Cyclic Analogues Research Articles

Therapeutic Potential of Natural Metabolites Coupled Pyrazole and Its Bio‐Isosteres: Medicinal Perspectives and SAR Studies

AbstractNatural products have been extensively explored for their role in drug design and development to eradicate numerous types of diseases. Also, heterocycles‐based motifs are known to possess a wide range of therapeutic applications. Among them, pyrazole is a well‐exploited scaffold by researchers in the different fields of medicinal chemistry. Recently, pharmacophoric hybridization became most urged approach in which two biologically active pharmacophoric skeletons tend to fuse together in any structural portion. Hence, pyrazole and its cyclic bio‐isosteres may clubbed together to design and develop novel potent molecules against clinical disorders with least toxicity profile. In the present review, we aim to compile the numerous recent advancements in the medicinal chemistry of natural metabolites containing pyrazole and its bio‐isosteres hybrid compounds with the following objectives: (1) To summarize the recent literature reports of last six years that are focused on the biological potential of natural pyrazole and its bio‐isosteres hybrid derivatives; (2) To deliberate current developments in the medicinal aspect of natural compounds through their structural alteration by introducing pyrazole and its cyclic analogues; (3) To emphasize the complete correlation between structure activity relationship (SAR) and therapeutic response to disclose productive concepts for the generation of potential semi‐synthetic candidates.

A novel antimicrobial peptide with broad-spectrum and exceptional stability derived from the natural peptide Brevicidine

The global issue of antibiotic resistance is increasingly severe, highlighting the urgent necessity for the development of new antibiotics. Brevicidine, a natural cyclic lipopeptide, exhibits remarkable antimicrobial activity against Gram-negative bacteria. In this study, a comprehensive structure-activity relationship of Brevicidine was investigated through 20 newly synthesized cyclic lipopeptide analogs, resulting in the identification of an optimal linear analog 22. The sequence of analog 22 consisted of five d-amino acids and four non-natural amino acid 2,5-diaminovaleric acid (Orn) and conjugated with decanoic acid at N-terminal. Compared to Brevicidine, analog 22 was easier to synthesize, and exerted broad spectrum antimicrobial activity and excellent stability (t1/2 = 40.98 h). Additionally, analog 22 demonstrated a rapid bactericidal effect by permeating non-specifically through the bacterial membranes, thereby minimizing the likelihood of inducing resistance. Moreover, it exhibited remarkable efficacy in combating bacterial biofilms and reversing bacterial resistance to conventional antibiotics. Furthermore, it effectively suppressed the growth of bacteria in vital organs of mice infected with S. aureus ATCC 25923. In conclusion, analog 22 may represent a potential antimicrobial peptide for further optimization.

Exploration of the Binding Mechanism of Cyclic Dinucleotide Analogs to Stimulating Factor Proteins and the Implications for Subsequent Analog Drug Design.

Cyclic dinucleotides (CDNs) are cyclic molecules consisting of two nucleoside monophosphates linked by two phosphodiester bonds, which act as a second messenger and bind to the interferon gene stimulating factor (STING) to activate the downstream signaling pathway and ultimately induce interferon secretion, initiating an anti-infective immune response. Cyclic dinucleotides and their analogs are lead compounds in the immunotherapy of infectious diseases and tumors, as well as immune adjuvants with promising applications. Many agonists of pathogen recognition receptors have been developed as effective adjuvants to optimize vaccine immunogenicity and efficacy. In this work, the binding mechanism of human-derived interferon gene-stimulating protein and its isoforms with cyclic dinucleotides and their analogs was theoretically investigated using computer simulations and combined with experimental results in the hope of providing guidance for the subsequent synthesis of cyclic dinucleotide analogs.

Applications of biaryl cyclization in the synthesis of cyclic enkephalin analogs with a highly restricted flexibility

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta–meta, meta–para, para–meta, and para–para configuration. Conformational properties of the peptides were studied by CD and NMR. CD studies allowed only to compare conformations of individual peptides while NMR investigations followed by XPLOR calculations provided detailed information on their conformation. Reliability of the XPLOR calculations was confirmed by quantum chemical ones performed for one of the analogs. No intramolecular hydrogen bonds were found in all the peptides. They are folded and adopt the type IV β-turn conformation. Due to a large steric strain, the aromatic carbon atoms forming the biaryl bond are distinctly pyramidalized. Seven of the peptides were tested in vitro for their affinity for the µ-opioid receptor.

Nucleation of a key beta-turn promotes cyclotide oxidative folding

Cyclotides are plant-derived peptides characterized by a head-to-tail cyclic backbone and a cystine knot motif comprised of three disulfide bonds. Formation of this motif via in vitro oxidative folding can be challenging and result in misfolded isomers with non-native disulfide connectivities. Here we investigated the effect of β-turn nucleation on cyclotide oxidative folding. Two types of β-turn mimics were grafted into kalata B1 (kB1), individually replacing each of the four β-turns in the folded cyclotide. Insertion of D-Pro-Gly into loop 5 was beneficial to the folding of both cyclic kB1 and a linear form of the peptide. The linear grafted analog folded four-times faster in aqueous conditions than cyclic kB1 in optimized conditions. Additionally, the cyclic analogue folded without the need for redox agents by transitioning through a native-like intermediate that was on-pathway to product formation. Kalata B1 is from the Mobius subfamily of cyclotides. Grafting D-Pro-Gly into loop 5 of cyclotides from two other subfamilies also had a beneficial effect on folding. Our findings demonstrate the importance of a β-turn nucleation site for cyclotide oxidative folding, which could be adopted as a chemical strategy to improve the in vitro folding of diverse cystine-rich peptides.

Design, synthesis, and evaluation of cyclic C7-bridged monocarbonyl curcumin analogs containing an o-methoxy phenyl group as potential agents against gastric cancer

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R 2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

(227) Use of the CNS Agent Bremelanotide in Men with Sexual Dysfunction: Results from a Sexual Medicine Clinic

Abstract Introduction Bremelanotide is a centrally acting, cyclic heptapeptide analog of the neuropeptide α-melanocyte-stimulating hormone with elevated affinity for the melanocortin-4 receptor. Bremelanotide modulates dopaminergic pathways involved in sexual desire and arousal. In an fMRI study, compared to placebo, bremelanotide was shown to improve connectivity between the amygdala and the insula during visual sexual stimulation, improve sexual brain processing, enhance cerebellar and supplementary motor area activity, and deactivate the secondary somatosensory cortex. Bremelanotide 1.75 mg/0.3 ml (Vyleesi®) is subcutaneously delivered by a single-use auto injector which has been shown to result in increased genital blood flow within hours of administration in both men and women. While phase 2 studies were performed in men with erectile dysfunction (ED), bremelanotide is currently FDA approved as an on-demand treatment for premenopausal women with generalized, acquired hypoactive sexual desire disorder (HSDD). Since its availability in September 2019, providers in our facility have been prescribing bremelanotide to premenopausal women, but off label to postmenopausal women, and to men diagnosed with ED and other types of sexual dysfunction after undergoing a biopsychosocial evaluation. Objective To better understand the use at our sexual medicine clinic of bremelanotide in men, we analyzed on and off label prescribing patterns and refill rates over a 46-month period in both our male and female patients with various sexual dysfunctions. Methods Bremelanotide prescription dispensing data specific to our sexual medicine facility during the period of September 2019 (inception) through June 30, 2023, was compiled. The analysis included the breakdown of prescription dispenses for men, premenopausal women (categorized by age 18-50) and postmenopausal women (categorized by age >50), with further analysis regarding refills and refill rates. Results Over the 46-month period, bremelanotide has been dispensed for various sexual dysfunctions: 76 times to premenopausal women, 104 times to postmenopausal women, and 444 times to men in our clinic. For premenopausal women, 29% of these dispenses were refills, for postmenopausal women, 52% of these dispenses were refills, and for men, 65% of these dispenses were refills. Over the last 18 months (January 1, 2022, through June 30, 2023), refill rates have been 47% for premenopausal women (n = 30), 52% for postmenopausal women (n = 29), and 73% for men (n = 219). Conclusions The refill rate and prescribing practices of any medication reflects, in part, the safety and efficacy of the treatment in a real-world setting. We observed increasing refill rates of bremelanotide in all patients. Of note, our male patients have particularly high refill rates, implying that bremelanotide, a centrally acting agent, can be used on demand to successfully treat a variety of sexual dysfunctions. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Palatin Technologies, Sprout Pharmaceuticals.

Design, synthesis and antibacterial activity of novel 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives

Based on the observed biological activity of 1,2,4-triazin-5-one derivatives and their cyclic analogues, a novel series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives that contain ester moiety compounds 3a-3g, carboxylic acid moiety compounds 4a-4g and piperazine amide moiety compounds 5a-5k at position-3 of the thiazolotriazinone scaffold were synthesized. The intermolecular cyclization occurred regioselectively at N2-position of 1,2,4-triazine ring was characterized by X-ray single-crystal diffraction analysis. The in vitro biological activities of the target compounds were assayed against some bacterial strains. Compared with ciprofloxacin, compounds 3g and 4g exhibited more excellent antibacterial activity, especially the activity against Staphylococcus aureus and Escherichia coli, showing that the fluorine at the para position of the benzyl group would be the best choice. In addition, compounds 4e-4g with carboxylic acid moiety can enhance the antibacterial activity. Compounds 5g-5k containing bulky 1-(substituted phenyl)piperazine moiety were found with slightly less biological activity. Similar to ciprofloxacin, the docking result of target compounds with DNA topoisomerase II indicates the carboxyl group of the target compounds with carboxylic acid moiety has a crucial salt bridge interaction with Mg2+ in the protein.

Synthesis of Original Cyclic Dinucleotide Analogues Using the Sulfo-click Reaction.

The stimulator of interferon genes (STING) protein plays a crucial role in the activation of the innate immune response. Activation of STING is initiated by cyclic dinucleotides (CDNs) which prompted the community to synthesize structural analogues to enhance their biological properties. We present here the synthesis and biological evaluation of four novel CDN analogues composed of an N-acylsulfonamide linkage. These CDNs were obtained in high overall yields via the sulfo-click reaction as a key step.

De Novo Synthesis of Acridone-Based Zn-Metal-Organic Framework (Zn-MOF) as a Photocatalyst: Application for Visible Light-Mediated Oxidation of Sulfides and Enaminones.

Acridone, a cyclic analogue of benzophenone that undergoes efficient intersystem crossing (ISC) to the triplet-excited state with near-unity quantum yield, was elaborated as a 3-connecting triacid linker, i.e., H3AcTA, to develop a photocatalytic metal-organic framework (MOF) for energy transfer applications; the triacid linker inherently features concave shapes, an attribute that is important for the construction of MOFs with significant porosity. Metal ion (Zn2+)-assisted self-assembly of the triacid yielded a Zn-MOF, i.e., Zn-AcTA, with a solvent-accessible volume of ca. 31%. The protection of the acridone chromophore in the MOF in conjunction with a wider cross-section of its absorption in the visible region renders the MOF an excellent heterogeneous photosensitizer for singlet oxygen (1O2) generation by energy transfer to the ground-state triplet oxygen (3O2). It is shown that the Zn-MOF can be applied as a photosensitizing catalyst for visible light-mediated oxidation of various sulfides to sulfoxides and enaminones to amino-esters via 1,2-acyl migration. It is further demonstrated that the photocatalyst can be easily recycled without any loss of catalytic activity and structural integrity. Based on mechanistic investigations, 1O2 is established as the reactive oxygen species in photocatalytic oxidation reactions. The results constitute the first demonstration of rational development of a photocatalytic MOF based on acridone for heterogeneous oxidations mediated by 1O2.

Structure-Activity Relationships of a Novel Cyclic Hexapeptide That Exhibits Multifunctional Opioid Agonism and Produces Potent Antinociceptive Activity.

The cyclic peptide c[d-Lys2, Asp5]-DN-9 has recently been identified as a multifunctional opioid/neuropeptide FF receptor agonist, displaying potent analgesic activity with reduced side effects. This study utilized Tyr-c[d-Lys-Gly-Phe-Asp]-d-Pro-NH2 (0), a cyclic hexapeptide derived from the opioid pharmacophore of c[d-Lys2, Asp5]-DN-9, as a chemical template. We designed, synthesized, and characterized 22 analogs of 0 with a single amino acid substitution to investigate its structure-activity relationship. Most of these cyclic hexapeptide analogs exhibited multifunctional activity at μ and δ opioid receptors (MOR and DOR, respectively) and produced antinociceptive effects following subcutaneous administration. The lead compound analog 15 showed potent agonistic activities at the MOR, κ opioid receptor (KOR), and DOR in vitro and produced a strong and long-lasting analgesic effect through peripheral MOR and KOR in the tail-flick test. Further biological evaluation identified that analog 15 did not cause significant side effects such as tolerance, withdrawal, or reward liability.

Cyclization of l-leucyl-l-valine dipeptide in the crystal phase under non-isоthermal conditions

Thermal treatment of linear dipeptides in the solid phase makes it possible to obtain their cyclic analogues in high yield and without additional costs. At the same time, such reactions occurring under the constraints of a crystal lattice with the participation of molecules in the zwitterionic form have not been sufficiently studied. In this work, the cyclization reaction of the dipeptide L-leucyl-L-valine in the crystalline phase upon heating was studied. Using isoconversion kinetics approaches, a kinetic model describing this process is determined, and kinetic parameters are calculated, including activation energy, Arrhenius multiplier, and reaction order. The enantiomeric purity of the resulting cyclic product was assessed. The self-assembly of linear and cyclic dipeptides on a solid support was studied. The results of the study will be useful for establishing the mechanism of the cyclization reaction of dipeptides in the solid phase, and can also be used in the development of effective and cost-effective methods for the production of cyclic dipeptides.

All-Hydrocarbon Stapled Peptide Multifunctional Agonists at Opioid and Neuropeptide FF Receptors: Highly Potent, Long-Lasting Brain Permeant Analgesics with Diminished Side Effects.

Our previous study reported the multifunctional agonist for opioid and neuropeptide FF receptors DN-9, along with its cyclic peptide analogues c[D-Cys2, Cys5]-DN-9 and c[D-Lys2, Asp5]-DN-9. These analogues demonstrated potent antinociceptive effects with reduced opioid-related side effects. To develop more stable and effective analgesics, we designed, synthesized, and evaluated seven hydrocarbon-stapled cyclic peptides based on DN-9. In vitro calcium mobilization assays revealed that most of the stapled peptides, except 3, displayed multifunctional agonistic activities at opioid and neuropeptide FF receptors. Subcutaneous administration of all stapled peptides resulted in effective and long-lasting antinociceptive activities lasting up to 360 min. Among these stapled peptides, 1a and 1b emerged as the optimized compounds, producing potent central antinociception following subcutaneous, intracerebroventricular, and oral administrations. Additionally, subcutaneous administration of 1a and 1b caused nontolerance antinociception, with limited occurrence of constipation and addiction. Furthermore, 1a was selected as the final optimized compound due to its wider safety window compared to 1b.

A new insight into the mechanism of solid-state cyclization of dipeptides: The effect of the sequence of amino acid residues in phenylalanyl-leucine and leucyl-phenylalanine

Heat treatment of linear dipeptides in the solid state is a good strategy for obtaining their cyclic analogs with a high yield and minimal costs. However, the cyclization of dipeptides under the crystal lattice constraints is still poorly understood. In this work, the thermally induced cyclization of l-phenylalanyl-l-leucine and l-leucyl-l-phenylalanine in the solid state was studied. Kinetic parameters of these reactions were estimated using the approaches of nonisothermal kinetics. For the first time, a possible mechanism of the reaction and rate-determining step is discussed. The effect of the sequence of amino acid residues in the dipeptide molecules on temperature and activation energy of solid-state cyclization was observed. The optical purity of the reaction products was estimated. The effect of temperature on the state of dipeptides films was visualized using atomic force microscopy. The results obtained contribute to the understanding of the mechanisms of solid-state cyclization of dipeptides and can be useful in the development of methods for the synthesis of diketopiperazine derivatives.

Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations.

In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA-H) and salts of sodium (-Na), calcium (-Ca), ammonium (-NH4 ), triethylammonium (-TEA), tris(hydroxymethyl)aminomethane (-Tris), benethamine (-Bnet), and benzathine (-BZ) were prepared. Their solid-state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2 O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X-ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA-BZ featured the lowest aqueous solubility and hygroscopicity, with 50 μg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X-ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP - conformation at the phosphorus atom.

Probing naphthalene diimide and 3-hydroxypropylphosphate as end-conjugating moieties for improved thrombin binding aptamers: Structural and biological effects

The limitations associated with the in vivo use of the thrombin binding aptamer (TBA or TBA15) have dramatically stimulated the search of suitable chemically modified analogues in order to discover effective and reversible inhibitors of thrombin activity. In this context, we previously proposed cyclic and pseudo-cyclic TBA analogues with improved stability that proved to be more active than the parent aptamer.Herein, we have investigated a novel library of TBA derivatives carrying naphthalene diimide (NDI) moieties at the 3′- or 5′-end. In a subset of the investigated oligonucleotides, additional 3-hydroxypropylphosphate (HPP) groups were introduced at one or both ends of the TBA sequence. Evaluation of the G-quadruplex thermal stability, serum nuclease resistance and in vitro anticoagulant activity of the new TBA analogues allowed rationalizing the effect of these appendages on the activity of the aptamer on the basis of their relative position. Notably, most of the different TBA analogues tested were more potent thrombin inhibitors than unmodified TBA. Particularly, the analogue carrying an NDI group at the 5′-end and an HPP group at the 3′-end, named N-TBA-p, exhibited enhanced G-quadruplex thermal stability (ΔTm + 14° C) and ca. 10-fold improved nuclease resistance in serum compared to the native aptamer. N-TBA-p also induced prolonged and dose-dependent clotting times, showing a ca. 11-fold higher anticoagulant activity compared to unmodified TBA, as determined by spectroscopic methods. Overall, N-TBA-p proved to be in vitro a more efficient thrombin inhibitor than all the best ones previously investigated in our group. Its interesting features, associated with its easy preparation, make it a very promising candidate for future in vivo studies.

Electron-Poor Butenolides: The Missing Link between Acrylates and Maleic Anhydride in Radical Polymerization.

Butenolides are a class of 5-membered lactones that hold great potential as bio-based monomers to replace oil-derived acrylates, of which they are cyclic analogues. Despite this structural resemblance, the reactivity of the unsaturated ester moiety of electron-poor butenolides leans toward that of maleic anhydride, another essential monomer that does not homopolymerize but copolymerizes in a highly alternating fashion with polarized electron-rich comonomers. By studying the reactivity of 5-methoxy and 5-acyloxy butenolides through a combination of kinetics and density functional theory (DFT) experiments, we explain why electron-poor butenolides constitute a missing link between acrylates and maleic anhydride in radical polymerization.

The Factor beyond Schmidt's Criteria Impacting the Photo-Induced [2+2] Cycloaddition Reactivity and Photoactuation of Molecular Crystals Based on Cyclic Chalcone Analogues.

Generally, the potential reactive "olefin pairs" in the molecular crystals satisfying Schmidt's criteria could undergo topological [2+2] cycloaddition. In this study, another factor that affects the photodimerization reactivity of chalcone analogues was found. The cyclic chalcone analogues of (E)-2-(2,4-dichlorobenzylidene)-2,3-dihydro-1H-inden-1-one (BIO), (E)-2-(naphthalen-2-ylmethylene)-2,3-dihydro-1H-inden-1-one (NIO), (Z)-2-(2,4-dichlorobenzylidene)benzofuran-3(2H)-one (BFO), and (Z)-2-(2,4-dichlorobenzylidene)benzo[b]thiophen-3(2H)-one (BTO) have been synthesized. While the geometrical parameters for the molecular packing of the above four compounds did not exceed Schmidt's criteria, [2+2] cycloaddition did not occur in the crystals of BIO and BTO. The single crystal structures and Hirshfeld surface analyses revealed that interactions of C=O⋅⋅⋅H (CH2 ) existed between adjacent molecules in the crystal of BIO. Therefore, the carbonyl and methylene groups linked with one carbon atom in carbon-carbon double bond were tightly confined in the lattice, acting as a tweezer to inhibit free movement of the double bond and suppressing [2+2] cycloaddition. In the crystal of BTO, similar interactions of Cl⋅⋅⋅S and C=O⋅⋅⋅H (C6 H4 ) prevented free movement of the double bond. In contrast, the intermolecular interaction of C=O⋅⋅⋅H only exists around the carbonyl group in the crystals of BFO and NIO, leaving the C=C double bonds to move freely and allowing the occurrence of [2+2] cycloaddition. Driven by photodimerization, the needle-like crystals of BFO and NIO displayed evident photo-induced bending behavior. This work demonstrates that the intermolecular interactions around carbon-carbon double bond affect the [2+2] cycloaddition reactivity except for Schmidt's criteria. These findings provide valuable insights into the design of photomechanical molecular crystalline materials.

Fatigue Threshold R-Curves for Dental Lithium Disilicate Glass–Ceramics

Chemical and mechanical fatigue degradation in ceramic materials is generally inconspicuous yet ubiquitous, to the effect that clinical fractures still consist of the main cause of failure in all-ceramic restorations. Implications of this span wide, from a reduced survival prognosis for the affected teeth, including more frequent and increasingly invasive procedural interventions, to the financial burden borne by individuals and health care systems. To suffice as an effective corrective, restoration lifetimes need only to be extended so to outlive the patient. That opens a box of problems from a materials science standpoint, entailing inherent deficiencies of brittle materials to resist mechanical and environmental challenges. Efforts in developing more damage-tolerant and fatigue-resistant restoratives go thus hand in hand with understanding intrinsic mechanisms of crack growth behavior under conditions that simulate the oral environment. Here we developed experiments using size-relevant sharp precracked specimens with controlled size and geometry (truncated semielliptical crack in the surface-crack-in-biaxial-flexure method) to establish a relationship between crack size and strength. The tangent method was used to construct envelopes for the quasi-static resistance curves (R-curves), which served as template for deriving residual cyclic R-curve analogs. By means of experimentally obtained stress–cycle curves, lifetime and fatigue parameters were employed within a mechanistic framework to reveal constitutive toughening mechanisms during subcritical growth under cyclic loading in a wet environment. Using 3 modern dental lithium disilicate glass–ceramics, we demonstrate the extent of R-curve degradation up to a threshold of 10 million cycles (~30 y in service) and draw parallels between the scope of fatigue degradation and the size of the microstructural units responsible for toughening mechanisms in glass–ceramic materials. Our results indicate that larger microstructural elements endow glass–ceramics with a higher reaching quasi-static R-curve at the onset but degrading more rapidly to comparable levels of lithium disilicates having submicrometric and nanometric crystal phases.

Structure-Activity Relationship Study of Antimicrobial Peptide PE2 Delivered Novel Linear Derivatives with Potential of Eradicating Biofilms and Low Incidence of Drug Resistance.

The ongoing emergence of antibiotic-resistant pathogens had been dramatically stimulating and accelerating the need for new drugs. PE2 is a kind of cyclic lipopeptide with broad-spectrum antimicrobial activity. Herein, its structure-activity relationship was systematically investigated by employing 4 cyclic analogues and 23 linear analogues for the first time. The screened linear analogues 26 and 27 bearing different fatty acyls at N-termini and a Tyr residue at the 9th position had superior potency compared to the cyclic analogues and showed equivalent antimicrobial activity compared with PE2. Notably, 26 and 27 exhibited significant ability against multidrug-resistant bacteria, favorable resistance to protease, excellent performance against biofilm, low drug resistance, and high effectiveness against the mice pneumonia model. The antibacterial mechanisms of PE2 and linear derivatives 26 and 27 were also preliminarily explored in this study. As described above, 26 and 27 are promising antimicrobial candidates for the treatment of infections associated with drug-resistant bacteria.