Archiv der Pharmazie最新文献

The present review serves to highlight the antitumor worth of pyrazole derivatives. Several active pyrazole-based anticancer compounds proposed by a huge number of scientists worldwide are reported. Regarding the development of novel pyrazole-based anticancer agents at a faster tone, there is a need to correlate the latest information with previously available information to understand the situation of this moiety in anticancer drug discovery studies. Herein, different anticancer pyrazoles are classified according to their mode of action at different anticancer targets. The results provided evidence that pyrazole derivatives have potential applications for the treatment of a variety of tumor types. From the study's findings, the structure–activity relationship (SAR) results demonstrated that all the compounds containing substituted pyrazole represent an important scaffold for anticancer activities. Publications in this area are increasing, and therefore, new therapeutic applications involving members of pyrazole derivatives could be discovered in the near future, as many prospects have not been sufficiently studied so far for other targets. In other words, this review provides an overview of the state of knowledge about the structural characteristics of the most recent anticancer pyrazole derivatives and their SAR with various targets. This will allow medicinal chemists to identify promising structures to guide the design and synthesis of more effective and safer anticancer candidates.

Biocompatible silver nanoparticles (AgNPs) are employed with an active ingredient of milk thistle extract, silybin (SIB), to treat cancers. Strong cytotoxic effects of SIB-AgNPs against two distinct cell lines (MCF-7 and HepG2) are observed on a stable nano-platform that contains spherical nanoparticles within a limited size range. With a high radiochemical purity, radioiodination of SIB-AgNPs was accomplished. The investigation on the biodistribution of [¹³¹I]iodo-SIB-AgNPs in mice-bearing tumors showed that SIB-AgNPs prefer localization in tumor tissue. In conclusion, this work strengthens the case for [¹³¹I]iodo-SIB-AgNPs as an effective theranostic agent for tumor imaging and treatment.

The heptapeptide angiotensin Asp-Arg-Val-Tyr-Ile-His-Pro (ANG 1-7) is a key member of the ACE2/ANG-(1-7)/MasR axis, which is considered a counter-regulator of the classical renin–angiotensin system (RAS) axis concerning its homeostatic and neuromodulatory functions. Four new analogs of ANG 1-7 with general structures of Asp-Arg-Val-Tyr-Ile-His-Xxx-NH₂, where Xxx is 1-aminocyclopentanecarboxylic acid (Ac5c), 1-aminocyclohexane carboxylic acid (Ac6c), and (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical, spectral, DFT calculational, and behavioral methods. The presence of a cis-oriented primary amino group at the molecule's C-terminus is coupled with the structural rigidity of the pyrrolidine Pro ring in the peptide molecule ANG-P1. While in ANG-P2, the cis-oriented primary amino group is connected to the peptide motif by means of the amino acid His leading to the formation of a proline/GABA cis-chimera. The partition coefficient values suggest better lipophilicity of the compounds ANG-P1 and ANG-P2 related to easier passage through the target membranes. The correlation coefficient between the theoretically predicted and experimentally determined logP values is 0.991. The ANG-P1 analog has features comparable to ANG 1-7, but the peptides ANG-P2, ANG-C5, and ANG-C6 exhibit distinct effects, particularly on anxiety-like behavior, according to a comparison of the novel analogs with the precursor peptide. Regardless of how they affect exploration in the open field test, they induce anxiogenic behavior in the elevated plus maze test. The ANG-C5 analog differs from the other analogs because it is unable to create antinociception, despite the fact that ANG 1-7 and its analogs generated notable antinociception.

Nowadays, diseases have a high rate of incidence and mortality worldwide. On the other side, the drawbacks of conventional modalities in the suppression of diseases have encountered serious problematic issues for the health of human beings. For instance, although various approaches have been applied for the treatment of cancer, it has an ever-increasing rate of incidence and mortality throughout the globe. Thus, there is a fundamental requirement for the development of breakthrough technologies in the inhibition of diseases. Hyaluronic acid (HA) is one of the most practical biopolymers in the suppression of diseases. HA has lots of potential physicochemical (like rheological, structural, molecular weight, and ionization, etc.) and biomedical properties (bioavailability, biocompatibility, CD44 targeting and signaling pathways, components of biological organs, mucoadhesion, immunomodulation, etc.), which made it a potential candidate for the development of breakthrough tools in pharmaceutical and biomedical sciences. The ease of surface modification (carboxylation, amidation, hydroxylation, and esterification), high bioavailability and synthesis routes, and various administration routes are considered as other merits of HA-based vehicles. These mucopolysaccharide HA-based materials have been considerably developed for use in drug delivery systems (DDSs), cancer therapy, wound healing, antiaging, and tissue engineering. This review summarizes the advantages of HA-based DDS and scaffolds in the treatment of diseases.

Xylazine, traditionally used as a veterinary sedative, has recently emerged as a new psychoactive substance, being typically ingested in combination with fentanyl derivatives and hence raising significant public health concerns. Despite its increasing prevalence, little is known about its molecular interactions with human neuroreceptors, specifically the serotonin 7 (5-HT₇R) and kappa-opioid (KOR) receptors, which play critical roles in mood regulation, consciousness and nociception. Hence, the binding affinity and molecular interactions of xylazine with both 5-HT₇R and KOR through docking simulations and molecular dynamics calculations were investigated. These computational approaches revealed critical insights into receptor binding motifs and highlighted structural modifications that could enhance receptor affinity. The isosteric replacements within the xylazine structure to improve its binding efficacy were assessed, demonstrating that minimal structural modifications can potentiate its interaction with 5-HT₇R and KOR. These findings may well advance our understanding of xylazine's mechanism of action, possibly contributing to identifying suitable treatment/management approaches in treating xylazine-related overdoses.

Cancer, with its steadily increasing morbidity and mortality, will continue to pose a threat to humanity over an extended period. Chemotherapeutics play an indispensable role in cancer treatment, and hundreds of drugs have been approved for this purpose. Nevertheless, the fight against cancer remains a formidable challenge. This is mainly due to the emergence of multidrug resistance and the severe side effects associated with currently available anticancer drugs. Consequently, there is an urgent imperative to explore novel chemotherapeutic agents. 1,2,3-Triazoles belong to one of the most privileged classes of nitrogen-containing five-membered heterocycles and are regarded as prominent sources for the development of innovative anticancer chemotherapeutics. 1,2,3-Triazole hybrids, which possess multitargeted mechanisms of action within the cancer progression pathway, hold the potential to overcome multidrug resistance and mitigate side effects. Furthermore, several 1,2,3-triazole hybrids have already been approved for cancer therapy or are currently under clinical evaluation. This clearly demonstrates that 1,2,3-triazole hybrids are valuable scaffolds in the treatment and eradication of cancer. This review aims to provide insights into the anticancer therapeutic potential of 1,2,3-triazole hybrids, along with their mechanisms of action, crucial aspects of design, and structure–activity relationships (SARs). It encompasses articles published from 2021 onward.

Cycloartane triterpenoids are widely distributed in the plant kingdom, and there have been reports of hundreds of families containing cycloartane triterpenoids. But the types and content of cycloartane are different among various plants. In recent years, a large amount of cycloartane triterpenoids have been extracted and studied from different plants, and some types of cycloartane triterpenoids exhibit great pharmacological activities in terms of antiaging, antioxidant, anti-inflammatory, anticancer, antiarrhythmic effects, and so on. Herein, we have systematically reviewed these research on the structure of naturally occurring, synthetic, and semisynthetic cycloartane triterpenoids, with particular emphasis on their pharmacological activities.

Influenza infection represents a serious challenge for virological surveillance and healthcare systems in all countries globally. Despite obvious success in control of influenza through vaccination and antiviral drug development, this infection remains poorly controlled due to antigenic drift and fast selection of drug-resistant viral variants. The design of novel drugs with alternative targets and mechanisms of action is, therefore, an important goal for medical science worldwide. In the current study, we describe the chemical synthesis of novel tetrahydro-β-carboline derivatives containing a thiohydantoin fragment, as well as their antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1). In general, the library of compounds was of low toxicity. Of the 23 compounds under investigation, 10 (43.5%) displayed a selectivity index (SI) of 10 or higher, their activity strongly exceeding that of the reference compound rimantadine. The most active compounds have also demonstrated suppressing activity against the phylogenetically distinct influenza virus of type B. These compounds, similar to the reference compound zanamivir, were active at very late stages of the viral cycle (4–6 h postinfection), suggesting interference with processes of virion assembly and budding. However, no direct inhibiting activity against viral neuraminidase has been demonstrated. The results obtained can be considered as a rationale for further structural optimization and study of this group as potential broad-range antivirals effective against influenza viruses.

This study investigates the anticholinesterase (acetylcholinesterase [AChE] and butyrylcholinesterase [BChE]) and carbonic anhydrase (CAI and CAII) inhibitory activities of carnosic acid and its natural derivatives, including carnosol, rosmanol, 7-methoxy-rosmanol, 12-methoxy-carnosic acid, and isorosmanol. Among the tested compounds, rosmanol demonstrated exceptional potency, with IC₅₀ values of 0.73 nM for AChE and 0.75 nM for BChE, significantly outperforming tacrine. Rosmanol also exhibited remarkable inhibition of CA I (IC₅₀ = 0.21 nM), surpassing acetazolamide by over 450-fold, and moderate inhibition of CAII. Molecular docking and molecular mechanics generalized born surface area (MM-GBSA) studies revealed strong binding affinities for rosmanol, with docking scores of −11.757 kcal/mol (AChE) and −11.465 kcal/mol (BChE). The MM-GBSA binding free energy calculations further confirmed stable interactions for CA I (−63.24 kcal/mol) and AChE (−60.09 kcal/mol). Molecular dynamics simulations over 50 ns showed stable enzyme-ligand complexes, particularly for AChE and BChE (root mean square deviation ~1.5 Å), with key residues identified as crucial for stabilization. Other derivatives also displayed significant inhibitory activities, suggesting their potential as secondary leads. The ADMET analysis showed favorable pharmacokinetics and rosmanol emerged as a promising candidate. This comprehensive study highlights rosmanol as a multitarget therapeutic agent with potent anticholinesterase and CA inhibitory properties, offering promise for treating neurodegenerative and metabolic disorders.

New s-triazine hydrazone hybrids (4a–4r) were designed and synthesized as promising microbial DNA gyrase inhibitors. This was done by taking the lead DNA gyrase inhibitor (AstraZeneca arylaminotriazine) as a reference. The novel samples were subsequently tested as antimicrobial agents against certain pathogenic bacteria and unicellular fungi. The antibiofilm potential and the membrane leakage test were used to determine the mechanism of the antimicrobial response. The minimum inhibitory concentration (MIC) values of 4g, 4i, and 4r samples were between 62.5 and 250.0 µg/mL. The MIC values for the 4g candidate against Staphylococcus aureus, Candida albicans, Enterobacter agglomerans, and Klebsiella pneumonia are 62.5, 125.0, and 250.0 µg/mL, respectively. Conversely, the MIC of compound 4i was 62.5 µg/mL for C. albicans and E. agglomerans and 125.0 µg/mL for S. aureus and K. pneumonia. Besides, a molecular docking study was performed to validate both the binding affinity and binding mode of the newly designed analogs of s-triazine candidates toward bacterial DNA gyrase receptors. The synthesized nanocomposites had promising antimicrobial potentials, which are encouraging their use in biomedical applications. Consequently, the afforded compounds can be employed as promising antimicrobial lead compounds for future optimization.