Synthesis, biological activities, and structure-activity relationships of Morita-Baylis-Hillman adducts: An update.

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein.

Liver-specific delivery of spherical DNA frameworks for alleviation of hepatic ischemic reperfusion injury.

DNA nanostructures have long been developed for biomedical purposes, but their controlled delivery in vivo proposes a major challenge for disease theranostics. We previously reported that DNA nanostructures on the scales of tens and hundreds nanometers showed preferential renal excretion or kidney retention, allowing for sensitive evaluation and effective protection of kidney function, in response to events such as unilateral ureter obstruction or acute kidney injury. Encouraged by the positive results, we redirected our focus to the liver, specifically targeting organs noticeably lacking DNA materials, to explore the interaction between DNA nanostructures and the liver. Through PET imaging, we identified SDF and M13 as DNA nanostructures exhibiting significant accumulation in the liver among numerous candidates. Initially, we investigated and assessed their biodistribution, toxicity, and immunogenicity in healthy mice, establishing the structure-function relationship of DNA nanostructures in the normal murine. Subsequently, we employed a mouse model of liver ischemia-reperfusion injury (IRI) to validate the nano-bio interactions of SDF and M13 under more challenging pathological conditions. M13 not only exacerbated hepatic oxidative injury but also elevated local apoptosis levels. In contrast, SDF demonstrated remarkable ability to scavenge oxidative responses in the liver, thereby mitigating hepatocyte injury. These compelling results underscore the potential of SDF as a promising therapeutic agent for liver-related conditions. This aimed to elucidate their roles and mechanisms in liver injury, providing a new perspective for the biomedical applications of DNA nanostructures.

The current landscape of coumarin hybrids with antibreast cancer therapeutic applications: An updated review.

Globally, breast cancer (BC) has the highest prevalence among malignant diseases. BC is also the primary cause of death among women. Notably, BC morbidity has been increasing continuously at an approximate growth rate of 2.2% per year. Persistent BC is a major public health issue worldwide. Consequently, novel chemotherapeutic agents to combat this lethal disease should be developed urgently. Coumarins with interesting structural and mechanistic variations exhibit promising activity in several forms of BC, including BCs with multidrug resistance. In particular, coumarin hybrids composed of coumarin and one or more anti-BC pharmacophores can target different biological components in BC cells simultaneously. Thus, coumarin hybrids are useful scaffolds that can help improve the anti-BC efficacy of coumarins, reduce side effects, improve pharmacokinetics, minimize drug-drug interactions, and circumvent drug resistance. This review, in which articles published from 2020 to the present day have been evaluated, highlights the landscape of coumarin hybrids that exhibit therapeutic effects against breast cancer. These findings can aid further investigations on novel antibreast-cancer therapeutics.

Synthesis of 2,4-dihydroxyacetophenone derivatives as potent PDE-1 and -3 inhibitors: in vitro and in silico insights.

Aim: Synthesis of novel bis-Schiff bases having potent inhibitory activity against phosphodiesterase (PDE-1 and -3) enzymes, potentially offering therapeutic implications for various conditions. Methods: Bis-Schiff bases were synthesized by refluxing 2,4-dihydroxyacetophenone with hydrazine hydrate, followed by treatment of substituted aldehydes with the resulting hydrazone to obtain the product compounds. After structural confirmation, the compounds were screened for their in vitro PDE-1 and -3 inhibitory activities. Results: The prepared compounds exhibited noteworthy inhibitory efficacy against PDE-1 and -3 enzymes by comparing with suramin standard. To clarify the binding interactions between the drugs, PDE-1 and -3 active sites, molecular docking studies were carried out. Conclusion: The potent compounds discovered in this study may be good candidates for drug development.

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Development of an effective QSAR-based hazard threshold prediction model for the ecological risk assessment of aromatic hydrocarbon compounds.

The insufficient hazard thresholds of specific individual aromatic hydrocarbon compounds (AHCs) with diverse structures limit their ecological risk assessment. Thus, herein, quantitative structure-activity relationship (QSAR) models for estimating the hazard threshold of AHCs were developed based on the hazardous concentration for 5% of species (HC5) determined using the optimal species sensitivity distribution models and on the molecular descriptors calculated via the PADEL software and ORCA software. Results revealed that the optimal QSAR model, which involved eight descriptors, namely, Zagreb, GATS2m, VR3_Dzs, AATSC2s, GATS2c, ATSC2i, ω, and Vm, displayed excellent performance, as reflected by an optimal goodness of fit (R2adj = 0.918), robustness (Q2LOO = 0.869), and external prediction ability (Q2F1 = 0.760, Q2F2 = 0.782, and Q2F3 = 0.774). The hazard thresholds estimated using the optimal QSAR model were approximately close to the published water quality criteria developed by different countries and regions. The quantitative structure-toxicity relationship demonstrated that the molecular descriptors associated with electrophilicity and topological and electrotopological properties were important factors that affected the risks of AHCs. A new and reliable approach to estimate the hazard threshold of ecological risk assessment for various aromatic hydrocarbon pollutants was provided in this study, which can be widely popularised to similar contaminants with diverse structures.

Anticancer Activity of Metallodrugs and Metallizing Host Defense Peptides-Current Developments in Structure-Activity Relationship.

This article provides an overview of the development, structure and activity of various metal complexes with anti-cancer activity. Chemical researchers continue to work on the development and synthesis of new molecules that could act as anti-tumor drugs to achieve more favorable therapies. It is therefore important to have information about the various chemotherapeutic substances and their mode of action. This review focuses on metallodrugs that contain a metal as a key structural fragment, with cisplatin paving the way for their chemotherapeutic application. The text also looks at ruthenium complexes, including the therapeutic applications of phosphorescent ruthenium(II) complexes, emphasizing their dual role in therapy and diagnostics. In addition, the antitumor activities of titanium and gold derivatives, their side effects, and ongoing research to improve their efficacy and reduce adverse effects are discussed. Metallization of host defense peptides (HDPs) with various metal ions is also highlighted as a strategy that significantly enhances their anticancer activity by broadening their mechanisms of action.

Manipulating Alkyl Inner Side Chain of Acceptor for Efficient As-Cast Organic Solar Cells.

As-cast organic solar cells (OSCs) possess tremendous potential for low-cost commercial applications. Herein, five small-molecule acceptors (A1-A5) are designed and synthesized by selectively and elaborately extending the alkyl inner side chain flanking on the pyrrole motif to prepare efficient as-cast devices. As the extension of the alkyl chain, the absorption spectra of the films are gradually blue-shifted from A1 to A5 along with slightly uplifted lowest unoccupied molecular orbital energy levels, which is conducive for optimizing the trade-off between short-circuit current density and open-circuit voltage of the devices. Moreover, a longer alkyl chain improves compatibility between the acceptor and donor. The in situ technique clarifies that good compatibility will prolong molecular assembly time and assist in the preferential formation of the donor phase, where the acceptor precipitates in the framework formed by the donor. The corresponding film-formation dynamics facilitate the realization of favorable film morphology with a suitable fibrillar structure, molecular stacking, and vertical phase separation, resulting in an incremental fill factor from A1 to A5-based devices. Consequently, the A3-based as-cast OSCs achieve a top-ranked efficiency of 18.29%. This work proposes an ingenious strategy to manipulate intermolecular interactions and control the film-formation process for constructing high-performance as-cast devices.

Structural modifications and augmented affinity for bile salts in enzymatically denatured egg white.

Protein binding to bile salts (BSs) reduces cholesterol levels, but the exact mechanism is unclear. In this study, we performed simulated gastrointestinal digestion of egg white protein hydrolysate (EWPHs) and included an unenzyme digestion group (CK) to investigate the changes in BSs binding capacity before and after digestion, as well as the relationship between egg white protein (EWP) structure and BSs binding capacity. In addition, peptidomics and molecular docking were used to clarify EWP's binding mechanism. We found that the BSs binding ability of EWPHs was slightly decreased after digestion, but significantly higher than that of the CK group and the digested CK group (D-CK). Particle size analysis and electrophoresis demonstrated that smaller particles and lower molecular weights exhibited enhanced binding capacity to BSs. Fourier Transform infrared spectroscopy (FTIR) results revealed that a disordered structure favored BS binding ability enhancement. Peptides FVLPM and GGGVW displayed hypocholesterolemic efficacy.

The Sources, Structures and Cytotoxicity of Animal-derived Bisindole Compounds.

Bisindole compounds constitute a significant class of natural compounds distinguished by their characteristic bisindole structure and renowned for their anticancer properties. Over the past four decades, researchers have isolated 229 animal-derived bisindole compounds (ADBCs) from various animals. These compounds demonstrate a wide range of pharmacological properties, including cytotoxicity, antibacterial, antifungal, antiviral, and other activities. Notably, among these activities, cytotoxicity emerges as the most prominent characteristic of ADBCs. This review also summarizes the structureactivity relationship (SAR) studies associated with the cytotoxicity of these compounds and explores the druggability of these compounds. In summary, our objective is to provide an overview of the research progress concerning ADBCs, with the aim of fostering their continued development and utilization.

Synthesis and Biological Evaluation of Novel Biased Mu-Opioid Receptor Agonists.

This study explored the potential of a series of PZM21 analogues for pain treatment. Specifically, the hydroxyphenyl ring of PZM21 was replaced with a naphthyl ring, the thienyl ring was substituted with either a phenyl ring or furan rings, and the essential dimethylamine and urea groups were retained. These compounds aimed to enhance safety and minimize the adverse effects associated with opioid drugs. The research findings suggest that compound 6a does not induce ß-arrestin recruitment at low-nanomolar concentrations but exhibits significant analgesic effects in established mouse models. Compared to morphine, 6a shows advantages in alleviating respiratory depression and minimizing physical dependence. Molecular docking studies underscore the pivotal role of the D147 amino acid residue in the analgesic mechanism of 6a. Consequently, 6a is a compelling candidate for the development of safer opioid analgesics and warrants further attention.

Recent Advances in Polysaccharides from Chaenomeles speciosa (Sweet) Nakai.: Extraction, Purification, Structural Characteristics, Health Benefits, and Applications.

This article systematically reviews the extraction and purification methods, structural characteristics, structure-activity relationship, and health benefits of C. speciosa polysaccharides, and their potential application in food, medicine, functional products, and feed, in order to provide a useful reference for future research. Chaenomeles speciosa (Sweet) Nakai. has attracted the attention of health consumers and medical researchers as a traditional Chinese medicine with edible, medicinal, and nutritional benefits. According to this study, C. speciosa polysaccharides have significant health benefits, such as anti-diaetic, anti-inflammatory and analgesic, anti-tumor, and immunomodulatory effects. Researchers determined the molecular weight, structural characteristics, and monosaccharide composition and ratio of C. speciosa polysaccharides by water extraction and alcohol precipitation. This study will lay a solid foundation for further optimization of the extraction process of C. speciosa polysaccharides and the development of their products. As an active ingredient with high value, C. speciosa polysaccharides are worthy of further study and full development. C. speciosa polysaccharides should be further explored in the future, to innovate their extraction methods, enrich their types and biological activities, and lay a solid foundation for further research and development of products containing polysaccharides that are beneficial to the human body.

Synthesis and Biological Evaluation of New Compounds with Nitroimidazole Moiety.

Heterocyclic compounds, particularly those containing azole rings, have shown extensive biological activity, including anticancer, antibacterial, and antifungal properties. Among these, the imidazole ring stands out due to its diverse therapeutic potential. In the presented study, we designed and synthesized a series of imidazole derivatives to identify compounds with high biological potential. We focused on two groups: thiosemicarbazide derivatives and hydrazone derivatives. We synthesized these compounds using conventional methods and confirmed their structures via nuclear magnetic resonance spectroscopy (NMR), MS, and elemental analysis, and then assessed their antibacterial and antifungal activities in vitro using the broth microdilution method against Gram-positive and Gram-negative bacteria, as well as Candida spp. strains. Our results showed that thiosemicarbazide derivatives exhibited varied activity against Gram-positive bacteria, with MIC values ranging from 31.25 to 1000 µg/mL. The hydrazone derivatives, however, did not display significant antibacterial activity. These findings suggest that structural modifications can significantly influence the antimicrobial efficacy of imidazole derivatives, highlighting the potential of thiosemicarbazide derivatives as promising candidates for further development in antibacterial therapies. Additionally, the cytotoxic activity against four cancer cell lines was evaluated. Two derivatives of hydrazide-hydrazone showed moderate anticancer activity.

Evaluation of the Therapeutic Potential of Sulfonyl Urea Derivatives as Soluble Epoxide Hydrolase (sEH) Inhibitors.

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising anti-inflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template.

A Review of Machine Learning and QSAR/QSPR Predictions for Complexes of Organic Molecules with Cyclodextrins.

Cyclodextrins are macrocyclic rings composed of glucose residues. Due to their remarkable structural properties, they can form host-guest inclusion complexes, which is why they are frequently used in the pharmaceutical, cosmetic, and food industries, as well as in environmental and analytical chemistry. This review presents the reports from 2011 to 2023 on the quantitative structure-activity/property relationship (QSAR/QSPR) approach, which is primarily employed to predict the thermodynamic stability of inclusion complexes. This article extensively discusses the significant developments related to the size of available experimental data, the available sets of descriptors, and the machine learning (ML) algorithms used, such as support vector machines, random forests, artificial neural networks, and gradient boosting. As QSAR/QPR analysis only requires molecular structures of guests and experimental values of stability constants, this approach may be particularly useful for predicting these values for complexes with randomly substituted cyclodextrins, as well as for estimating their dependence on pH. This work proposes solutions on how to effectively use this knowledge, which is especially important for researchers who will deal with this topic in the future. This review also presents other applications of ML in relation to CD complexes, including the prediction of physicochemical properties of CD complexes, the development of analytical methods based on complexation with CDs, and the optimisation of experimental conditions for the preparation of the complexes.

Extraction, purification, structural characterization, and bioactivities of the genus Rhodiola L. polysaccharides: A review.

The genus Rhodiola L., an integral part of traditional Chinese medicine and Tibetan medicine in China, exhibits a broad spectrum of applications. This genus contains key compounds such as ginsenosides, polysaccharides, and flavonoids, which possess anti-inflammatory, antioxidant, hypoglycaemic, immune-enhancing, and anti-hypoxic properties. As a vital raw material, Rhodiola L. contributes to twenty-four kinds of Chinese patent medicines and 481 health food products in China, finding extensive application in the health food sector. Recently, polysaccharides have emerged as a focal point in natural product research, with applications spanning the medicine, food, and materials sectors. Despite this, a comprehensive and systematic review of polysaccharides from the genus Rhodiola L. polysaccharides (TGRPs) is warranted. This study undertakes a systematic review of both domestic and international literature, assessing the research advancements and chemical functional values of polysaccharides derived from Rhodiola rosea. It involves the isolation, purification, and identification of a variety of homogeneous polysaccharides, followed by a detailed analysis of their chemical structures, pharmacological activities, and molecular mechanisms, structure-activity relationship (SAR) of TGRPs. The discussion includes the influence of molecular weight, monosaccharide composition, and glycosidic bonds on their biological activities, such as sulfation and carboxymethylation et al. Such analyses are crucial for deepening the understanding of Rhodiola rosea and for fostering the development and exploitation of TGRPs, offering a reference point for further investigations into TGRPs and their resource utilization.

Novel casein-derived immunomodulatory peptide PFPEVFG: Activity assessment, molecular docking, activity site and mechanism of action.

Nowadays, there is still a gap in the knowledge of the structure-activity relationship of immunomodulatory peptides. In this study, PFPEVFG was selected as a peptide with immunomodulatory activity from casein hydrolysate by virtual screening and its immunomodulatory activity was verified by the phagocytosis, proliferation, and expression of cytokines (IL-6, IL-1ß, TNF-α) and chemokines (CXCL1, CXCL2) in RAW 264.7 macrophages. Next, molecular docking and double-stranded small interfering RNA (siRNA) mutually verified that the immunomodulatory activity of PFPEVFG was mediated by TLR2/4. Furthermore, the highest occupied molecular orbital (HOMO) analysis showed that the C19 = O20 site with a HOMO contribution of 32.22988% was its active site, and the phenylalanine, where the C19 = O20 site was located, was its active amino acid. Finally, the combination of pathway inhibitors and Western blot revealed that PFPEVFG activated macrophages through the nuclear factor-κB (NF-κB) signaling pathway. In summary, this study provided a new perspective on deeply understanding the structure-activity relationship of casein-derived immunomodulatory peptides, as well as a further theoretical and technological basis for the application of immunomodulatory peptides.

Discovery and evolution of berberine analogues as anti-Helicobacter pylori agents with multi-target mechanisms.

Thirty protoberberine derivatives, of which twenty five were new, were synthesized and evaluated for their anti-Helicobacter pylori (HP) activities, taking 2,3,10-trimethoxy-9-p-methylbenzylaminoprotopalmatine chloride 1 as the lead. Among them, berberine (BBR) derivative 7c displayed the highest potency against six tested metronidazole (MTZ)-resistant strains and two tested MTZ-susceptible strains with the MIC values of 0.4-1.6 µg/mL with favorable druglike profiles including low toxicity and high stabilities in plasma and artificial gastric fluid. Mechanistic study revealed that 7c might target HP urease with IC50 value of 0.27 µg/mL against Jack bean urease. Furthermore, 7c might change the permeability of the bacterial membrane and direct interact with HP DNA, which also contribute to its bactericidal activity. Therefore, BBR derivatives constituted a new family of anti-HP candidates, with the advantage of good safety profile and multi-target mechanisms, and are worthy for further investigation.

Intriguing steroid glycosides for cancer therapy by suppressing the DNA damage response and mTOR/S6K signaling pathways.

Two rare 8-hydroxysteroid glycosides (6-7), and their downstream metabolites (1-5) with an unprecedented 6/6/5/5/5-pentacyclic scaffold, together with seven known analogues (8-14) were isolated from the twigs and leaves of Strophanthus divaricatus. Their structures were fully assigned by analysis of the spectroscopic and ECD data, NMR calculations, X-ray crystallographic study, and chemical methods. In addition, the inhibitory effects of 1-14 on liver and lung cancer cell lines were evaluated, and preliminary structure-activity relationship was discussed. Data-independent acquisition (DIA)-based quantitative proteomic analysis and biological verification of H1299 cells suggested that this family of compounds may play an anticancer role by suppressing both DNA damage response (DDR) and mTOR/S6K signaling pathways.

Cephalostatins and ritterazines: Distinctive dimeric marine-derived steroidal pyrazine alkaloids with intriguing anticancer activities.

Cephalostatins and ritterazines represent fascinating classes of dimeric marine derived steroidal alkaloids with unique chemical structures and promising biological activities. Originally isolated from marine tube worms and the tunicate Ritterella tokioka collected off the coast of Japan, cephalostatins and ritterazines display potent anticancer effects by inducing apoptosis, disrupting cell cycle progression, and targeting multiple molecular pathways. This review covers the chemistry and bioactivities of 45 cephalostatins and ritterazines from 1988 to 2024, highlighting their complex structures and medicinal contributions. With insights into their structure activity relationships (SAR). Key structural elements, such as the pyrazine ring and 5/6 spiroketal moieties, are found crucial for their biological effects, suggesting interactions with lipid membranes or hydrophobic protein domains. Additionally, the formation of oxocarbenium ions from spiroketal cleavage may enhance their potency by covalently modifying DNA. The pharmacokinetics, ADMET and Drug likeness properties of these steroidal alkaloids are thoroughly addressed. Drug likeness analysis shows that these compounds fit well with the Rule of 4 (Ro4) for Protein-Protein Interaction Drugs (PPIDs), underscoring their potential in this area. Ten compounds (20, 27, 33, 34, 39, 40, 41, 42, 43, and 45) have demonstrated favourable pharmacokinetic and ADMET profiles, making them promising candidates for further research. Future efforts should focus on alternative administration routes, structural modifications, and innovative delivery systems, such as prodrugs and nanoparticles, to improve bioavailability and therapeutic effects. Advances in synthetic chemistry, mechanistic insights, and interdisciplinary collaborations will be essential for translating cephalostatins and ritterazines into effective anticancer therapies.

Exploring Nanozymes for Organic Substrates: Building Nano-organelles.

Since the discovery of the first peroxidase nanozyme (Fe3O4), numerous nanomaterials have been reported to exhibit intrinsic enzyme-like activity toward inorganic oxygen species, such as H2O2, oxygen, and O2•-. However, the exploration of nanozymes targeting organic compounds holds transformative potential in the realm of industrial synthesis. This review provides a comprehensive overview of the diverse types of nanozymes that catalyze reactions involving organic substrates and discusses their catalytic mechanisms, structure-activity relationships, and methodological paradigms for discovering new nanozymes. Additionally, we propose a forward-looking perspective on designing nanozyme formulations to mimic subcellular organelles, such as chloroplasts, termed "nano-organelles". Finally, we analyze the challenges encountered in nanozyme synthesis, characterization, nano-organelle construction and applications while suggesting directions to overcome these obstacles and enhance nanozyme research in the future. Through this review, our goal is to inspire further research efforts and catalyze advancements in the field of nanozymes, fostering new insights and opportunities in chemical synthesis.