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Conjugated oligoelectrolytes (COEs) are an emerging class of amphiphilic antimicrobial compounds with a modular molecular framework suitable for simple chemical derivatization. Here, a series of COE derivatives with a stilbene‐conjugated segment and triphenylphosphonium (TPP) pendant groups was designed and synthesized to understand how lipophilic cationic groups impact antimicrobial activity. In vitro evaluations against ESKAPE pathogens showed broad‐spectrum activity towards multi‐drug resistant (MDR) bacteria and mycobacteria, with TPP groups enhancing antimicrobial activity towards clinically relevant Gram‐negative strains compared to their ammonium analogues. We studied the interactions of DM6P, the most active TPP‐COE compound, with various membrane assays. Treatment of bacterial cells with DM6P showed enhanced permeability of cell membranes without inducing the development of significant bacterial resistance. Moreover, DM6P eliminated 99.99 % of methicillin‐resistant Staphyloccocus aureus (MRSA) in an in vivo wound model. These results represent a promising chemical strategy for increasing the activity spectrum of membrane‐active COE antibiotics to tackle challenging drug‐resistant targets. [ABSTRACT FROM AUTHOR]

While two-dimensional graphene oxide (GO) is used increasingly in biomedical applications, there is uncertainty on how specific physicochemical properties relate to biocompatibility in mammalian systems. Although properties such as lateral size and the colloidal properties of the nanosheets are important, the specific material properties that we address here is the oxidation state and reactive surface groups on the planar surface. In this study, we used a GO library, comprising pristine, reduced (rGO), and hydrated GO (hGO), in which quantitative assessment of the hydroxyl, carboxyl, epoxy, and carbon radical contents was used to study the impact on epithelial cells and macrophages, as well as in the murine lung. Strikingly, we observed that hGO, which exhibits the highest carbon radical density, was responsible for the generation of cell death in THP-1 and BEAS-2B cells as a consequence of lipid peroxidation of the surface membrane, membrane lysis, and cell death. In contrast, pristine GO had lesser effects, while rGO showed extensive cellular uptake with minimal effects on viability. In order to see how these in vitro effects relate to adverse outcomes in the lung, mice were exposed to GOs by oropharyngeal aspiration. Animal sacrifice after 40 h demonstrated that hGO was more prone than other materials to generate acute lung inflammation, accompanied by the highest lipid peroxidation in alveolar macrophages, cytokine production (LIX, MCP-1), and LDH release in bronchoalveolar lavage fluid. Pristine GO showed less toxicity, whereas rGO had minimal effects. We demonstrate that the surface oxidation state and carbon radical content play major roles in the induction of toxicity by GO in mammalian cells and the lung.

Positive allosteric modulation of the mu-opioid receptor is a promising strategy to address the ever-growing problem of acute and chronic pain management. Positive allosteric modulators (PAMs) of the mu-opioid receptor could be employed to enhance the efficacy of endogenous opioid peptides to a degree that provides pain relief without the need for traditional opioid drugs. Alternatively, PAMs might be used to enhance the action of opioid drugs and so provide an opioid-sparing effect, allowing for the use of lower doses of opioid agonists and potentially decreasing associated side effects. BMS-986122 (2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl)-sulfonyl]-thiazolidine) has been previously identified as a PAM of the mu-opioid receptor. In the present work, we have designed and synthesized 33 analogs of BMS-986122 to explore the structure-activity relationships of this scaffold and confirm its allosteric mechanism of action. Among several newly identified modulators, the most promising compound ( 14b ) had improved activity to increase the in vitro potency of the standard mu-opioid agonist DAMGO and showed in vivo activity in mice to enhance the antinociceptive action of morphine.

Plants from the Panax genus have significant medicinal and nutritional benefits. Many Panax species are traditionally used in Chinese medicine and have gained popularity as food and health products because of their tonic effects and high safety. Their key bioactive components include polysaccharides, which are hydrophilic biomolecules that have demonstrated significant potential in the food and pharmaceutical industries because of their multiple health-promoting qualities, such as immunomodulatory, antitumor, antiaging, blood glucose and blood lipid regulation, antiviral, hepatoprotective, and gastrointestinal protective properties. Additionally, polysaccharides are abundant in health products made from the genus Panax , such as energy drinks and herbal teas. However, compared with more extensively studied components, such as ginsenosides and saponins, polysaccharides from the genus Panax (GPPs) have been the subject of relatively limited research. This review provides a comprehensive overview of the extraction and purification technology, structural characteristics, biological activities, applications, and structure-activity relationships of GPPs. Ultimately, this information establishes a theoretical foundation for the further development and application of GPPs in nutrition and medicine.

Structural modification of natural products is an effective strategy to discover potent lead compounds with improved medicinal performance. Toosendanin (TSN), a natural limonoid with diverse pharmacological properties, was selected as the starting material for structural modification to obtain more active anti-cancer agents in the current study. A library containing 25 structurally diverse derivatives (including 12 new ones) were constructed on the basis of the structure-guided modification of TSN. Subsequent cytotoxic assay of this library discovered that compounds 14, 18, and 25 showed more significant antiproliferative activity than the precursor TSN in MDA-MB-468 cell model and so as compounds 14, 17–19, 21, and 25 in Hela cell model. Among them, the new derivative 29-O-(6-chloronicotinoyl)-toosendanin (25) exhibited the most potent antiproliferative activity (IC50s 0.05–0.06 μM), being more active than TSN (IC50s 0.14–0.24 μM) and even the first-line drug adriamycin (IC50s ∼ 0.07 μM) in both tested cancer cell lines. The SARs study uncovered that the hemiacetal group, the 14,15-epoxy ring, 1-OH, 7-OH, 3-OAc, and 12-OAc were viewed as the essential active groups and the 29-OH was the critically active modification position of TSN for the enhancement of cytotoxicity. The discovering of 25 from TSN-based derivatives might serve as a lead compound for anti-cancer chemotherapy, which may shed light on rationally design TSN-based derivatives for obtaining more potent anti-tumor agents.

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors’ selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.

The active splicing strategy has witnessed improvement in bioactivity and antifungal spectra in pesticide discovery. Herein, a series of simple-structured molecules ( Y1 - Y53 ) containing chloro-substituted benzyl esters were designed using the above strategy. The structure-activity relationship (SAR) analysis demonstrated that the fatty acid fragment-structured esters were more effective than those containing an aromatic acid moiety or naphthenic acid part. Compounds Y36 and Y41 , which featured a thiazole-4-acid moiety and trifluoromethyl aliphatic acid part, respectively, exhibited excellent in vivo curative activity (89.4%, 100 mg/L Y36 ) and in vitro fungicidal activity (EC 50 = 0.708 mg/L, Y41 ) against Botrytis cinerea . Determination of antifungal spectra and analysis of scanning electron microscopy (SEM), membrane permeability, cell peroxidation, ergosterol content, oxalic acid pathways, and enzymatic assays were performed separately here. Compound Y41 is cost effective due to its simple structure and shows promise as a disease control candidate. In addition, Y41 might act on a novel target through a new pathway that disrupts the cell membrane integrity by inducing cell peroxidation.

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331 , exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596 , a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598 , a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.

Exploratory SAR studies of a new phenyl indole chemotype for p97 inhibition revealed C-5 indole substituent effects in the ADPGlo assay that did not fully correlate with either electronic or steric factors. A focused series of methoxy-, trifluoromethoxy-, methyl-, trifluoromethyl-, pentafluorosulfanyl-, and nitro-analogues was found to exhibit IC50s from low nanomolar to double-digit micromolar. Surprisingly, we found that the trifluoromethoxy-analogue was biochemically a better match of the trifluoromethyl-substituted lead structure than a pentafluorosulfanyl-analogue. Moreover, in spite of their almost equivalent strongly electron-depleting effect on the indole core, pentafluorosulfanyl- and nitro-derivatives were found to exhibit a 430-fold difference in p97 inhibitory activities. Conversely, the electronically divergent C-5 methyl- and nitro-analogues both showed low nanomolar activities.

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4- d ]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model. A series of pyrazolo[3,4- d ]pyridazinone derivatives were synthesized. Kinase inhibition, cell proliferation, and whole blood stability assays were performed, allowing us to explore structure−activity relationship and to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Compound 10h displayed highly potent antitumor efficacy in the NCI-H1581 xenograft model. [Display omitted] [ABSTRACT FROM AUTHOR]

The discovery of antibiotics has led to the effective treatment of bacterial infections that were otherwise fatal and has had a transformative effect on modern medicine. Teixobactin is an unusual depsipeptide natural product that was recently discovered from a previously unculturable soil bacterium and found to possess potent antibacterial activity against several Gram positive pathogens, including methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococci. One of the key features of teixobactin as an antibiotic lead is that resistance could not be generated in a laboratory setting. This is proposed to be a result of a mechanism of action that involves binding to essential cell wall synthesis building blocks, lipid II and lipid III. Since the initial isolation report in 2015, significant efforts have been made to understand its unique mechanism of action, develop efficient synthetic routes for its production, and thus enable the generation of analogues for structure−activity relationship studies and optimization of its pharmacological properties. Our review provides a comprehensive treatise on the progress in understanding teixobactin chemistry, structure−activity relationships, and mechanisms of antibacterial activity. Teixobactin represents an exciting starting point for the development of new antibiotics that can be used to combat multidrug‐resistant bacterial ("superbug") infections. [ABSTRACT FROM AUTHOR]

To accelerate the development of novel fungicides, a variety of N -(pyrazol-5-yl)benzamide derivatives with a diphenylamine moiety were designed and synthesized using a pharmacophore recombination strategy based on the structure of pyrazol-5-yl-aminophenyl-benzamides. The bioassay results demonstrated that most of the target compounds had excellent in vitro antifungal activities against Sclerotinia sclerotiorum , Valsa mali , and Botrytis cinerea . In particular, compound 5IIIh exhibited remarkable activity against S. sclerotiorum (EC 50 = 0.37 mg/L), which was similar to that of fluxapyroxad (EC 50 = 0.27 mg/L). In addition, compound 5IIIc (EC 50 = 1.32 mg/L) was observed to be more effective against V. mali than fluxapyroxad (EC 50 = 12.8 mg/L) and comparable to trifloxystrobin (EC 50 = 1.62 mg/L). Furthermore, compound 5IIIh demonstrated remarkable in vivo protective antifungal properties against S. sclerotiorum , with an inhibition rate of 96.8% at 100 mg/L, which was close to that of fluxapyroxad (99.6%). Compounds 5IIIc (66.7%) and 5IIIh (62.9%) exhibited good in vivo antifungal effects against V. mali at 100 mg/L, which were superior to that of fluxapyroxad (11.1%) but lower than that of trifloxystrobin (88.9%). The succinate dehydrogenase (SDH) enzymatic inhibition assay was conducted to confirm the mechanism of action. Molecular docking analysis further revealed that compound 5IIIh has significant hydrogen-bonding, π-π, and p-π conjugation interactions with ARG 43, SER 39, TRP 173, and TYR 58 in the binding site of SDH, and the binding mode was similar to that of the commercial fungicide fluxapyroxad. All of the results suggest that compound 5IIIh could be a potential SDH inhibitor, offering a valuable reference for future studies.

The emergence of multi-drug-resistant bacteria is threatening to human health and life around the world. In particular, methicillin-resistant Staphylococcus aureus (MRSA) causes fatal injuries to human beings and serious economic losses to animal husbandry due to its easy transmission and difficult treatment. Currently, the development of novel, highly effective, and low-toxicity antimicrobials is important to combat MRSA infections. Thiazole-containing compounds with good biological activity are widely used in clinical practice, and appropriate structural modifications make it possible to develop new antimicrobials. Here, we review thiazole-containing compounds and their antibacterial effects against MRSA reported in the past two decades and discuss their structure-activity relationships as well as the corresponding antimicrobial mechanisms. Some thiazole-containing compounds exhibit potent antibacterial efficacy in vitro and in vivo after appropriate structural modifications and could be used as antibacterial candidates. This Review provides insights into the development of thiazole-containing compounds as antimicrobials to combat MRSA infections.

The phytotoxicities of a selection of eudesmanolides and guaianolides, including natural products and new derivatives obtained by semisynthesis from plant-isolated sesquiterpene lactones, were evaluated in bioassays against three weeds of concern in agriculture ( Amaranthus viridis L., Echinochloa crus-galli L., and Lolium perenne L.). Both eudesmanolides and guaianolides were active against the root and shoot growth of all the species, with the eudesmanolides generally showing improved activities. The IC 50 values obtained for the herbicide employed as positive control (on root and shoot growth, respectively, A. viridis : 27.8 and 85.7 μM; E. crus-galli : 167.5 and 288.2 μM; L. perenne : 99.1 and 571.4 μM) were improved in most of the cases. Structure-activity relationships were discussed, finding that hydroxylation of the A-ring and C-13 as well as the position, number, and orientation of the hydroxyl groups and the presence of an unsaturated carbonyl group can significantly influence the level of phytotoxicity. γ-Cyclocostunolide was the most active compound in the series, followed by others such as dehydrozaluzanin C and α-cyclocostunolide (outstanding their IC 50 values on A. viridis )─natural products that can therefore be suggested as models for herbicide development if further research indicates effectiveness on a larger scale and environmental safety in ecotoxicological assessments.

Abstract A series of reduced lipophilic N-benzylic imidazo[1,2-a]pyridine carboxamides (IPAs) with various side chains were designed and synthesized as new anti-TB agents in this work. Five derivatives A2 , A3 , A4 , B1 and B9 exhibit excellent in vitro activity (MIC: < 0.035 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains, and acceptable PK properties. Compound B1 bearing a cyclohexylmethyl piperazine moiety, the same side chain of PBTZ169, was found to have obviously greater AUC 0-∞ and C max than Q203 and PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery. Graphical abstract Image 1 Highlights • Novel reduced lipophilic imidazo[1,2-a]pyridine-3-carboxamide derivatives were synthesized. • SARs were summarized for further antitubercular agents discovery. • Anti-MDR-TB activity, cytotoxicity and PK properties were investigated. • Compound B1 may serve as a new and promising candidate for further study. [ABSTRACT FROM AUTHOR]

Commercial vanadium oxide catalysts exhibit high efficiency for the selective catalytic reduction (SCR) of NO with NH 3 , especially in the presence of NO 2 (i.e., occurrence of fast NH 3 -SCR). The high-activity sites and their working principle for the fast NH 3 -SCR reaction, however, remain elusive. Here, by combining in situ spectroscopy, isotopic labeling experiments, and density functional theory (DFT) calculations, we demonstrate that polymeric vanadyl species act as the main active sites in the fast SCR reaction because the coupling effect of the polymeric structure alters the elementary reaction step and effectively avoids the high energy barrier of the rate-determining step over monomeric vanadyl species. This study unveils the high-activity dinuclear mechanism of the NO 2 -involved SCR reaction over vanadia-based catalysts and provides a fundamental basis for developing high-efficiency and low V 2 O 5 -loading SCR catalysts.

Rusts are one of the most important fungal diseases, the known target sites have already developed serious resistance to the main existing classifications of fungicides. In order to discover novel fungicides with a promising activity on rusts, twenty new substituted difluoromethylpyrimidinamine derivatives were designed and synthesized with the aid of the intermediate derivatization methods starting from ethyl 4,4-difluoro-3-oxobutanoate that is the common raw material in some newly launched important succinate dehydrogenase inhibitor (SDHI) fungicides. Their structures were identified by 1 H NMR, 13 C NMR, 19 F NMR, IR, elemental analyses and HRMS. All the compounds were screened for in vivo fungicidal activity against southern corn rust (SCR). The preliminary bioassay results indicated that 5-chloro-6-(difluoromethyl)- N -(2-(6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)ethyl)pyrimidin-4-amine (compound J , R 1 = CHF 2 , Alk = CH 2 CH 2 , Rn = 3-CF 3 ) is the optimal structure with desired fungicidal activity against SCR (EC 50 = 2.16 mg/L), significantly higher than commercial fungicides diflumetorim (EC 50 = 53.26 mg/L) and propiconazole (EC 50 = 3.92 mg/L). The structure–activity relationship of the synthesized compounds was discussed as well. This study also demonstrated that difluoromethylpyrimidinamine derivatives can be further utilized as a promising antifungal agent to control rust. Further synthesis and structure optimization studies are currently in progress. [ABSTRACT FROM AUTHOR]

In the first part of this paper, docking method was employed in order to study the binding mechanism of breast cancer resistance protein (BCRP) with a group of previously synthesized TPS-A derivatives which known as potent inhibitors of this protein to get insight into drug binding site of BCRP and to explore structure–activity relationship of these compounds. Molecular docking results showed that most of these compounds bind in the binding site of BCRP at the interface between the membrane and outer environment. In the second part, a group of designed TPS-A derivatives which showed good binding energies in the binding site of αβ-tubulin in the previous study were chosen to study their binding energies in the binding site of BCRP to investigate their simultaneous inhibitory effect on both αβ-tubulin and BCRP. The results showed that all of these compounds bind to the binding site of BCRP with relatively suitable binding energies and therefore could be potential inhibitors of both αβ-tubulin and BCRP proteins. Finally, virtual consensus docking method was utilized with the aim of design of new 2,5-diketopiperazine derivatives with significant inhibitory effect on both αβ-tubulin and BCRP proteins. For this purpose binding energies of a library of 2,5-diketopiperazine derivatives in the binding sites of αβ-tubulin and BCRP was investigated by using AutoDock and AutoDock vina tools. Molecular docking results revealed that a group of 36 compounds among them exhibit strong anti-tubulin and anti-BCRP activity. [ABSTRACT FROM AUTHOR]

Keywords: antimicrobial agents; conjugated oligoelectrolytes; mycobacteria; phosphonium; structure-activity relationships EN antimicrobial agents conjugated oligoelectrolytes mycobacteria phosphonium structure-activity relationships 1 1 1 05/11/23 20230508 NES 230508 B Triphenylphosphonium functionalization of a conjugated oligoelectrolyte b (COE) with a stilbene core improved its spectrum of activity to include ESKAPE pathogens and mycobacteria while crucially retaining the membrane-perturbing mode of action characteristic of COEs. The efficacy of the lead compound in vivo highlights the potential of the COE molecular platform for designing more effective antibiotics. Antimicrobial agents, conjugated oligoelectrolytes, mycobacteria, phosphonium, structure-activity relationships. [Extracted from the article]

Quantification in the driving patterns of activity descriptors on structure-activity relationships and reaction mechanisms over heterogeneous catalysts is still a great challenge and needs to be addressed urgently. Herein, with the example of typical Mn-based catalysts, based on the activity regularity and many characterizations, the chemisorbed oxygen density (ρ O β ) and particle size ( d TEM ) have been proposed as the two-dimensional descriptors for selective catalytic reduction of NO, whose role is in quantifying the contents of vacancy defects and the amounts of active sites located on terraces or interfaces, respectively. They can be utilized to construct and quantify the driving patterns for the structure-activity relationships and reaction mechanisms of NO reduction. As a consequence, a complementary modulation for E a by ρ O β and d TEM is described quantitatively in terms of the fitted functions. Moreover, based on the structure-activity relationships and the quantification laws of in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), the reaction efficiency (RE) of the specific combined NO x -intermediate is identified as the trigger to drive the Langmuir-Hinshelwood mechanism and modulated by the descriptors complementally and collaboratively following the fitted quantification functions. Either of the two descriptors at its lower values plays a dominant role in regulating E a and RE, and the dominant factor evolves progressively: d TEM ↔ coupling d TEM with ρ O β ↔ ρ O β , when the dependency of E a and RE on the descriptors is adopted to identify the dominant factor and domains. Therefore, this work has quantitatively accounted for the essence of activity modulation and may provide insight into the quantitative driving patterns for reaction activity and mechanism.

Aging refers to the gradual physiological changes that occur in an organism after reaching adulthood, resulting in senescence and a decline in biological functions, ultimately leading to death. Epidemiological evidence shows that aging is a driving factor in the developing of various diseases, including cardiovascular diseases, neurodegenerative diseases, immune system disorders, cancer, and chronic low-grade inflammation. Natural plant polysaccharides have emerged as crucial food components in delaying the aging process. Therefore, it is essential to continuously investigate plant polysaccharides as potential sources of new pharmaceuticals for aging. Modern pharmacological research indicates that plant polysaccharides can exert antiaging effects by scavenging free radicals, increasing telomerase activity, regulating apoptosis, enhancing immunity, inhibiting glycosylation, improving mitochondrial dysfunction regulating gene expression, activating autophagy, and modulating gut microbiota. Moreover, the antiaging activity of plant polysaccharides is mediated by one or more signaling pathways, including IIS, mTOR, Nrf2, NF-κB, Sirtuin, p53, MAPK, and UPR signaling pathways. This review summarizes the antiaging properties of plant polysaccharides and signaling pathways participating in the polysaccharide-regulating aging process. Finally, we discuss the structure-activity relationships of antiaging polysaccharides.

The existing agricultural insecticides have developed drug resistance from long-term use. Isoxazoline derivatives are new insecticides discovered in the 21st century. Because of their unique insecticidal mechanism, high selectivity, safety, and no significant cross resistance with the existing pesticides on the market, they have become a hot spot in the field of pesticide research. Herein, a series of novel isoxazoline derivatives containing ether and oxime-ether structures were designed and synthesized by a scaffold-hopping strategy using the pesticide fluralaner as a template structure. Through the investigation of insecticidal activity and the systematic structure-activity relationship, a series of compounds with high insecticidal activities were found, and compounds I-4 , II-9 , and II-13 with LC 50 values of 0.00008-0.00036 mg/L against diamondback moth emerged as novel insecticide candidates. These compounds also exhibited broad spectrum fungicidal activities against 14 plant fungi. The current work provides a reference for the design of new isoxazoline compounds based on the scaffold-hopping strategy.

Structural modification of natural products is an effective strategy to discover potent lead compounds with improved medicinal performance. Toosendanin (TSN), a natural limonoid with diverse pharmacological properties, was selected as the starting material for structural modification to obtain more active anti-cancer agents in the current study. A library containing 25 structurally diverse derivatives (including 12 new ones) were constructed on the basis of the structure-guided modification of TSN. Subsequent cytotoxic assay of this library discovered that compounds 14 , 18 , and 25 showed more significant antiproliferative activity than the precursor TSN in MDA-MB-468 cell model and so as compounds 14 , 17 – 19 , 21 , and 25 in Hela cell model. Among them, the new derivative 29- O -(6-chloronicotinoyl)-toosendanin (25) exhibited the most potent antiproliferative activity (IC 50 s 0.05–0.06 μM), being more active than TSN (IC 50 s 0.14–0.24 μM) and even the first-line drug adriamycin (IC 50 s ∼ 0.07 μM) in both tested cancer cell lines. The SARs study uncovered that the hemiacetal group, the 14,15-epoxy ring, 1-OH, 7-OH, 3-OAc, and 12-OAc were viewed as the essential active groups and the 29-OH was the critically active modification position of TSN for the enhancement of cytotoxicity. The discovering of 25 from TSN-based derivatives might serve as a lead compound for anti-cancer chemotherapy, which may shed light on rationally design TSN-based derivatives for obtaining more potent anti-tumor agents. [ABSTRACT FROM AUTHOR]

A new quinoline alkaloid, 5-hydroxy-6-methoxy-N-methyl-2-phenylquinoline-4-one (1), and seventeen known quinoline alkaloids (2-18) were isolated from the roots of Orixa japonica. The structure of 1 was determined by analysis of spectroscopic data. Among them, compounds 2, 3, and 13 were isolated from this plant for the first time. All isolates were screened for the anti-pathogenic fungi activities, including Rhizoctonia solani, Magnaporthe oryzae, and Phomopsis sp. The results showed that five compounds (4, 8, 10, 11, and 12) exhibited significant anti-pathogenic fungi effects at 50.0 μg/mL. In special, compound 10 exhibited the best antifungal activities toward R. solani and M. oryzae with the IC 50 values of 37.86 and 44.72 μM, respectively, better than that of the positive control, hymexazol (IC 50 121.21 and 1518.18 μM, respectively). Moreover, eleven new quinoline alkaloids derivatives (12a-12k) were designed and synthesized to investigate the structure-activity relationships (SARs). The SARs analysis indicated that the furo[2,3-b]quinoline skeleton and the methoxy at C-7 (compounds 8, 11, and 12) played a key role for improving the antifungal activities., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

We designed and synthesized a series of pyridine spiro derivatives and evaluated their insecticidal and antiviral activities. Some compounds exhibited good insecticidal and antiviral activities. Notably, the E series of compounds displayed good insecticidal activity against Tetranychus urticae . Compounds E20 (EC 50 = 63.68 mg/L) and F4 (EC 50 = 47.81 mg/L) exhibited inactivation activities against the tobacco mosaic virus (TMV), which were similar to that of Ningnanmycin (EC 50 = 58.01 mg/L). Molecular docking showed that compounds E20 and F4 exhibited satisfactory affinities for the TMV coat protein (TMV-CP), with binding energies (-6.7 and -6.4 kcal/mol, respectively) slightly lower than that of Ningnanmycin (-6.3 kcal/mol). Further, molecular dynamics analysis revealed that compounds E20 and F4 exhibited better binding stability values than Ningnanmycin. Microscale thermophoresis showed that compounds E20 ( K d = 0.053 ± 0.016 μM) and F4 ( K d = 0.045 ± 0.022 μM) bound more strongly to TMV-CP than Ningnanmycin ( K d = 0.10 ± 0.029 μM). The results of transmission electron microscopy showed that these two compounds hindered the self-assembly and growth of TMV. In summary, we showed that these pyridine spiro derivatives could be used as a basis for the research and development of novel pesticides.

Despite their clinical success in drug delivery applications, the potential of theranostic nanomedicines is hampered by mechanistic uncertainty and a lack of science-informed regulatory guidance. Both the therapeutic efficacy and the toxicity of nanoformulations are tightly controlled by the complex interplay of the nanoparticle's physicochemical properties and the individual patient/tumor biology; however, it can be difficult to correlate such information with observed outcomes. Additionally, as nanomedicine research attempts to gradually move away from large-scale animal testing, the need for computer-assisted solutions for evaluation will increase. Such models will depend on a clear understanding of structure-activity relationships. This review provides a comprehensive overview of the field of cancer nanomedicine and provides a knowledge framework and foundational interaction maps that can facilitate future research, assessments, and regulation. By forming three complementary maps profiling nanobio interactions and pathways at different levels of biological complexity, a clear picture of a nanoparticle's journey through the body and the therapeutic and adverse consequences of each potential interaction are presented.

Daptomycin is a clinical antibiotic used to treat serious infections caused by Gram-positive bacteria. Although there is debate about the action mechanism of daptomycin, it is known that daptomycin requires both calcium and phosphatidylglycerol (PG) to exert its antibacterial effect. Despite the importance and uniqueness of the interaction of daptomycin with PG, very little is known about this interaction or the nascent daptomycin-PG complex. In this work, we establish a structure-activity relationship between daptomycin and PG through the synthesis of PG analogues. In total, nine PGs were synthesized using a divergent approach employing phosphoramidite chemistry. The interaction between daptomycin and these PGs was studied using fluorescence, circular dichroism, and isothermal titration calorimetry. It was determined that daptomycin is highly sensitive to the modification of the headgroup of PG and both hydroxyl groups influence membrane binding, oligomerization, and backbone structure. Methylation of each hydroxyl in the headgroup suggests that the binding pocket envelops both hydroxyl groups. A PG acyl tail chain length of at least 7-8 carbons is required for stoichiometric binding at micromolar peptide concentrations. Daptomycin binds to PG having 8-carbon, linear, unsaturated acyl groups (C8PGs) at the micromolar concentration and interacts with C8PG in essentially the same manner as when the PG is incorporated into a liposome, and thus, preassembly of individual PG moieties is not a prerequisite for binding, structural transition, and oligomerization.

To develop novel succinate dehydrogenase inhibitors (SDHIs), two series of novel N -4-fluoro-pyrazol-5-yl-benzamide and N -4-chloro-pyrazol-5-yl-benzamide derivatives were designed and synthesized, and their antifungal activities were evaluated against Valsa mali , Sclerotinia sclerotiorum , FusaHum graminearum Sehw , Physalospora piricola , and Botrytis cinerea . The bioassay results showed that some of the target compounds exhibited good antifungal activities in vitro against V. mali and S. sclerotiorum . Remarkably, compound 9Ip displayed good in vitro activity against V. mali with an EC 50 value of 0.58 mg/L. This outcome was 21-fold greater than that of fluxapyroxad (12.45 mg/L) and close to that of the commercial fungicide tebuconazole (EC 50 = 0.36 mg/L). In addition, in viv o experiments proved that compound 9Ip has good protective fungicidal activity with an inhibitory rate of 93.2% against V. mali at 50 mg/L, which was equivalent to that of the positive control tebuconazole (95.5%). The results of molecular docking indicated that there were obvious hydrogen bonds and p-π interactions between compound 9Ip and succinate dehydrogenase (SDH), which could explain the probable action mechanism. In addition, the SDH enzymatic inhibition assay was carried out to further prove its mode of action. Our studies suggest that compound 9Ip could be a fungicidal lead to discover more potent SDHIs for crop protection.

The serendipitous discovery of the HPPD inhibitors from allelopathic plants opened the way for searching new and effective herbicidal agents by application of classical hit-to-lead optimization approaches. A plethora of active and selective compounds were discovered that belong to three major classes of cyclohexane-based triketones, pyrazole-based diketones, and diketonitriles. In addition, to enhance inhibitory constant and herbicidal activity, many efforts were also made to gain broader weed control, crop safety, and eventual agricultural applicability. Moreover, HPPD inhibitors emerged as therapeutic agents for inherited and metabolic human diseases as well as vector-selective insecticides in the control of hematophagous arthropods. Given the large set of experimental data available, structure-activity relationship analysis could be used to derive suggestions for next generation optimized compounds.

Daptomycin is an important antibiotic used for treating serious infections caused by Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Establishing structure-activity relationships of daptomycin is important for developing new daptomycin-based antibiotics with expanded clinical applications and for tackling the ever-increasing problem of antimicrobial resistance. Toward this end, Dap-K6-E12-W13, an active analogue of daptomycin in which the uncommon amino acids in daptomycin are replaced with their common counterparts, was used as a model system for studying the effect of amino acid variation at positions 8 and 11 on in vitro biological activity against a model organism, Bacillus subtilis , and calcium-dependent insertion into model membranes. None of the new peptides were more active than Dap-K6-E12-W13; however, substitution at positions 8 and/or 11 with cationic residues resulted in little or no loss of activity, and some of these analogues were able to insert into model membranes at lower calcium ion concentrations than the parent peptide. Incorporation of these cationic residues into positions 8 and/or 11 of daptomycin itself yielded some derivatives that exhibited lower minimum inhibitory concentrations than daptomycin against B. subtilis 1046 as well as comparable and sometimes superior activity against clinical isolates of MRSA.

Dimeric mixed-ligand oxidovanadium complexes [V 2 O 2 (1,3-pdta)(bpy) 2 ]·9H 2 O ( 1 ) and [V 2 O 2 (1,3-pdta)(phen) 2 ]·6H 2 O ( 2 ) feature a symmetric binuclear structure bridged by 1,3-pdta, which is different from our previous reported asymmetric binuclear complex [V 2 O 2 (edta)(phen) 2 ]·11H 2 O ( 3 ).In this study, a wide range of analytical techniques were carried out to fully characterize the complexes 1 and 2 and further investigate their structural stabilities. Density functional theory calculations of 1 and 2 also suggest that they might have good reactivity with biomolecules as anticancer agents. To assess and screen the antitumor activities of compounds 1-3 together with their four corresponding monomeric complexes [VO(ida)(phen)], [VO(ida)(bpy)], [VO(OH)(phen) 2 ]Cl, and [VO(Hedta)] - , we have performed in vitro experiments with hepatocellular carcinoma HepG2 and SMMC-7721 cell lines by MTT analyses. Complex 2 was found to have the highest inhibitory potency against the growth of HepG2 and SMMC-7721 cells (IC 50 = 2.07 ± 0.72 μM for HepG2; 13.00 ± 3.06 μM for SMMC-7721) compared to other compounds. The structure-activity relationship studies showed that the antitumor effect of compound 2 is higher than that of other compounds. After studying the monomeric compounds of 1-3 , their effects were also ranked. Moreover, complex 2 displayed stronger binding affinity toward calf thymus DNA ( K b = 5.71 × 10 4 M -1 ) and cleavage activities than the other complexes ( K b = 1.34 × 10 4 M -1 for 1 and 5.22 × 10 4 M -1 for 3 , respectively). We further extended the cellular mechanisms of drug action and found that 2 could block DNA synthesis and cell division of HepG2 and 7721 cells and further induce apoptosis by flow cytometry assays. In short, these results indicate that binuclear oxidovanadium compounds could have potential as simple, effective, and safe antitumor agents.

Multidrug-resistant bacteria represent a global health problem increasingly leading to infections that are untreatable with our existing antibiotic arsenal. Therefore, it is critical to identify novel effective antimicrobials. Venoms represent an underexplored source of potential antibiotic molecules. Here, we engineered a peptide (IsCT1-NH 2 ) derived from the venom of the scorpion Opisthacanthus madagascariensis , whose application as an antimicrobial had been traditionally hindered by its high toxicity. Through peptide design and the knowledge obtained in preliminary studies with single and double-substituted analogs, we engineered IsCT1 derivatives with multiple amino acid substitutions to assess the impact of net charge on antimicrobial activity and toxicity. We demonstrate that increased net charge (from +3 to +6) significantly reduced toxicity toward human erythrocytes. Our lead synthetic peptide, [A] 1 [K] 3 [F] 5 [K] 8 -IsCT1-NH 2 (net charge of +4), exhibited increased antimicrobial activity against Gram-negative and Gram-positive bacteria in vitro and enhanced anti-infective activity in a mouse model. Mechanism of action studies revealed that the increased antimicrobial activity of our lead molecule was due, at least in part, to its enhanced ability to permeabilize the outer membrane and depolarize the cytoplasmic membrane. In summary, we describe a simple method based on net charge tuning to turn highly toxic venom-derived peptides into viable therapeutics.

This article describes the discovery of novel potent muscarinic receptor antagonists identified during a search for more active histamine H 3 receptor (H 3 R) ligands. The idea was to replace the flexible seven methylene linker with a semirigid 1,4-cyclohexylene or p -phenylene substituted group of the previously described histamine H 3 R antagonists ADS1017 and ADS1020 . These simple structural modifications of the histamine H 3 R antagonist led to the emergence of additional pharmacological effects, some of which unexpectedly showed strong antagonist potency at muscarinic receptors. This paper reports the routes of synthesis and pharmacological characterization of guanidine derivatives, a novel chemotype of muscarinic receptor antagonists binding to the human muscarinic M 2 and M 4 receptors (hM 2 R and hM 4 R, respectively) in nanomolar concentration ranges. The affinities of the newly synthesized ADS10227 (1-{4-{4-{[4-(phenoxymethyl)cyclohexyl]methyl}piperazin-1-yl}but-1-yl}-1-(benzyl)guanidine) at hM 2 R and hM 4 R were 2.8 nM and 5.1 nM, respectively.

Chalcones, containing an α , β -unsaturated ketone fragment, are an important pharmacologically active agents because of their diverse mechanisms. This review provides an update on the recent developments (2009–2019.3) in the antibacterial activity of natural and synthetic chalcones. Moreover, the structure–activity relationships and mechanisms are also carefully summarized which will provide some important guidance for design and synthesis in future. This comprehensive and critical review will be helpful for medicinal chemists to develop more candidate antibacterial agents. Image 1 • A review of the antibacterial activity of natural and synthetic chalcones. • The structure–activity relationships and antibacterial mechanisms are described. • The review will be helpful for further research and application of chalcones as antibacterial agents. [ABSTRACT FROM AUTHOR]

Life-threatening invasive fungal infections represent an urgent threat to human health worldwide. The limited set of antifungal drugs has critical constraints such as resistance development and/or adverse side effects. One approach to overcome these limitations is to mimic naturally occurring antifungal peptides called defensins. Inspired by their advantageous amphiphilic properties, a library of 35 synthetic, linear, ternary polyacrylamides was prepared by controlled/living radical polymerization. The effect of the degree of polymerization (20, 40, and 100) and varying hydrophobic functionalities (branched, linear, cyclic, or aromatic differing in their number of carbons) on their antifungal activity was investigated. Short copolymers with a calculated log P of ∼1.5 revealed optimal activity against the major human fungal pathogen Candida albicans and other pathogenic fungal species with limited toxicity to mammalian host cells (red blood cells and fibroblasts). Remarkably, selected copolymers outperformed the commercial antifungal drug amphotericin B, with respect to the therapeutic index, highlighting their potential as novel antifungal compounds.

To promote the discovery and development of new fungicides, a series of novel pyrazol-5-yl-benzamide derivatives were designed, synthesized by hopping and inversion of amide groups of pyrazole-4-carboxamides, and evaluated for their antifungal activities. The bioassay data revealed that compound 5IIc exhibited an excellent in vitro activity against Sclerotinia sclerotiorum with an EC 50 value of 0.20 mg/L, close to that of commercial fungicide Fluxapyroxad (EC 50 = 0.12 mg/L) and Boscalid (EC 50 = 0.11 mg/L). For Valsa mali , compound 5IIc (EC 50 = 3.68 mg/L) showed a significantly higher activity than Fluxapyroxad (EC 50 = 12.67 mg/L) and Boscalid (EC 50 = 14.83 mg/L). In addition, in vivo experiments proved that compound 5IIc has an excellent protective fungicidal activity with an inhibitory rate of 97.1% against S. sclerotiorum at 50 mg/L, while the positive control Fluxapyroxad showed a 98.6% inhibitory effect. The molecular docking simulation revealed that compound 5IIc interact with TRP173, SER39, and ARG43 of succinate dehydrogenase (SDH) through a hydrogen bond and p-π interaction, which could explain the probable mechanism of the action between compound 5IIc and target protein. Also, the SDH enzymatic inhibition assay was carried out to further validate its mode of action. These results demonstrate that compound 5IIc could be a promising fungicide candidate and provide a valuable reference for further investigation.

κ opioid receptor (κOR) is a subtype of opioid receptors, and there are two major κOR agonists currently available, morphinans and arylacetamides, which are structurally distinct from each other. Numerous efforts had been made to correlate these series of compounds in order to establish a consensus binding pattern for κOR agonists. Unfortunately, no morphinan-based agent with an arylacetamidyl substituent has been identified as a κOR agonist with a pharmacological profile similar to arylacetamides. Since the recently described morphinan-based compound SLL-039 was identified as a selective and potent κOR agonist that contains a unique benzamidyl substituent in structure similar to arylacetamides, numerous arylacetamidyl substituents were introduced to this scaffold to examine whether the structure-activity relationships (SARs) of arylacetamides in conferring κOR agonistic activities could be reproduced by these analogues. Thus, a series of N -cyclopropylmethyl-7α-arylacetamidylphenyl-6,14-endoethanotetrahydronorthebaine analogues were designed, synthesized, and assayed for biological activities. Among these compounds, compound 4j with a 3',4'-dimethylphenylacetamidyl substituent showed a single digit low nanomolar affinity to the κOR and relatively high subtype selectivity in binding assays, but this profile was not reproduced in functional assays. In contrast, compound 4i displayed moderately selective κOR agonistic activities in functional assays, which was inconsistent with its nonselective nature in binding assays. Overall, introduction of an arylacetamidyl substituent to the morphinan-based scaffold was associated with pharmacological diversity in both binding and functional activities on opioid receptors in vitro . The resultant SARs were inconsistent with that of classical arylacetamides as κOR agonists, despite bearing a similar arylacetamidyl substituent in the structure. Therefore, the arylacetamidyl substituent of the morphinan-based scaffold was found to be disconnected from that of arylacetamides in conferring κOR activities.

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4- d ]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure-activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3-arylisoquinolones 3 h [3-(4-(benzyloxy)-3-methoxyphenyl)-7,8-dimethoxyisoquinolin-1(2H)-one] and 4 a [3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-dimethoxyisoquinolin-1(2H)-one] were found to have potent inhibitory effects on hCES2A (IC 50 =0.68 μΜ, K i =0.36 μΜ) and excellent specificity (more than 147.05-fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h, with an IC 50 value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure-activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity., (© 2020 Wiley-VCH GmbH.)

A solid-phase platform for the precise and sequential synthesis of enterobactin analogues is described. This chemistry unites the power of solid-phase peptide synthesis with the unique opportunities and applications offered by siderophore chemistry. Here, a series of hybrid enterobactin hydroxamate/catecholate (HEHC) analogues were synthesized using both catechols and amino acid derived hydroxmate chelators. The HEHC analogues were evaluated for their ability to bind free iron and to promote growth in siderophore-auxotrophic mutant bacteria. We find that, in contrast to S. aureus or E. coli , a number of HEHC analogues promote growth in P. aeruginosa and structure-activity relationships (SARs) exist for the growth promotion via HEHC analogues in this organism.