Machine learning-based q-RASAR predictions of the bioconcentration factor of organic molecules estimated following the organisation for economic co-operation and development guideline 305.

In this study, we utilized an innovative quantitative read-across (RA) structure-activity relationship (q-RASAR) approach to predict the bioconcentration factor (BCF) values of a diverse range of organic compounds, based on a dataset of 575 compounds tested using Organisation for Economic Co-operation and Development Test Guideline 305 for bioaccumulation in fish. Initially, we constructed the q-RASAR model using the partial least squares regression method, yielding promising statistical results for the training set (R2 =0.71, Q2LOO=0.68, mean absolute error [MAE]training=0.54). The model was further validated using the test set (Q2F1=0.77, Q2F2=0.75, MAEtest=0.51). Subsequently, we explored the q-RASAR method using other regression-based supervised machine-learning algorithms, demonstrating favourable results for the training and test sets. All models exhibited R2 and Q2F1 values exceeding 0.7, Q2LOO values greater than 0.6, and low MAE values, indicating high model quality and predictive capability for new, unidentified chemical substances. These findings represent the significance of the RASAR method in enhancing predictivity for new unknown chemicals due to the incorporation of similarity functions in the RASAR descriptors, independent of a specific algorithm.

A patent review of SCF E3 ligases inhibitors for cancer：Structural design, pharmacological activities and structure-activity relationship.

Currently, as the largest family of E3 ubiquitin ligases, Skp1-Cullin 1-F-box (SCF) E3 ligase complexes have attracted extensive attention. Among SCF complexes, Skp2, ß-TrCP, and FBXW7 have undergone extensive research on their structures and functions. Previous studies suggest Skp2, ß-TrCP, and FBXW7 are overexpressed in numerous cancers. Thus, the SCF E3 ligase complex has become a significant target for the development of anti-cancer drugs. Over the past few decades, a variety of anti-tumor inhibitors targeting the SCF E3 ligase complex have been attempted. However, since almost none of the SCF E3 ligase inhibitors passed clinical trials, the design and synthesis of the new inhibitors are needed. Here, we will introduce the structure and function of Skp2, ß-TrCP, and FBXW7, their connections with cancer development, the relevant in vitro and in vivo activities, selectivity, structure-activity relationships, and the therapeutic or preventive application of small molecule inhibitors targeting these three F-box proteins reported in the patent (2010-present). This information will help develop drugs targeting the SCF E3 ubiquitin ligase, providing new strategies for future cancer treatments.

Peptide nanozymes: An emerging direction for functional enzyme mimics.

The abundance of molecules on early Earth likely enabled a wide range of prebiotic chemistry, with peptides playing a key role in the development of early life forms and the evolution of metabolic pathways. Among peptides, those with enzyme-like activities occupy a unique position between peptides and enzymes, combining both structural flexibility and catalytic functionality. However, their full potential remains largely untapped. Further exploration of these enzyme-like peptides at the nanoscale could provide valuable insights into modern nanotechnology, biomedicine, and even the origins of life. Hence, this review introduces the groundbreaking concept of "peptide nanozymes (PepNzymes)", which includes single peptides exhibiting enzyme-like activities, peptide-based nanostructures with enzyme-like activities, and peptide-based nanozymes, thus enabling the investigation of biological phenomena at nanoscale dimensions. Through the rational design of enzyme-like peptides or their assembly with nanostructures and nanozymes, researchers have found or created PepNzymes capable of catalyzing a wide range of reactions. By scrutinizing the interactions between the structures and enzyme-like activities of PepNzymes, we have gained valuable insights into the underlying mechanisms governing enzyme-like activities. Generally, PepNzymes play a crucial role in biological processes by facilitating small-scale enzyme-like reactions, speeding up molecular oxidation-reduction, cleavage, and synthesis reactions, leveraging the functional properties of peptides, and creating a stable microenvironment, among other functions. These discoveries make PepNzymes useful for diagnostics, cellular imaging, antimicrobial therapy, tissue engineering, anti-tumor treatments, and more while pointing out opportunities. Overall, this research provides a significant journey of PepNzymes' potential in various biomedical applications, pushing them towards new advancements.

A Multimodal, In Vivo Approach for Assessing Structurally and Phenotypically Related Neuroactive Molecules.

A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABAA potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging. This revealed that analogs effect a range of behavioral responses, including sedation with and without enhancing the acoustic startle response. Interestingly, a subset of compounds effect sedation and enhancement of motor responses to both acoustic and light stimuli. Patch clamp recordings of cells with a human GABAA receptor confirmed that behavior-modulating isoflavones modify the GABA signaling. To better understand these molecules' nuanced effects on behavior, we performed whole brain imaging to reveal that analogs differentially effect neuronal activity. These studies demonstrate a multimodal approach to assessing activities of neuroactives.

Effects of derivatization and probiotic transformation on the antioxidative activity of fruit polyphenols.

Fruits contain numerous polyphenols in the form of conjugates, which exhibit low antioxidant activity. Probiotic fermentation is a strategy to improve the antioxidant activity of these conjugated polyphenols by modifying their structure. However, the mechanisms underlying the effects of functional groups and derivatizations on the antioxidative activities of polyphenols and the antioxidation enhancement by probiotic biotransformation haven't been comprehensively explored. This review aimed to explore the structure-antioxidant activity relationships of four functional groups and three derivatizations in flavonoids and phenolic acids. Further, the review elucidated the antioxidant mechanisms underlying the biotransformation of flavonoids and phenolic acids as glycoside, methylated, and ester conjugates by probiotic biotransformation. Deglycosylation, demethylation, and hydrolysis catalyzed by enzymes produced by Bifidobacterium and Lactobacillus facilitated the conversion of conjugated polyphenols into flavonoids and phenolic acids with hydrolyzed forms and highly active functional groups, thereby increasing hydrogen supply and electron transfer capacity to enhance the antioxidant activity.

Evaluation of structural features of anabolic-androgenic steroids: entanglement for organ-specific toxicity.

Anabolic-androgenic steroids (AASs), more correctly termed "steroidal androgens", are a broad category of compounds including both synthetic derivatives and endogenously produced androgens like testosterone, which have long been employed as performance-enhancing substances, primarily among recreational athletes and some professionals. While their short-term effects on muscle physiology are well-documented, the long-term health consequences remain inadequately understood. A key finding is the disruption of hormone production, leading to reversible and irreversible changes, particularly with prolonged use. While debate exists over the prevalence of adverse effects, studies suggest a spectrum of somatic and psychiatric consequences, highlighting the need for improved understanding and prevention strategies. AASs are not only affect muscle structure but also influence mood, behavior, and body image, potentially exacerbating substance dependence and psychological distress. Liver alterations are a prominent concern, with oxidative stress implicated in AAS-induced hepatotoxicity. Reproductive complications, including gonadal atrophy and infertility, are common, alongside virilization and feminization effects in both genders. Cardiovascular effects are particularly worrisome, with AASs implicated in hypertension, dyslipidemia, and increased thrombotic risk, contributing to cardiovascular morbidity and mortality. Moreover, AASs may enhance cancer risks, potentially accelerating carcinogenesis in various tissues, including the prostate. The review emphasizes the need for comprehensive public health initiatives to mitigate harm, including harm minimization strategies, routine health screenings, and targeted interventions for AAS users. Understanding the complex interplay of biological mechanisms and systemic effects is crucial for informing clinical management and preventive measures. This review also examines the biological impact of AASs on human muscles, detailing mechanisms of action, chemistry, and associated health risks such as liver damage, cardiovascular disease, and endocrine dysfunction.

Structural properties, bioactivities, structure-activity relationships and bio-applications of polysaccharides from Auricularia auricula: A review.

Auricularia auricula (A. auricula), is a medicinal and edible fungus in China for thousands of years with rich nutrition and delicious taste. The main active ingredient of A. auricula is polysaccharide, which has antitumor, hypoglycemic, antioxidant, and immune regulation bioactivities. It is widely recognized that the biological activity of polysaccharides is closely related to the chemical structure and advanced structure. In terms of polysaccharides extracted from A. auricula (AAPs), there were distinguished structures reported due to the different original resources and extraction methods, leading to various bioactivities. However, the structure-activity relationship of AAPs has scarcely been reviewed till now. In addition, polysaccharides were found to have specific self-assembly properties recently, together with their bioactivities, endowing them with unique physicochemical properties. Nowadays, an increasing number of polysaccharides, such as cellulose, chitin, and pectin, have been used to construct various functional materials in the fields of food, cosmetics, and biomedical materials. Therefore, the construction of functional materials by AAPs is of great research significance. This article aims to provide a systematic review of the structure-activity relationship of AAPs and summarize the functional materials constructed based on AAPs to provide theoretical references for further research and application of AAPs.

A Chemical Toolbox to Unveil Synthetic Nature-Inspired Antifouling (NIAF) Compounds.

The current scenario of antifouling (AF) strategies to prevent the natural process of marine biofouling is based in the use of antifouling paints containing different active ingredients, believed to be harmful to the marine environment. Compounds called booster biocides are being used with copper as an alternative to the traditionally used tributyltin (TBT); however, some of them were recently found to accumulate in coastal waters at levels that are deleterious for marine organisms. More ecological alternatives were pursued, some of them based on the marine organism mechanisms' production of specialized metabolites with AF activity. However, despite the investment in research on AF natural products and their synthetic analogues, many studies showed that natural AF alternatives do not perform as well as the traditional metal-based ones. In the search for AF agents with better performance and to understand which molecular motifs were responsible for the AF activity of natural compounds, synthetic analogues were produced and investigated for structure-AF activity relationship studies. This review is a comprehensive compilation of AF compounds synthesized in the last two decades with highlights on the data concerning their structure-activity relationship, providing a chemical toolbox for researchers to develop efficient nature-inspired AF agents.

Recent Advances in Anti-Inflammatory Compounds from Marine Microorganisms.

Marine microbial secondary metabolites with diversified structures have been found as promising sources of anti-inflammatory lead compounds. This review summarizes the sources, chemical structures, and pharmacological properties of anti-inflammatory natural products reported from marine microorganisms in the past three years (2021-2023). Approximately 252 anti-inflammatory compounds, including 129 new ones, were predominantly obtained from marine fungi and they are structurally divided into polyketides (51.2%), terpenoids (21.0%), alkaloids (18.7%), amides or peptides (4.8%), and steroids (4.3%). This review will shed light on the development of marine microbial secondary metabolites as potential anti-inflammatory lead compounds with promising clinical applications in human health.

Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases.

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.

Structure Derivatization of IgG-Binding Peptides and Analysis of Their Secondary Structure by Circular Dichroism Spectroscopy.

Mid-sized cyclic peptides are a promising modality for modern drug discovery. Their larger interaction area coupled with an appropriate secondary structure is more suitable than small molecules for binding to the target protein. In this study, we conducted a structure derivatization of an immunoglobulin G (IgG)-binding peptide (15-IgBP), a ß-hairpin-like cyclic peptide with a twisted ß-strand and assessed the effect of the secondary structure on IgG-binding activity using circular dichroism (CD) spectra analysis. As a result, derivatization at the Ala5 and Gly9 positions affected the secondary structure of 15-IgBP, in particular the appearance of a small positive peak in the 220-240 nm region characteristic of 15-IgBP in the CD spectrum. Maintaining this peak at a moderate level may be important for the expression of IgG binding activity. We found the small methyl group at Ala5 to be crucial for retaining the preferred secondary structure; we also found Gly9 could be replaced by D-amino acids. By integrating these findings with previous results of the structure-activity relationship, we obtained four potent affinity peptides for IgG binding (Kd = 4.24-5.85 nM). Furthermore, we found the Gly9 position can be substituted for D-Lys. This is a new potential site for attaching functional units for conjugation with IgG for the preparation of homogeneous antibody-drug conjugates.

One-Step Organic Synthesis of 18ß-Glycyrrhetinic Acid-Anthraquinone Ester Products: Exploration of Antibacterial Activity and Structure-Activity Relationship, Toxicity Evaluation in Zebrafish.

To combine the activity characteristics of 18ß-glycyrrhetinic acid (18ß-GA) and anthraquinone compounds (rhein and emodin), reduce toxicity, and explore the structure-activity relationship (SAR) of anthraquinones, 18ß-GA-anthraquinone ester compounds were synthesized by one-step organic synthesis. The products were separated and purified by HPLC and characterized by NMR and EI-MS. It was finally determined as di-18ß-GA-3-rhein ester (1, New), GA dimer (2, known), 18ß-GA-3-emodin ester (3, known), and di-18ß-GA-1-emodin ester (4, new). The MIC of three reactants and four products against Escherichia coli and Staphylococcus aureus were detected in vitro. Its developmental toxicity and cardiotoxicity were assessed using zebrafish embryos. The experimental results showed that rhein had the best antibacterial activity against Staphylococcus aureus with MIC50 of 2.4 mM, and it was speculated that -COOH, -OH, and intramolecular hydrogen bonds in anthraquinone compounds would enhance the antibacterial effect, while the presence of-CH3 might weaken the antibacterial activity. Product 1 increased the hatching rate and survival rate of zebrafish embryos and reduced the malformation rate and cardiomyocyte apoptosis. This experiment lays the foundation for further studying the SAR of anthraquinones and providing new drug candidates.

Exploring the Potential of Terpenoids as a Possible Treatment for Cancer: Structure-Activity Relationship and Mechanistic Studies.

Cancer stands as a significant global health challenge due to its mortality rates and the complexities involved in its treatment. Addressing issues, such as metastasis, recurrence, chemoresistance, and treatment-related toxicity, remains pivotal in cancer therapy advancement. Therefore, exploration of novel therapeutic agents has emerged as a priority. As the risk of cancer continues to rise, effective measures must be taken to combat it. One promising approach is to explore natural remedies, such as terpenoids, which have demonstrated anticancer activity. Utilizing terpenoids could aid in the development of potent compounds to fight cancer. By studying the structural makeup of various terpenoid derivatives from previous research, we can identify which structural groups are essential for their anticancer activity. This understanding of the structure-activity relationship is crucial for developing new, effective anticancer agents based on terpenoids. Terpenoids, a diverse class of plant-derived secondary metabolites composed of multiple isoprene units, have garnered attention for their potential anticancer and pharmacological qualities. Some terpenoids exhibit notable anticancer effects by concentrating on several stages of cancer development. They show promise in blocking the initiation of early carcinogenesis by the induction of cell cycle arrest, the inhibition of cancer cell differentiation, and the induction of apoptosis. This study delves into the investigation of specific terpenoids showcasing promising anticancer activity against prevalent malignancies, including breast, colon, ovarian, and lung cancers. The study also explores the relationship between the structure and activity of these compounds, which sheds light on how effective they are against a variety of cancer cell types. The comprehensive discussion centres on elucidating terpenoids with substantial potential for combating diverse cancer types, offering insights into their structural features and promising anticancer mechanisms.

Recent advances in scanning electrochemical microscopy for energy applications.

Scanning electrochemical microscopy (SECM) is a scanning probe technique capable of imaging substrate topography and measuring the local electrochemical reactivity of interfaces. Since introduced by Allen J. Bard and co-workers in 1989, it has expanded into a wide variety of fields, such as nanomaterial characterization, energy, kinetics, electrocatalysis, metal anti-corrosion, biology and instrumental development. SECM uses an ultra-microelectrode as the probe to record redox current during probe scanning across sample surfaces to obtain local topography and electrochemical reactivity of samples. Specifically, three main topics are reviewed and discussed: (1) the working principles and operating modes of SECM; (2) the recent developments in the application of SECM in energy science, including solar cell, rechargeable batteries, fuel cell and supercapacitors, with an emphasis on the last five years (2019-2023); (3) the perspectives and outlook of SECM in various energy devices. We anticipate that a wider adoption of SECM by the energy community will allow for the operando characterization of many types of reactions, and hold the potential to provide new insights into the structure/activity and composition/activity relationships.

Novel benzimidazole-based azine derivatives as potent urease inhibitors: synthesis, in vitro and in silico approach.

Aim: In light of various biological activities of benzimidazole and azines, this study focuses on reporting novel derivatives of benzimidazole nucleus.Methods: Twenty novel azines of benzimidazole were synthesized, characterized and tested for in vitro urease inhibitory activity.Results: All these derivatives showed excellent to good inhibition in the range of IC50 values 14.21 ± 1.87 to 76.11 ± 1.81 µM by comparing with standard thiourea 21.14 ± 0.42 µM. Docking studies were performed for the targeted benzimidazole derivatives to understand the binding mechanics. The results indicated higher binding efficacy compared with the reference inhibitor.Conclusion: This work identifies potential lead candidates for novel urease inhibitors, which with industrial support may be harnessed for the development of new drugs.

[Box: see text].

Design, Synthesis, and Antimicrobial Activity Evaluation of Novel Isocryptolepine Derivatives against Phytopathogenic Fungi and Bacteria.

This research adopted the Fischer indole synthesis method to continue constructing a novel drug-like chemical entity based on the guidance of isocryptolepine and obtained four series of derivatives: Y, Da, Db, and Dc. The antimicrobial activity of these derivatives against plant pathogens was further evaluated. The results showed that Dc-2 had the best antifungal effect against Botrytis cinerea, and its EC50 value was up to 1.29 µg/mL. In addition, an in vivo activity test showed that the protective effect of Dc-2 on apples was 82.2% at 200 µg/mL, which was better than that of Pyrimethanil (45.4%). Meanwhile, it was found by scanning electron microscopy and transmission electron microscopy that the compound Dc-2 affected the morphology of mycelia. The compound Dc-2 was found to damage the cell membrane by PI and ROS staining. Through experiments such as leakage of cell contents, it was found that the compound Dc-2 changed the permeability of the cell membrane and caused the leakage of substances in the cell. According to the above studies, compound Dc-2 can be used as a candidate lead compound for further structural optimization and development.

Identification and molecular mechanism of novel antioxidant peptide from fish sauce: A combined quantum chemistry and molecular simulation.

Fish sauce, derived from fermented fish, exhibits a notable antioxidant effect after a six-month fermentation process, and we propose that potential antioxidant peptides were present in the fish sauce. We isolated, purified, and identified potential bioactive antioxidant peptides by using fish sauce fermented for 6 months. Additionally, molecular simulation was employed to investigate the antioxidant action mechanism of these bioactive peptides. The molecular docking results revealed that FS4-1 (MHQLSKK), FS4-2 (VLDNSPER), FS4-3 (MNPPAASIK), FS6-1(VLKQAAAGR), and FS6-2 (SPDVSPRR), could dock with the Keap1 receptor. The primary force (Van der Waals' force and hydrogen bonds) and key sites (GLY509 and ALA510) of Keap1 binding to peptides were determined. The active center was located in the side chain of amino acid Met at positions C7H78 and C7H79. We here identified antioxidant peptides in fish sauce and revealed the antioxidant mechanism through molecular simulations.

Fluoroquinolones tackling antimicrobial resistance: Rational design, mechanistic insights and comparative analysis of norfloxacin vs ciprofloxacin derivatives.

Antimicrobial resistance poses a global health concern and develops a need to discover novel antimicrobial agents or targets to tackle this problem. Fluoroquinolone (FN), a DNA gyrase and topoisomerase IV inhibitor, has helped to conquer antimicrobial resistance as it provides flexibility to researchers to rationally modify its structure to increase potency and efficacy. This review provides insights into the rational modification of FNs, the causes of resistance to FNs, and the mechanism of action of FNs. Herein, we have explored the latest advancements in antimicrobial activities of FN analogues and the effect of various substitutions with a focus on utilizing the FN nucleus to search for novel potential antimicrobial candidates. Moreover, this review also provides a comparative analysis of two widely prescribed FNs that are ciprofloxacin and norfloxacin, explaining their rationale for their design, structure-activity relationships (SAR), causes of resistance, and mechanistic studies. These insights will prove advantageous for new researchers by aiding them in designing novel and effective FN-based compounds to combat antimicrobial resistance.

A comprehensive review of synthetic strategies and SAR studies for the discovery of PfDHODH inhibitors as antimalarial agents. Part 2: Non-DSM compounds.

Malaria remains a severe global health concern, with 249 million cases reported in 2022, according to the World Health Organization (WHO) [1]. PfDHODH is an essential enzyme in malaria parasites that helps to synthesize certain building blocks for their growth and development. It has been confirmed that targeting Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme could lead to new and effective antimalarial drugs. Inhibitors of PfDHODH have shown potential for slowing down parasite growth during both the blood and liver stages. Over the last two decades, many species selective PfDHODH inhibitors have been designed, including DSM compounds and other non-DSM compounds. In the first chapter [2] of this review, we have reviewed all synthetic schemes and structure-activity relationship (SAR) studies of DSM compounds. In this second chapter, we have compiled all the other non-DSM PfDHODH inhibitors based on dihydrothiophenones, thiazoles, hydroxyazoles, and N-alkyl-thiophene-2-carboxamides. The review not only offers an insightful overview of the synthetic methods employed but also explores into alternative routes and innovative strategies involving different catalysts and chemical reagents. A critical aspect covered in the review is the SAR studies, which provide a comprehensive understanding of how structural modifications impact the efficacy of PfDHODH inhibitors and challenges related to the discovery of PfDHODH inhibitors. This information is invaluable for scientists engaged in the development of new antimalarial drugs, offering insights into the most promising scaffolds and their synthetic techniques.