,2,3-triazole-quinolines, 1,2,3-triazole-quinolones, 1,2,3-triazole-pyridines, and 1,2,3-triazole-pyrimidines, with anticancer therapeutic potential, and explores their mechanisms of action, critical aspects of design as well as structure–activity relationships (SARs), covering articles published from 2021 to the present, to pave the way for the development of innovative and efficient therapeutic interventions for cancer therapy.

Alzheimer's disease (AD) is a prevalent neurological illness that affects over 80% of aged adults globally in cases of dementia. Although the exact pathophysiological causes of AD remain unclear, its pathogenesis is primarily driven by several distinct biochemical alterations: (i) the accumulation of toxic Aβ plaques, (ii) the hyperphosphorylation of tau proteins, (iii) oxidative stress resulting in cell death, and (iv) an imbalance between the two main neurotransmitters, glutamate and acetylcholine (ACh). Currently, there are very few medications available and no treatment. Presently marketed medications include memantine, an N-methyl-d-aspartate receptor (NMDA) antagonist, and acetylcholinesterase (AChE) inhibitors: rivastigmine, donepezil, and galantamine. Unfortunately, these medications are only useful in the initial stages of AD. The mentioned medications only provide symptomatic relief and do not slow down the disease progression in the advanced stages. Therefore, there is an urgent need to develop potential candidates to treat AD, symptomatically and therapeutically. Many research groups focus on natural products due to their diverse therapeutic profiles and easy availability. One such natural product is deoxyvasicinone, isolated from Adhatoda vasica. Given its broad pharmacological profile, various researchers have developed semisynthetic hybrids of deoxyvasicinone to address multifaceted diseases like AD. In this review article, we tried to summarize the semisynthetic hybrids of deoxyvasicinone developed over the past decade (2014–2024) for managing AD. We focus on their design, pharmacological activity, and structure–activity relationship (SAR) analysis. We hope this review enhances the reader's understanding of future exploratory options for deoxyvasicinone hybrids in AD management.

Multidrug resistance (MDR) due to the overexpression of the P-glycoprotein (P-gp) efflux pump remains a significant challenge in cancer therapy, also in breast cancer. Traditional pharmacological approaches have focused on using inhibitors to modulate P-gp expression and function. Curcumin, a polyphenol derived from Curcuma longa L., is one of the most extensively studied natural compounds with the potential as an effective P-gp inhibitor. Despite its promising attributes, the clinical application of P-gp inhibitors is complicated by P-gp's presence in healthy cells, such as those in the intestinal barrier and blood–brain barrier, which can lead to increased toxicity. To address these challenges, we developed a novel multifunctional nanomaterial by covalently bonding halloysite nanotubes (HNTs) with hectorite (Ht) and loading it with curcumin and doxorubicin. The efficacy of the co-delivery of curcumin and doxorubicin by HNTs-Ht nanomaterial was evaluated by cytotoxicity assays on MCF-7R cells, both in two-dimensional (2D) and in three-dimensional (3D) models. The obtained data show that curcumin causes increased doxorubicin accumulation by acting as a substrate for P-gp transport and as a stimulator of the adenosine triphosphate (ATP)-dependent drug efflux transporter on a doxorubicin-resistant breast cancer cell line. The results suggest that the HNTs-Ht nanomaterial could provide a promising approach to improve chemotherapy effectiveness by overcoming MDR and enhancing treatment outcomes.

This report explores the potential of novel 6-aryloxy-2-aminopyrimidine-benzonitrile scaffolds as promising anti-infective agents in the face of the increasing threat of infectious diseases. Starting from 2-amino-4,6-dichloropyrimidine, a series of 24 compounds inspired from the antiviral drugs dapivirine, etravirine, and rilpivirine were designed and synthesized via a two-step reaction sequence in good yields. Biological testing of synthetic analogs revealed potent inhibition against both viral and tuberculosis targets. Notably, compounds 5p (2,4-dimethyl substitution; IC₅₀ = 44 ± 4.9 µM; selectivity index [SI] = 20) and 5 s (3-thiophenphenyl; IC₅₀ = 6 ± 1 µM; SI = 120) showed significant antiviral activity against pandemic influenza virus A/Puerto Rico/8/34 (H1N1) with positive toxicity profiles and also exhibited good IC₅₀ values (5p, IC₅₀ = 10 ± 2 µM; SI = 9 and 5 s, IC₅₀ = 16 ± 2 µM; SI = 60) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Wuhan strain) compared with favipiravir. In addition, analogs 5a, 5r, 5t, and 5u showed good antitubercular activity against Mycobacterium tuberculosis H37Rv strain and compounds 3, 5f, 5n, and 5q showed moderate antibacterial activity against gram+ve and gram-ve bacterial strains, suggesting that this scaffold has a broad spectrum of therapeutic effects.

New derivatives 6a–m with benzimidazole–indole–amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on α-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the α-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose. Moreover, the anti-AChE activity of these compounds, with the exception of one compound, was better than that of tacrine (standard inhibitor). The most potent compound against α-glucosidase was 3-methylphenyl derivative 6i and the most potent compound against AChE was 3,4-dimethoxyphenethyl derivative 6m. All the synthesized compounds were placed in the active sites of α-glucosidase and AChE by in silico docking method and the obtained binding energies were approximately in agreement with the in vitro observed data. Interaction modes of the most potent compounds 6i and 6m demonstrated that these compounds interacted with important residues of their target enzymes. Molecular dynamics simulation was conducted specifically on compound 6i in complex with α-glucosidase to obtain deeper insights into the behavior of this molecule. Furthermore, in silico pharmacokinetic and toxicity studies on the most potent compound predicted that these compounds have good profiles in terms of oral absorption and toxicity.

Bacteria biofilm infection seriously challenges clinical drug therapy. Nitric oxide (NO) was reported to disperse biofilm, eliminate bacteria resistance and kill bacteria. In this study, on the basis of membrane targeting of α-mangostin (α-MG) and the dispersion effect of NO on bacteria biofilms, we designed and synthesized 30 NO donors that α-MG was conjugated with a nitrobenzene or a nitrate and other four representative reference derivatives. Compound 23 with 2-chloro-4-nitrobenzoyl introduced in the position C6 of α-MG exhibited the prominent ability to eradicate Staphylococcous aureus biofilm, and a more long-lasting and stable bactericidal effect in vitro, and lower hemolytic activity over α-MG. Moreover, a mouse wound model infected by S. aureus biofilm supported the in vivo reduced bacterial burden closely associated with the NO release from compound 23 that exerted a dispersing effect on biofilms. Therefore, our design strategy can provide a promising and effective solution to intervene in biofilm infection with high specificity.

In this study, four depsides were isolated from Origanum dictamnus L. and Satureja pilosa Velen. medicinal plants and their structures were assessed by means of one-dimensional (1D)- and two-dimensional (2D)-nuclear magnetic resonance, high resolution mass spectrometry, and electronic circular dichroism analyses. The compound 1, herein reported for the first time, salvianolic acid P 2, clinopodic acid I 3, and clinopodic acid O 4 were all profiled in vitro on a panel of human (h) expressed carbonic anhydrases (CAs; EC 4.2.1.1) and preferential inhibition for the tumor-associated human carbonic anhydrase (hCA) IX and hCA XII over the constitutively expressed hCA I and hCA II isoforms was observed. X-ray crystallography allowed us to assess the binding mode of salvianolic acid P 2 to hCA II. The compounds exhibited significant cytotoxic effects on the human triple-negative breast cancer cell line MDA-MB-231, suggesting that this class of depsides are promising molecules for future investigation.