Unique Scaffold Research Articles

Synthetic studies on the tetrasubstituted D-ring of cystobactamids lead to potent terephthalic acid antibiotics

Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions. We varied the two oxygenated substituents and replaced both amide connectors with bioisosteres. Synthetic routes were developed that included metal-mediated aromatic functionalization or heterocycle formations, leading to 19 novel analogues. The antibiotic efficacy of all analogues was determined against bacteria from the ESKAPE pathogen panel. While the replacement and the repositioning of hydroxy and isopropoxy substituents was not advantageous, exchanging PABA by terephthalic acid amides led to the highly potent analogue 42 with broad-spectrum activity, insensitivity towards AlbD-mediated degradation and promising pharmacokinetic properties in mice. The study highlights the steep structure-activity relationships in the tetrasubstituted D-ring and a surprisingly favorable reversion of the amide connecting C and D.

Alligamycin A, an antifungal β-lactone spiroketal macrolide from Streptomyces iranensis

Fungal infections pose a great threat to public health and there are only four main types of antifungal drugs, which are often limited with toxicity, drug-drug interactions and antibiotic resistance. Streptomyces is an important source of antibiotics, represented by the clinical drug amphotericin B. Here we report the discovery of alligamycin A (1) as an antifungal compound from the rapamycin-producer Streptomyces iranensis through genome-mining, genetics and natural product chemistry approaches. Alligamycin A harbors a unique chemical scaffold with 13 chiral centers, featuring a β-lactone moiety, a [6,6]-spiroketal ring, and an unreported 7-oxo-octylmalonyl-CoA extender unit incorporated by a potential crotonyl-CoA carboxylase/reductase. It is biosynthesized by a type I polyketide synthase which is confirmed through CRISPR-based gene editing. Alligamycin A displayed potent antifungal effects against numerous clinically relevant filamentous fungi, including resistant Aspergillus and Talaromyces species. β-Lactone ring is essential for the antifungal activity since alligamycin B (2) with disruption in the ring abolished the antifungal effect. Proteomics analysis revealed alligamycin A potentially disrupts the integrity of fungal cell walls and induces the expression of stress-response proteins in Aspergillus niger. Discovery of the potent antifungal candidate alligamycin A expands the limited antifungal chemical space.

1,2‐Diaza‐1,3‐Dienes as a Multifaceted Synthons for the Synthesis of Heterocycles: A Fifteen‐Years Update

AbstractThe discovery of structurally unique scaffolds entities with increased complexity and balanced physicochemical properties has the potential to allow synthetic chemists to exploit areas of chemical space that were previously inaccessible. Among the different strategies employed for generating N‐heterocycles, cyclization and cycloaddition reactions represent a valuable synthetic tool. The purpose of this minireview is to summarize the recent advances (2009‐present) from our laboratory on the generation of intriguing five‐, six‐ and seven‐membered mono‐ or poly‐heterocyclic architectures (linear, fused and spiro) employing 1,2‐diaza‐1,3‐dienes (DDs) as key synthons.

Convergent evolution links molybdenum insertase domains with organism-specific sequences

In all domains of life, the biosynthesis of the pterin-based Molybdenum cofactor (Moco) is crucial. Molybdenum (Mo) becomes biologically active by integrating into a unique pyranopterin scaffold, forming Moco. The final two steps of Moco biosynthesis are catalyzed by the two-domain enzyme Mo insertase, linked by gene fusion in higher organisms. Despite well-understood Moco biosynthesis, the evolutionary significance of Mo insertase fusion remains unclear. Here, we present findings from Neurospora crassa that shed light on the critical role of Mo insertase fusion in eukaryotes. Substituting the linkage region with sequences from other species resulted in Moco deficiency, and separate expression of domains, as seen in lower organisms, failed to rescue deficient strains. Stepwise truncation and structural modeling revealed a crucial 20-amino acid sequence within the linkage region essential for fungal growth. Our findings highlight the evolutionary importance of gene fusion and specific sequence composition in eukaryotic Mo insertases.

Remote Enantioselective ε-Alkylation of Copper Ethynylallenylidenes: Precise Control of Central and Axial Chirality.

Chiral tetrasubstituted allenes have emerged as important architectures for engineering biologically active compounds. The construction of unique tetrasubstituted allene scaffolds with precise control of continuous central and axial chirality remains yet to be developed. Here, we report a remote enantioselective ε-alkylation of yne-propargylic acetates with enals enabled by NHC and copper cooperative catalysis, leading to a series of tetrasubstituted allenes with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >95:5 dr). This method features high regioselectivity and simultaneous control of axial and central chirality. Mechanistic studies suggest a cooperative activation mode and synergistical control of distal chirality created from the copper ethynylallenylidenes.

Discovery of Propionic Acid Derivatives with a 5-THIQ Core as Potent and Orally Bioavailable Keap1-Nrf2 Protein-Protein Interaction Inhibitors for Acute Kidney Injury.

Keap1 plays a crucial role in regulating the Nrf2-mediated cytoprotective response and is increasingly targeted for oxidative stress-related diseases. Using small molecules to disrupt the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as a new strategy for developing Nrf2 activators. Through extensive structure-activity relationship studies, we identified compound 56, which features a unique 5-tetrahydroisoquinoline scaffold and acts as a potent inhibitor of the Keap1-Nrf2 PPI. Compound 56 exhibited significant inhibitory activity (IC50 = 16.0 nM) and tight Keap1 binding affinity (Kd = 3.07 nM), along with acceptable oral bioavailability (F = 20%). Notably, 56 enhanced antioxidant defenses in HK-2 renal tubular epithelial cells and significantly reduced plasma creatinine and blood urea nitrogen levels in acute kidney injury (AKI) mice. These findings collectively position compound 56 as a promising candidate for the treatment of AKI.

Molecular Mechanism-Driven Discovery of Novel Small Molecule Inhibitors against Drug-Resistant SARS-CoV-2 Mpro Variants.

Under the selective pressure of nirmatrelvir, a peptidomimetic covalent drug targeting SARS-CoV-2 Mpro, various drug-resistant mutations on Mpro have been acquired in vitro. Among the mutations, L50F and E166V, along with the combination of L50F and E166V, are particularly representative and pose considerable obstacles to the effective treatment of COVID-19. Our previous study identified NMI-001 and NMI-002 as novel nonpeptide inhibitors that target SARS-CoV-2 Mpro, possessing unique scaffolds and binding modes different from those of nirmatrelvir. In view of these findings, we proposed a drug design strategy aimed at rapidly identifying inhibitors that can combat mutation-induced drug resistance. Initially, molecular dynamics (MD) simulation was employed to investigate the binding mechanisms of NMI-001 and NMI-002 against the three drug-resistant mutants (Mpro_L50F, Mpro_E166V, and Mpro_L50F+E166V). Then, we conducted two phases of high-throughput virtual screening. In the first phase, NMI-001 served as a template to perform scaffold hopping-based similarity search in a library of 15,742,661 compounds. In the second phase, 968 compounds exhibiting similarity to NMI-001 were evaluated via molecular docking and MD simulations. Six compounds that may be effective against at least one mutant were identified, and five compounds were procured for conducting in vitro assays. Finally, the compound Z1557501297 (NMI-003) exhibiting inhibitory effects against the E166V (IC50 = 27.81 ± 2.65 μM) and L50F+E166V (IC50 = 8.78 ± 0.74 μM) mutants was discovered. The binding modes referring to NMI-003-Mpro_E166V and NMI-003-Mpro_L50F+E166V were further elucidated at the atomic level. In summary, NMI-003 reported herein is the first compound with activity against E166V and L50F+E166V, which provides a good starting point to design novel antiviral drugs for the treatment of drug-resistant SARS-CoV-2.

Hierarchically structured nanofibrous scaffolds spatiotemporally mediate the osteoimmune micro-environment and promote osteogenesis for periodontitis-related alveolar bone regeneration

Periodontitis suffer from inflammation-induced destruction of periodontal tissues, resulting in the serious loss of alveolar bone. Controlling inflammation and promoting bone regeneration are two crucial aspects for periodontitis-related alveolar bone defect treatment. Herein, we developed a hierarchically structured nanofibrous scaffold with a nano-embossed sheath and a bone morphogenetic protein 2-loaded core to match the periodontitis-specific features that spatiotemporally modulated the osteoimmune environment and promoted periodontal bone regeneration. We investigated the potential of this unique scaffold to treat periodontitis-related alveolar bone defects in vivo and in vitro. The results demonstrated that the hierarchically structured scaffold effectively reduced the inflammatory levels in macrophages and enhanced the osteogenic potential of bone mesenchymal stem cells in an inflammatory microenvironment. Moreover, in vivo experiments revealed that the hierarchically structured scaffold significantly ameliorated inflammation in the periodontium and inhibited alveolar bone resorption. Notably, the hierarchically structured scaffold also exhibited a prolonged effect on promoting alveolar bone regeneration. These findings highlight the significant therapeutic potential of hierarchically structured nanofibrous scaffolds for the treatment of periodontitis, and their promising role in the field of periodontal tissue regeneration. Statement of Significance: We present a novel hierarchically structured nanofibrous scaffold of coupling topological and biomolecular signals for precise spatiotemporal modulation of the osteoimmune micro-environment. Specifically, the scaffold was engineered via coaxial electrospinning of the poly(ε-caprolactone) sheath and a BMP-2/polyvinyl alcohol core, followed by surface-directed epitaxial crystallization to generate cyclic nano-lamellar embossment on the sheath. With this unique hierarchical structure, the cyclic nano-lamellar sheath provided a direct nano-topographical cue to alleviate the osteoimmune environment, and the stepwise release of BMP-2 from the core provided a biological cue for bone regeneration. This research underscores the potential of hierarchically structured nanofibrous scaffolds as a promising therapeutic approach for periodontal tissue regeneration and highlights their role in advancing periodontal tissue engineering.

Endophytic Fungi: A Treasure Trove of Antifungal Metabolites.

Emerging and reemerging fungal infections are very common in nosocomial and non-nosocomial settings in people having poor immunogenic profiles either due to hematopoietic stem cell transplants or are using immunomodulators to treat chronic inflammatory disease or autoimmune disorders, undergoing cancer therapy or suffering from an immune weakening disease like HIV. The refractory behavior of opportunistic fungi has necessitated the discovery of unconventional antifungals. The emergence of black fungus infection during COVID-19 also triggered the antifungal discovery program. Natural products are one of the alternative sources of antifungals. Endophytic fungi reside and co-evolve within their host plants and, therefore, offer a unique bioresource of novel chemical scaffolds with an array of bioactivities. Hence, immense possibilities exist that these unique chemical scaffolds expressed by the endophytic fungi may play a crucial role in overcoming the burgeoning antimicrobial resistance. These chemical scaffolds so expressed by these endophytic fungi comprise an array of chemical classes beginning from cyclic peptides, sesquiterpenoids, phenols, anthraquinones, coumarins, etc. In this study, endophytic fungi reported in the last six years (2018-2023) have been explored to document the antifungal entities they produce. Approximately 244 antifungal metabolites have been documented in this period by different groups of fungi existing as endophytes. Various aspects of these antifungal metabolites, such as antifungal potential and their chemical structures, have been presented. Yet another unique aspect of this review is the exploration of volatile antifungal compounds produced by these endophytic fungi. Further strategies like epigenetic modifications by chemical as well as biological methods and OSMAC to induce the silent gene clusters have also been presented to generate unprecedented bioactive compounds from these endophytic fungi.

Computer science for English learners: supporting teacher learning and improved practice to engage multilinguals in AP computer science principles

Multilingual learners, also known as English learners (ELs), are underrepresented in K-12 computer science (CS) courses, where they often struggle. This paper demonstrates how a Computer Science for English Learners (CSforEL) professional development (PD) program supported Advanced Placement CS Principles (APCSP) teachers in attending to both content and language demands while teaching ELs. We highlight qualitative findings showcasing how CSforEL PD yielded (micro)shifts in teacher practice and EL Student-Content interactions. Specifically, we discuss how unique instructional scaffolds offered within the PD shifted teachers’ awareness regarding EL students’ needs, and helped them support their EL students more effectively.

Naturally Occurring Xanthones and Their Biological Implications.

Xanthones are chemical substances in higher plants, marine organisms, and lower microorganisms. The most prevalent naturally occurring sources of xanthones are those belonging to the families Caryophyllaceae, Guttiferae, and Gentianaceae. Structurally, xanthones (9H xanthan-9-one) are heterocyclic compounds with oxygen and a γ-pyrone component. They are densely packed with a two-benzene ring structure. The carbons in xanthones are numbered from their nucleus and biosynthetic construct. They have mixed shikimate-acetate (higher plants) and acetate-malonate (lower organisms) biosynthetic origins, which influence their classification. Based on the level of oxidation of the C-ring, they are classified into monomers, dimers, and heterodimers. While based on the level of oxygenation or the type of ring residue, they can be categorized into mono-, di-, tri-, tetra-, penta- and hexa-oxygenated xanthones, bis-xanthones, prenylated and related xanthones, xanthonolignoids, and other miscellaneous xanthones. This structural diversity has made xanthones exhibit considerable biological properties as promising antioxidant, antifungal, antimicrobial, and anticancer agents. Structure-activity relationship studies suggest C-1, C-3, C-6, and C-8 as the key positions that influence the biological activity of xanthones. Furthermore, the presence of functional groups, such as prenyl, hydroxyl, glycosyl, furan, and pyran, at the key positions of xanthones, may contribute to their spectrum of biological activity. The unique chemical scaffolds of xanthones, their notable biological activities, and the structure-activity relationships of some lead molecules were discussed to identify lead molecules as possible drug candidates.

Vascular network-inspired diffusible scaffolds for engineering functional neural organoids.

Organoids, three-dimensional in vitro organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present Vascular network-Inspired Diffusible (VID) scaffolds to fully recapture the benefits of physiological diffusion physics for generating functional organoids and phenotyping their drug response. In a proof-of-concept application, the VID scaffolds, 3D-printed meshed tubular channel networks, support the successful generation of engineered human midbrain organoids almost without necrosis and hypoxia in commonly used well-plates. Compared to conventional organoids, these engineered organoids develop with more physiologically relevant features and functions including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared to conventional organoids with significant diffusion limits. Combining these unique scaffolds and engineered organoids may provide insights for organoid development and therapeutic innovation.

Bovine Placentome-Derived Extracellular Matrix: A Sustainable 3D Scaffold for Cultivated Meat.

Cultivated meat, an advancement in cellular agriculture, holds promise in addressing environmental, ethical, and health challenges associated with traditional meat production. Utilizing tissue engineering principles, cultivated meat production employs biomaterials and technologies to create cell-based structures by introducing cells into a biocompatible scaffold, mimicking tissue organization. Among the cell sources used for producing muscle-like tissue for cultivated meats, primary adult stem cells like muscle satellite cells exhibit robust capabilities for proliferation and differentiation into myocytes, presenting a promising avenue for cultivated meat production. Evolutionarily optimized for growth in a 3D microenvironment, these cells benefit from the biochemical and biophysical cues provided by the extracellular matrix (ECM), regulating cell organization, interactions, and behavior. While plant protein-based scaffolds have been explored for their utilization for cultivated meat, they lack the biological cues for animal cells unless functionalized. Conversely, a decellularized bovine placental tissue ECM, processed from discarded birth tissue, achieves the biological functionalities of animal tissue ECM without harming animals. In this study, collagen and total ECM were prepared from decellularized bovine placental tissues. The collagen content was determined to be approximately 70% and 40% in isolated collagen and ECM, respectively. The resulting porous scaffolds, crosslinked through a dehydrothermal (DHT) crosslinking method without chemical crosslinking agents, supported the growth of bovine myoblasts. ECM scaffolds exhibited superior compatibility and stability compared to collagen scaffolds. In an attempt to make cultivate meat constructs, bovine myoblasts were cultured in steak-shaped ECM scaffolds for about 50 days. The resulting construct not only resembled muscle tissues but also displayed high cellularity with indications of myogenic differentiation. Furthermore, the meat constructs were cookable and able to sustain the grilling/frying. Our study is the first to utilize a unique bovine placentome-derived ECM scaffold to create a muscle tissue-like meat construct, demonstrating a promising and sustainable option for cultivated meat production.

Preparation and properties of biomimetic bone repair hydrogel with sandwich structure.

One of the critical factors that determines the biological properties of scaffolds is their structure. Due to the mechanical and structural discrepancies between the target bone and implants, the poor internal architecture design and difficulty in degradation of conventional bone implants may cause several adverse outcomes. To date, many scaffolds, such as 3-D printed sandwich structures, have been successfully developed for the repair of bone defects; however, the steps of these methods are complex and costly. Hydrogels have emerged as a unique scaffold material for repairing bone defects because of their good biocompatibility and excellent physicochemical properties. However, studies exploring bioinspired hydrogel scaffolds with hierarchical structures are scarce. More efforts are needed to incorporate bioinspired structures into hydrogel scaffolds to achieve optimal osteogenic properties. In this study, we developed a low-cost and easily available hydrogel matrix that mimicked the natural structure of the bone's porous sandwich to promote new bone growth and tissue integration. A comprehensive evaluation was conducted on the microstructure, swelling rate, and mechanical properties of this hydrogel. Furthermore, a 3D finite element analysis was employed to model the structure-property relationship. The results indicate that the sandwich-structured hydrogel is a promising scaffold material for bone injury repair, exhibiting enhanced compressive stress, elastic modulus, energy storage modulus, and superior force transmission.

Dimolybdenum (II,II) paddlewheel complexes bearing non-steroidal anti-inflammatory drug ligands: Insights into the chemico-physical profile and first biological assessment

Multinuclear complexes are metal compounds featured by adjacent bound metal centers that can lead to unconventional reactivity. Some M2L4-type paddlewheel dinuclear complexes with monoanionic bridging ligands feature promising properties, including therapeutic ones. Molybdenum has been studied for the formation of multiple-bonded M2+ compounds due to their unique scaffold, redox, and spectroscopic properties as well as for applications in several fields including catalysis and biology. These latter are much less explored and only sporadic studies have been carried out. Here, a series of four dimolybdenum (II,II) carboxylate paddlewheel complexes were synthesized using different Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) as ligands. The reaction of (NH4)5[Mo2Cl9]·H2O with the selected NSAIDs in methanol produced the complexes Mo2(μ-O2CR)4 where RCO2 is ibuprofen (1), naproxen (2), aspirin (3) and indomethacin (4). The products were obtained in good yields and extensively characterized with integrated techniques. Stability and solution behaviour were studied using a mixed experimental and computational approach. Finally, the biological activity of 1 and 3 (i.e. the most reactive and the most stable compounds of the series, respectively) was preliminarily assessed confirming the disassembling of the molecules in the biological milieu. Overall, some very interesting results emerged for these unconventional compounds from a mechanistic point of view.

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4.

The control of malaria, a disease caused by Plasmodium parasites that kills over half a million people every year, is threatened by the continual emergence and spread of drug resistance. Therefore, new molecules with different mechanisms of action are needed in the antimalarial drug development pipeline. Peptides developed from host defense molecules are gaining traction as anti-infectives due to theood of inducing drug resistance. Human platelet factor 4 (PF4) has intrinsic activity against P. falciparum, and a macrocyclic helix-loop-helix peptide derived from its active domain recapitulates this activity. In this study, we used a stepwise approach to optimize first-generation PF4-derived internalization peptides (PDIPs) by producing analogues with substitutions to charged and hydrophobic amino acid residues or with modifications to terminal residues including backbone cyclization. We evaluated the in vitro activity of PDIP analogues against P. falciparum compared to their overall helical structure, resistance to breakdown by serum proteases, selective binding to negatively charged membranes, and hemolytic activity. Next, we combined antiplasmodial potency-enhancing substitutions that retained favorable membrane and cell-selective properties onto the most stable scaffold to produce a backbone cyclic PDIP analogue with four-fold improved activity against P. falciparum compared to first-generation peptides. These studies demonstrate the ability to modify PDIP to select for and combine desirable properties and further validate the suitability of this unique peptide scaffold for developing a new molecule class that is distinct from existing antimalarial drugs.

Quinoline Derivatives in Discovery and Development of Pesticides.

Finding highly active molecular scaffold structures is always the key research content of new pesticide discovery. In the research and development of new pesticides, the discovery of new agricultural molecular scaffold structures and new targets still faces great challenges. In recent years, quinoline derivatives have developed rapidly in the discovery of new agriculturally active molecules, especially in the discovery of fungicides. The unique quinoline scaffold has many advantages in the discovery of new pesticides and can provide innovative and feasible solutions for the discovery of new pesticides. Therefore, we reviewed the use of quinoline derivatives and their analogues as molecular scaffolds in the discovery of new pesticides since 2000. We systematically summarized the agricultural biological activity of quinoline compounds and discussed the structure-activity relationship (SAR), physiological and biochemical properties, and mechanism of action of the active compounds, hoping to provide ideas and inspiration for the discovery of new pesticides.

Synthesis of triazole AD-1 derivatives and its mechanism of mediating DNA damage of ROS in lung cancer cells

Based on the significant biological activities and the remarkable physical and chemical properties of 1H-1,2,3-triazole pharmacophore, we herein adopted the strategy of click chemistry to combine the triazole fragment and the unique scaffold of 25-OCH3-PPD (AD-1) to design a series of potent compounds inducing apoptosis and DNA damage. The anti-proliferative effect was verified by MTT assay and colony formation assay. DNA double-stand breaks (DSBs) were obtained by observing the nuclear focus formation and the protein expression of γ-H2AX. Cell cycle arrest was evaluated by the cycle-related proteins such as CDK2, CDK4, CDK6, Cyclin D1 and P21. Apoptosis was assessed by flow cytometry, mitochondrial membrane potential (MMP) detection and the expression of apoptosis-related proteins. Reactive oxygen species (ROS) generation was measured with 2′, 7′-dichlorofluorescein diacetate (DCFH-DA) staining. According to SAR analysis, the most potent compound 6a exhibited great inhibitory effect against A549 cells, which IC50 value of 2.84 ± 0.68 μM. Furthermore, 6a remarkably induced DNA damage, cell cycle arrest and apoptosis in A549 cells. 6a treatment increased the levels of ROS. Network pharmacology and molecular docking predicted the potential signaling pathways and ligand-receptor interactions, and the results of western blotting showed that 6a inhibited the PI3K/Akt/Bcl-2 signaling pathway by decreasing PI3K and Bcl-2 and total level of Akt expression, while Bax and Cyt c were increasing in 6a-treated A549 cells. As mentioned above, 6a has a potent inhibitory effect in A549 cells through induction of DNA damage, apoptosis via ROS generation and modulation of PI3K/Akt/Bcl-2 signaling pathway.

The Helix Ring Peptide U11 from the Venom of the Ant, Tetramorium bicarinatum, Acts as a Putative Pore-Forming Toxin.

An insect neuroactive helix ring peptide called U11-MYRTX-Tb1a (abbreviated as U11) from the venom of the ant, Tetramorium bicarinatum. U11 is a 34-amino-acid peptide that is claimed to be one of the most paralytic peptides ever reported from ant venoms acting against blowflies and honeybees. The peptide features a compact triangular ring helix structure stabilized by a single disulfide bond, which is a unique three-dimensional scaffold among animal venoms. Pharmacological assays using Drosophila S2 cells have demonstrated that U11 is not cytotoxic but instead suggest that it may modulate potassium channels via the presence of a functional dyad. In our work described here, we have tested this hypothesis by investigating the action of synthetically made U11 on a wide array of voltage-gated K and Na channels since it is well known that these channels play a crucial role in the phenomenon of paralysis. Using the Xenopus laevis oocyte heterologous expression system and voltage clamp, our results have not shown any modulatory effect of 1 μM U11 on the activity of Kv1.1, Kv1.3, Kv1.4, Kv1.5, Shaker IR, Kv4.2, Kv7.1, Kv10.1, Kv11.1 and KQT1, nor on DmNav and BgNav. Instead, 10 μM U11 caused a quick and irreversible cytolytic effect, identical to the cytotoxic effect caused by Apis mellifera venom, which indicates that U11 can act as a pore-forming peptide. Interestingly, the paralytic dose (PD50) on blowflies and honeybees corresponds with the concentration at which U11 displays clear pore-forming activity. In conclusion, our results indicate that the insecticidal and paralytic effects caused by U11 may be explained by the putative pore formation of the peptide.

Unique aminothiazolyl coumarins as potential DNA and membrane disruptors towards Enterococcus faecalis

Aminothiazolyl coumarins as potentially new antimicrobial agents were designed and synthesized in an effort to overcome drug resistance. Biological activity assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungi including drug-resistant pathogens. Especially, aminothiazolyl 7-propyl coumarin 8b and 4-dichlorobenzyl derivative 11b exhibited bactericidal potential (MBC/MIC = 2) toward clinically drug-resistant Enterococcus faecalis with low cytotoxicity to human lung adenocarcinoma A549 cells, rapidly bactericidal effects and no obvious bacterial resistance development against E. faecalis. The preliminary antibacterial action mechanism studies suggested that compound 11b was able to disturb E. faecalis membrane effectively, and interact with bacterial DNA isolated from resistant E. faecalis through noncovalent bonds to cleave DNA, thus inhibiting the growth of E. faecalis strain. Further molecular modeling indicated that compounds 8b and 11b could bind with SER-1084 and ASP-1083 residues of gyrase-DNA complex through hydrogen bonds and hydrophobic interactions. Moreover, compound 11b showed low hemolysis and in vivo toxicity. These findings of aminothiazolyl coumarins as unique structural scaffolds might hold a large promise for the treatments of drug-resistant bacterial infection.