Piezo1 and its inhibitors: Overview and perspectives.

The cation channel Piezo1, a crucial mechanotransducer found in various organs and tissues, has gained considerable attention as a therapeutic target in recent years. Following this trend, several Piezo1 inhibitors have been discovered and studied for potential pharmacological properties. This review provides an overview of the structural and functional importance of Piezo1, as well as discussing the biological activities of Piezo1 inhibitors based on their mechanism of action. The compounds addressed include the toxin GsMTx4, Aß peptides, certain fatty acids, ruthenium red and gadolinium, Dooku1, as well as the natural products tubeimoside I, salvianolic acid B, jatrorrhzine, and escin. The findings revealed that misexpression of Piezo1 can be associated with a number of chronic diseases, including hypertension, cancer, and hemolytic anemia. Consequently, inhibiting Piezo1 and the subsequent calcium influx can have beneficial effects on various pathological processes, as shown by many in vitro and in vivo studies. However, the development of Piezo1 inhibitors is still in its beginnings, with many opportunities and challenges remaining to be explored.

Development of Cytotoxic GW7604-Zeise's Salt Conjugates as Multitarget Compounds with Selectivity for Estrogen Receptor- Positive Tumor Cells.

(E/Z)-3-(4-((E)-1-(4-Hydroxyphenyl)-2-phenylbut-1-enyl)phenyl)acrylic acid (GW7604) as a carrier was esterified with alkenols of various lengths and coordinated through the ethylene moiety to PtCl3, similar to Zeise's salt (K[PtCl3(C2H4)]). The resulting GW7604-Alk-PtCl3 complexes (Alk = Prop, But, Pent, Hex) degraded in aqueous solution only by exchange of the chlorido ligands. For example, GW7604-Pent-PtCl3 coordinated the amino acid alanine in the cell culture medium, bound the isolated nucleotide 5'-GMP, and interacted with the DNA (empty plasmid pSport1). It accumulated in estrogen receptor (ER)-positive MCF-7 cells primarily via cytosolic vesicles, while it was only marginally taken up in ER-negative SKBr3 cells. Accordingly, GW7604-Pent-PtCl3 and related complexes were inactive in SKBr3 cells. GW7604-Pent-PtCl3 showed high affinity to ERα and ERß without mediating agonistic or ER downregulating properties. GW7604-Alk ligands also increased the cyclooxygenase (COX)-2 inhibitory potency of the complexes. In contrast to Zeise's salt, the GW7604-Alk-PtCl3 complexes inhibited COX-1 and COX-2 to the same extent.

Evaluating the Potency of Selected Antibiotic Medications Dispensed in Community Pharmacies in Gwale, Kano, Nigeria.

The worsening of antibiotic resistance is a multifactorial process. One aspect of this is the counterfeiting of antibiotic medications. This is supposed to be particularly high in developing countries, including Nigeria. Therefore, the potency of some antibiotic drugs dispensed in community pharmacies in Gwale, Kano, Nigeria, was investigated in this case study. Three products, each from different manufacturers, with the active ingredients of ceftriaxone, gentamicin, ciprofloxacin, and metronidazole, respectively, were included in this study. By means of a disc-diffusion assay, the effect against the typed strains Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) as well as Clostridium tetani isolated from soil was tested. Clinical isolates of S. aureus and E. coli were also used. While antibiotics, with the exception of ciprofloxacin-containing preparations against C. tetani, showed acceptable efficacy against the typed strains by comparison with the clinical science laboratory references, a predominant failure was observed with the clinical isolates. Thus, the investigated drug preparations can be considered of acceptable quality for the treatment of susceptible bacterial infections. This excludes counterfeits in the sampled preparations. However, the insufficient efficacy against clinical isolates further documents the severity of nosocomial bacteria.

Development of Zeise's Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors.

Zeise's salt derivatives of the potassium trichlorido[η2-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl3/ASA-But-PtCl3 derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl3 and ASA-But-PtCl3 interfere with the arachidonic acid cascade as part of their mode of action to reduce the growth of COX-1/2-expressing tumor cells. With the aim to increase the antiproliferative activity by strengthening the inhibitory potency against COX-2, F, Cl, or CH3 substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl3 reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE2 formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH3 derivatives, indicating COX inhibitory potency in cellular systems. The CH3-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC50 values of 16-27 µM. In COX-negative MCF-7 cells, they were 2-3-fold less active. These data clearly demonstrate that it is possible to increase the cytotoxicity of ASA-Prop-PtCl3 and ASA-But-PtCl3 derivatives by enhancing COX-2 inhibition.

Development of Activity Rules and Chemical Fragment Design for In Silico Discovery of AChE and BACE1 Dual Inhibitors against Alzheimer's Disease.

Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer's disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and ß-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.

Phytochemical Screening, GC-MS Analysis, and Evaluating In Vivo Antitrypanosomal Effects of a Methanolic Extract of Garcinia kola Nuts on Rats.

Trypanosomiasis is a serious disease that affects both humans and animals, causing social and economic losses. Efforts to find new therapeutic approaches are warranted to improve treatment options. Therefore, the purpose of this communication includes the phytochemical screening of a methanolic extract of Garcinia kola nuts and the in vivo evaluation of its biological activity against rats infected with Trypanosoma brucei brucei and treated with 4 different concentrations of the extract (0.01, 0.1, 1, and 10 mg/kg). Treatment with suramin served as a positive control, while the negative control received no drug. Since the general toxicity of the extract could be ruled out, efficacy was evaluated based on physiological changes, such as induction of trypanosome parasitemia, influence on body temperature, and body weight. Survival was assessed during this study. Physical parameters, behavioral characteristics, and various hematological indices were also monitored. Based on the (patho)physiological and behavioral parameters (e.g., no parasitemia, no increase in body temperature, an increase in body weight, no loss of condition, no alopecia, and no gangrene), the efficacy of the extract was evident, which was also confirmed by 100% survival, while in the negative control, all rats died during the observation period. Since overall very similar results were obtained as a result of treatment with the established suramin, the in vivo antitrypanosomal activity of a methanolic extract of G. kola nuts on rats can be demonstrated in this communication. This opens the way, for example, for further development of drug formulations based on this methanolic extract.

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors.

In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, thiols, short-chain fatty acids, and cyclic peptides. Fluorination plays an important role in the medicinal-chemical design of new active representatives. As a result of the introduction of fluorine into the chemical structure, parameters such as potency or selectivity towards isoforms of HDACs can be increased. However, the impact of fluorination cannot always be clearly deduced. Nevertheless, a change in lipophilicity and, hence, solubility, as well as permeability, can influence the potency. The selectivity towards certain HDACs isoforms can be explained by special interactions of fluorinated compounds with the structure of the slightly different enzymes. Another aspect is that for a more detailed investigation of newly synthesized fluorine-containing active compounds, fluorination is often used for the purpose of labeling. Aside from the isotope 19F, which can be detected by nuclear magnetic resonance spectroscopy, the positron emission tomography of 18F plays a major role. However, to our best knowledge, a survey of the general effects of fluorination on HDACis development is lacking in the literature to date. Therefore, the aim of this review is to highlight the introduction of fluorine in the course of chemical synthesis and the impact on biological activity, using selected examples of recently developed fluorinated HDACis.

A graphite furnace-atomic absorption spectrometry-based rubidium efflux assay for screening activators of the Kv 7.2/3 channel.

For the characterization of Kv 7.2/3 channel activators, several analytical methods are available that vary in effort and cost. In addition to the technically elaborate patch-clamp method, which serves as a reference method, there exist several medium to high-throughput screening methods including a rubidium efflux flame-atomic absorption spectrometry (F-AAS) assay and a commercial thallium uptake fluorescence-based assay. In this study, the general suitability of a graphite furnace atomic absorption spectrometry (GF-AAS)-based rubidium efflux assay as a screening method for Kv 7.2/3 channel activators was demonstrated. With flupirtine serving as a reference compound, 16 newly synthesizedcompounds and the known Kv 7.2/3 activator retigabine were first classified as either active or inactive by using the GF-AAS-based rubidium (Rb) efflux assay. Then, the results were compared with a thallium (Tl) uptake fluorescence-based fluorometric imaging plate reader (FLIPR) potassium assay. Overall, 16 of 17 compounds were classified by the GF-AAS-based assay in agreement with their channel-activating properties determined by the more expensive Tl uptake, fluorescence-based assay. Thus, the performance of the GF-AAS-based Rb assay for primary drug screening of Kv 7.2/3-activating compounds was clearly demonstrated, as documented by the calculated Z'-factor of the GF-AAS-based method. Moreover, method development included optimization of the coating of the microtiter plates and the washing procedure, which extended the range of this assay to poorly adherent cells such as the HEK293 cells used in this study.

Synthesis and biological evaluation of salophen nickel(II) and cobalt(III) complexes as potential anticancer compounds.

Recent in vitro investigations of N,N'-bis(salicylidene)-1,2-phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL-60 leukemia, and cisplatin-sensitive and -resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1-3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4-6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin-1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin-1, but even enhanced upon simultaneous application to the tumor cells.

Development and Application of an Atomic Absorption Spectrometry-Based Method to Quantify Magnesium in Leaves of Dioscorea polystachya.

The Chinese yam (Dioscorea polystachya, DP) is known for the nutritional value of its tuber. Nevertheless, DP also has promising pharmacological properties. Compared with the tuber, the leaves of DP are still very little studied. However, it may be possible to draw conclusions about the plant quality based on the coloration of the leaves. Magnesium, as a component of chlorophyll, seems to play a role. Therefore, the aim of this research work was to develop an atomic absorption spectrometry-based method for the analysis of magnesium (285.2125 nm) in leaf extracts of DP following the graphite furnace sub-technique. The optimization of the pyrolysis and atomization temperatures resulted in 1500 °C and 1800 °C, respectively. The general presence of flavonoids in the extracts was detected and could explain the high pyrolysis temperature due to the potential complexation of magnesium. The elaborated method had linearity in a range of 1-10 µg L-1 (R2 = 0.9975). The limits of detection and quantification amounted to 0.23 µg L-1 and 2.00 µg L-1, respectively. The characteristic mass was 0.027 pg, and the recovery was 96.7-102.0%. Finally, the method was applied to extracts prepared from differently colored leaves of DP. Similar magnesium contents were obtained for extracts made of dried and fresh leaves. It is often assumed that the yellowing of the leaves is associated with reduced magnesium content. However, the results indicated that yellow leaves are not due to lower magnesium levels. This stimulates the future analysis of DP leaves considering other essential minerals such as molybdenum or manganese.

Comparison of the University Pharmacy Education Programs in Germany and Vietnam.

During the global COVID pandemic, the importance of professionals in the health care sector has been put in a new light, including pharmacists. In this context, the focus is also on how pharmacists are trained in different countries. Through an exchange of pharmacy teaching staff from a German to a Vietnamese university, the pharmacy education programs in both countries were compared. Aspects such as access to studies, structure of studies, and further training opportunities were considered. Differences and similarities emerged. In both countries, students first acquire basic knowledge and then delve deeper into pharmaceutical content in main studies. There is, expectedly, a great overlap in the content of the courses. Overall, the education at Vietnamese universities seems to be more practice-oriented due to a large number of placements. This also allows a specialization, which can be pursued in Germany with self-interest after graduation. There, the preparation for everyday work in the community pharmacy is separated from the university by a mandatory practical year. For the future, efforts are being made in both countries to strengthen the importance of clinical pharmacy in the curriculum. To this end, the Vietnamese are taking their inspiration from abroad in many cases, including Germany.

Extensively Drug-Resistant Klebsiella pneumoniae Counteracts Fitness and Virulence Costs That Accompanied Ceftazidime-Avibactam Resistance Acquisition.

The ability of extensively drug-resistant (XDR) Klebsiella pneumoniae to rapidly acquire resistance to novel antibiotics is a global concern. Moreover, Klebsiella clonal lineages that successfully combine resistance and hypervirulence have increasingly occurred during the last years. However, the underlying mechanisms of counteracting fitness costs that accompany antibiotic resistance acquisition remain largely unexplored. Here, we investigated whether and how an XDR sequence type (ST)307 K. pneumoniae strain developed resistance against the novel drug combination ceftazidime-avibactam (CAZ-AVI) using experimental evolution. In addition, we performed in vitro and in vivo assays, molecular modeling, and bioinformatics to identify resistance-conferring processes and explore the resulting decrease in fitness and virulence. The subsequent amelioration of the initial costs was also addressed. We demonstrate that distinct mutations of the major nonselective porin OmpK36 caused CAZ-AVI resistance that persists even upon following a second experimental evolution without antibiotic selection pressure and that the Klebsiella strain compensates the resulting fitness and virulence costs. Furthermore, the genomic and transcriptomic analyses suggest the envelope stress response regulator rpoE and associated RpoE-regulated genes as drivers of this compensation. This study verifies the crucial role of OmpK36 in CAZ-AVI resistance and shows the rapid adaptation of a bacterial pathogen to compensate fitness- and virulence-associated resistance costs, which possibly contributes to the emergence of successful clonal lineages. IMPORTANCE Extensively drug-resistant Klebsiella pneumoniae causing major outbreaks and severe infections has become a significant challenge for health care systems worldwide. Rapid resistance development against last-resort therapeutics like ceftazidime-avibactam is a significant driver for the accelerated emergence of such pathogens. Therefore, it is crucial to understand what exactly mediates rapid resistance acquisition and how bacterial pathogens counteract accompanying fitness and virulence costs. By combining bioinformatics with in vitro and in vivo phenotypic approaches, this study revealed the critical role of mutations in a particular porin channel in ceftazidime-avibactam resistance development and a major metabolic regulator for ameliorating fitness and virulence costs. These results highlight underlying mechanisms and contribute to the understanding of factors important for the emergence of successful bacterial pathogens.

Introducing Audio Podcasts into a Practical Laboratory Course for Pharmacy Students as a Novel Tool for Performance Assessment.

The use of digital tools can positively impact higher education for both scholars and faculty. In recent years, it has become apparent that podcasts are a suitable medium for use in teaching. They are provided almost exclusively by lecturers for students, with students passively listening to them rather than actively participating in their production. However, this could also be valuable for students. Therefore, this pilot study investigated the extent to which the creation of a podcast would be accepted by students as a method for capturing pharmacy students' understanding of the learning content. The evaluation was performed as part of the "Clinical Chemistry" practical course, which was attended by third-year pharmacy students in groups of three. After passing the station dealing with practical clinical chemistry relevant diagnostic systems, the groups were asked to produce an educational podcast covering the essential content on the topics of urine test strips or pulse oximetry, respectively. Student attitudes toward the adoption of podcasts as a tool for performance assessment were determined with an anonymous and voluntary survey. The respondents reported that they had fun creating the podcast, which enabled them to look at the instructional content from a different perspective. Competencies such as social and communication skills and media literacy as well as self-organized and self-directed learning were also promoted. However, the students assumed that the tool is not ideally suited for dealing with extensive topics. Nonetheless, the students clearly support the continued creation of podcasts as a performance assessment tool. In addition, they suggest integrating podcasts into other courses within the pharmacy curriculum. This may also be related to the infrequent use of novel technologies, such as podcasts, in their education thus far.

Development of methylated cobalt-alkyne complexes with selective cytotoxicity against COX-positive cancer cell lines.

Derivatives of the cytotoxic cyclooxygenase (COX) inhibitor [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) with a methyl group in the 3, 4, 5, or 6 position of the acetylsalicylic acid (ASS) scaffold were synthesized with the aim to achieve enhanced selectivity for COX-2. From this modification, a higher specificity for COX-2-expressing tumors is expected, preventing COX-1-mediated side effects. The cobalt-alkyne complexes were tested for their COX-inhibitory and antiproliferative properties as well as their cellular uptake. Methylation reduced the effects at the isolated COX-1, whereas those at the isolated COX-2 remained nearly constant compared to Co-ASS. In cellular systems, the new compounds showed superior cytotoxicity toward the COX-positive HT-29 colon carcinoma cells than cisplatin. The reduced growth-inhibitory potency in T-24 cells, which express distinctly fewer COX enzymes (COX-1/COX-2 = 50/1) than HT-29 cells (COX-1/COX-2 = 50/50), and the only marginal activity in COX-negative MCF-7 breast cancer cells point to an interference in the arachidonic acid cascade through COX-2 inhibition as part of the mode of action, especially as the cellular uptake was even higher in MCF-7 cells than in T-24 cells. These findings clearly demonstrate that the methylated cobalt-alkyne complexes possess promising potential for further development as reasonable alternatives to the limited platinum-based antitumor agents.

Comprehensive Evaluation of Biological Effects of Pentathiepins on Various Human Cancer Cell Lines and Insights into Their Mode of Action.

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.

Synthesis, characterization and biological activity of bis[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(i) complexes.

A series of bis[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(i) complexes (2a-f) containing methyl, fluoro or methoxy substituents at various positions in the 4-aryl ring was synthesized and evaluated for their anti-cancer properties in A2780 (wild-type and Cisplatin-resistant) ovarian carcinoma as well as LAMA 84 (imatinib-sensitive and -resistant) and HL-60 leukemia cell lines. The bis-NHC gold(i) complexes were more active compared to their related mono-NHC gold(i) analogues and reduced proliferation and metabolic activity in a low micromolar range. With the exception of 2d (3-F), the compounds displayed higher potency than the established drugs Auranofin and Cisplatin. The lack of effects against non-cancerous lung fibroblast SV-80 cells indicated a high selectivity towards tumor cells. All tested complexes generated reactive oxygen species in A2780cis cells; however, the induction of apoptosis was very low. Furthermore, thioredoxin reductase is not the main target of these complexes, because its inhibition pattern did not correlate with their biological activity.

Correlation Analysis of Protein Expression of 10 HDAC/Sirtuin Isoenzymes with Sensitivities of 23 Anticancer Drugs in 17 Cancer Cell Lines and Potentiation of Drug Activity by Co-Treatment with HDAC Inhibitors.

Inhibiting the activity of histone deacetylase (HDAC) is an ongoing strategy in anticancer therapy. However, to our knowledge, the relationships between the expression of HDAC proteins and the antitumor drug sensitivity of cancer cells have not been studied until now. In the current work, we investigated the relative expression profiles of 10 HDAC isoenzymes comprising the classes I-III (HDAC1/2/4/6; Sirt1/2/3/5/6/7) in a panel of 17 cancer cell lines, including the breast, cervix, oesophageal, lung, oral squamous, pancreas, as well as urinary bladder carcinoma cells. Correlations between the data of mRNA expression for these enzymes obtained from the National Cancer Institute (NCI) 60 cancer cell line program were also examined. Next, we performed univariate analysis between the expression patterns of HDAC/Sirt isoenzymes with the sensitivity of a 16 cell panel of cancer cell lines towards several antitumor drugs. In a univariate correlation analysis, we found a strong relation between Sirt2 expression and cytotoxicity caused by busulfan, etoposide, and hydroxyurea. Moreover, it was identified that Sirt5 correlates with the effects exerted by oxaliplatin or topotecan, as well as between HDAC4 expression and these two drugs. Correlations between the data of mRNA expression for enzymes with the potencies of the same anticancer agents obtained from the NCI 60 cancer cell line program were also found, but none were the same as those we found with our protein expression data. Additionally, we report here the effects upon combination of the approved HDAC inhibitor vorinostat and one other known inhibitor trichostatin A as well as newer hetero-stilbene and diazeno based sirtuin inhibitors on the potency of cisplatin, lomustine, and topotecan. For these three anticancer drugs, we found a significantly enhanced cytotoxicity when co-incubated with HDAC inhibitors, demonstrating a potentially beneficial influence of HDAC inhibition on anticancer drug treatment.

Investigating the antibacterial activity of salen/salophene metal complexes: Induction of ferroptosis as part of the mode of action.

The continuous increase of resistant bacteria including Staphylococcus aureus and its methicillin-resistant phenotype (MRSA) is currently one of the major challenges in medicine. Therefore, the discovery of novel lead structures for the design of drugs to fight against infections caused by these bacteria is urgently needed. In this structure-activity relationship study, metal-based drugs were investigated for the treatment of resistant pathogens. The selected Ni(II), Cu(II), Zn(II), Mn(III), and Fe(II/III) complexes differ in their salen- and salophene-type Schiff base ligands. The in vitro activity was evaluated using gram-positive (S. aureus and MRSA) and gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Especially the iron(III) complexes displayed promising antimicrobial effects against gram-positive bacteria, with MIC90 values ranging from 0.781 to 50 µg/mL. Among them, chlorido[(N,N'-bis(salicylidene)-1,2-phenylenediamine]iron(III) (6) showed the best MIC90 value (0.781 µg/mL = 1.93 µmol/L) against S. aureus and MRSA. Complex 6 was comparably potent as ciprofloxacin against S. aureus (0.391 µg/mL = 1.18 µmol/L) and only marginally less active than tetracycline against MRSA (0.391 µg/mL = 0.88 µmol/L). As part of the mode of action, ferroptosis was identified. Applying compound 6 (10 µg/mL), both gram-positive strains grown in PBS were killed within 20 min. This efficacy basically documents that salophene iron(III) complexes represent possible lead structures for the further development of antibacterial metal complexes.

Cell death-inducing properties of selected dendrimers against different breast cancer and leukemia cell lines.

Dendrimers represent an opportunity for targeted drug delivery into tumor cells. This is facilitated, for example, by loading of dendrimers with anticancer compounds. However, to assess the effects caused by such conjugates, knowledge of the cytotoxicity of the dendrimers themselves is necessary. The poly(amido amine)-derived dendrimers G1 (Phe)6 , G1 (Dan)3 , and G2 were selected due to their different numbers of free amino groups and the poly(propylene imine) (PPI) dendrimer PPI-G3 served as a reference. The compounds were evaluated for cell-death induction using breast cancer (MCF-7, MDA-MB-231) and leukemia (LAMA-84, K562, SD-1, SUP-B15) cell lines. The compounds exhibited concentration-dependent effects in the low micromolar range against the mammary carcinoma cells. A dependency on the generation, and particularly on the type of dendrimer, was deduced while the quantity of the free amino groups was subsidiary. G2 revealed to be most cytotoxic, also against all tested leukemia cell lines. The cell line SD-1, however, was susceptible to all dendrimers. The mode of cell death was mainly determined by necrosis, especially at higher concentrations, while apoptosis played a subordinate role. The other dendrimers exerted no antimetabolic effects against LAMA-84, K562, and SUP-B15 cells. Therefore, these dendrimers are generally suitable as nontoxic drug carriers for leukemia cells.