Recent contributions of pyridazine as a privileged scaffold of anticancer agents in medicinal chemistry: An updated review.

Pyridazine, as a privileged scaffold, has been extensively utilized in drug development due to its multiple biological activities. Especially around its distinctive anticancer property, a massive number of pyridazine-containing compounds have been synthesized and evaluated that target a diverse array of biological processes involved in cancer onset and progression. These include glutaminase 1 (GLS1) inhibitors, tropomyosin receptor kinase (TRK) inhibitors, and bromodomain containing protein (BRD) inhibitors, targeting aberrant tumor metabolism, cell signal transduction and epigenetic modifications, respectively. Pyridazine moieties functioned as either core frameworks or warheads in the above agents, exhibiting promising potential in cancer treatment. Therefore, the review aims to summarize the recent contributions of pyridazine derivatives as potent anticancer agents between 2020 and 2024, focusing mainly on their structure-activity relationships (SARs) and development strategies, with a view to show that the application of the pyridazine scaffold by different medicinal chemists provides new insights into the rational design of anticancer drugs.

Toxicity reference values for force health protection: Provisional occupational exposure guidelines.

Force Health Protection programs in the U.S. Air Force endeavor to sustain the operational readiness of the warfighters. We have previously identified hundreds of chemical substances of interest and toxicity reference value (TRV) knowledge gaps that constrain risk based-decision-making for potential exposures. Multiple approaches to occupational TRV estimation were used to generate possible guideline values for 84 compounds (18% of the substances of interest). These candidate TRVs included values from international databases, chemical similarity (nearest neighbor) approaches, empirical adjustments to account for duration differences, quantitative activity relationships, and thresholds of toxicological concern. This present work describes derivation of provisional TRVs from these candidate values. Rodent bioassay-derived long-term worker Derived No-Effect Levels (DNELs) were deemed presumptively the most reliable, but only 19 such DNELs were available for the 84 substances with TRV gaps. In the absence of DNELs, the quality of the approaches and consistency among candidate values were key elements of the weight of evidence used to select the most suitable guideline values. The use of novel nearest-neighbor approaches, empirical adjustment of short term TRVs, and occupational exposure bands were found to be options that would allow occupational TRV estimation with reasonable confidence for nearly all substances evaluated.

Carbohydrate elicitor-induced plant immunity: Advances and prospects.

The perceived negative impacts of synthetic agrochemicals gave way to alternative, biological plant protection strategies. The deployment of induced resistance, comprising boosting the natural defense responses of plants, is one of those. Plants developed multi-component defense mechanisms to defend themselves against biotic and abiotic stresses. These are activated upon recognition of stress signatures via membrane-localized receptors. The induced immune responses enable plants to tolerate and limit the impact of stresses. A systemic cascade of signals enables plants to prime un-damaged tissues, which is crucial during secondary encounters with stress. Comparable stress tolerance mechanisms can be induced in plants by the application of carbohydrate elicitors such as chitin/chitosan, ß-1,3-glucans, oligogalacturonides, cellodextrins, xyloglucans, alginates, ulvans, and carrageenans. Treating plants with carbohydrate-derived elicitors enable the plants to develop resistance appliances against diverse stresses. Some carbohydrates are also known to have been involved in promoting symbiotic signaling. Here, we review recent progresses on plant resistance elicitation effect of various carbohydrate elicitors and the molecular mechanisms of plant cell perception, cascade signals, and responses to cascaded cues. Besides, the molecular mechanisms used by plants to distinguish carbohydrate-induced immunity signals from symbiotic signals are discussed. The structure-activity relationships of the carbohydrate elicitors are also described. Furthermore, we forwarded future research outlooks that might increase the utilization of carbohydrate elicitors in agriculture in order to improve the efficacy of plant protection strategies.

Structure-activity relationships of thiadiazole agonists of the human secretin receptor.

Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity. We were able to enhance the in vitro activity and to maintain the specificity of the parent compound. We found the most active candidate to be quite stable in plasma, although it was metabolized by hepatic microsomes. This chemical probe should be useful for in vitro studies and needs to be tested for in vivo pharmacological activity. This could be an important lead toward the development of a first-in-class orally active agonist of the secretin receptor, which could be useful for multiple disease states.

New potent EV-A71 antivirals targeting capsid.

The enterovirus is a genus of single-stranded, highly diverse positive-sense RNA viruses, including Human Enterovirus A-D and Human Rhinovirus A-C species. They are responsible for numerous diseases and some infections can progress to life-threatening complications, particularly in children or immunocompromised patients. To date, there is no treatment against enteroviruses on the market, except for polioviruses (vaccine) and EV-A71 (vaccine in China). Following a decrease in enterovirus infections during and shortly after the (SARS-Cov2) lockdown, enterovirus outbreaks were once again detected, notably in young children. This reemergence highlights on the need to develop broad-spectrum treatment against enteroviruses. Over the last year, our research team has identified a new class of small-molecule inhibitors showing anti-EV activity. Targeting the well-known hydrophobic pocket in the viral capsid, these compounds show micromolar activity against EV-A71 and a high selectivity index (SI) (5h: EC50, MRC-5 = 0.57 µM, CC50, MRC-5 >20 µM, SI > 35; EC50, RD = 4.38 µM, CC50, RD > 40 µM, SI > 9; 6c: EC50, MRC-5 = 0.29 µM, CC50, MRC-5 >20 µM, SI > 69; EC50, RD = 1.66 µM, CC50, RD > 40 µM, SI > 24; Reference: Vapendavir EC50, MRC-5 = 0.36 µM, CC50, MRC-5 > 20 µM, EC50, RD = 0.53 µM, CC50, RD > 40 µM, SI > 63). The binding mode of these compounds in complex with enterovirus capsids was analyzed and showed a series of conserved interactions. Consequently, 6c and its derivatives are promising candidates for the treatment of enterovirus infections.

Simplified Method for Kinetic and Thermodynamic Screening of Cardiotonic Steroids Through the K + -Dependent Phosphatase Activity of Na + /K + -ATPase with Chromogenic pNPP Substrate .

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na+/K+-ATPase (NKA, EC 3.6.3.9). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (kon), dissociation rate (koff) and equilibrium (Ki) constants of CTS for structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of Ki of the cardenolides digitoxigenin, essentially due to a reduction of kon In contrast, the Ki of the structurally related bufadienolide bufalin increased much less due to the reduction of its koff partially compensating the decrease of its kon When evaluating the kinetics of 15 natural and semi-synthetic CTS, we observed that both kon and koff correlated with Ki (Spearman test), suggesting that differences in potency depend on variations of both kon and koff A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of koff rather than an increase of kon Rising the temperature did not alter the koff of digitoxin, generating a ∆H‡ (koff) of -10.4 {plus minus} 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of kon, koff, and Ki of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds. Significance Statement We described a fast, simple, and cost-effective method for the measurement of phosphatase pNPPase activity enabling structure-kinetics relationships of Na+/K+-ATPase inhibitors, which are important compounds due to their antitumor effect and endogenous role. Using 15 compounds, some of them original, we were able to delineate the kinetics and/or thermodynamics differences due to the type of sugar and lactone ring present in the steroid structure.

Dual Antimicrobial and Anticancer Activity of Membrane-Active Peptide BP52.

The linear undecapeptide BP52 was previously reported to have antibacterial activity against phytopathogenic bacteria species. Due to the structural similarities to naturally occurring cationic helical antimicrobial peptides, it was speculated that this peptide could potentially target microbial pathogens and cancer cells found in mammals. Consequently, this study aims to further investigate the structural and biological properties of this peptide. Our findings indicate that BP52 exhibits strong antimicrobial and anticancer activity while displaying relatively low levels of hemolytic activity. Hence, this study suggests that BP52 could be a potential lead compound for drug discovery against infectious diseases and cancer. Besides, new insights into the relationships between the structure and the multifunctional properties of antimicrobial peptides were also explored.

An insight into structure-activity relationships in subclass IIb bacteriocins: Plantaricin EvF.

This study reports the structure-activity relationships of a unique subclass IIb bacteriocin, plantaricin EvF, which consists of two peptide chains and possesses potent antimicrobial activity. Because the plantaricin Ev peptide chain lacks an α-helix structure, plantaricin EvF is unable to exert its antimicrobial activity through helix-helix interactions like typical subclass IIb bacteriocins. We have shown by various structural evaluation methods that plantaricin Ev can be stabilized by hydrogen bonding at amino acid residues R3, V12, and R13 to the N-terminal region of plantaricin F. This binding gives plantaricin EvF a special spade-shaped structure that exerts antimicrobial activity. In addition, the root-mean-square deviations (RMSDs) of the amino acid residues Y6, F8, and R13 of plantaricin Ev pre- and post-binding were 1.512, 1.723, and 1.369, respectively, indicating that they underwent large structural changes. The alanine scanning experiments demonstrated the important role of the above key amino acids in maintaining the structural integrity of plantaricin EvF. This study not only reveals the unique structural features of plantaricin EvF, but also provides an insight into the structure-activity relationships of subclass IIb bacteriocins.

Chromenone: An emerging scaffold in anti-Alzheimer drug discovery.

Alzheimer's disease (AD) presents a growing global health concern. In recent decades, natural and synthetic chromenone have emerged as promising drug candidates due to their multi-target potential. Natural chromenone, quercetin, scopoletin, esculetin, coumestrol, umbelliferone, bergapten, and methoxsalen (xanthotoxin), and synthetic chromenone hybrids comprising structures like acridine, 4-aminophenyl, 3-arylcoumarins, quinoline, 1,3,4-oxadiazole, 1,2,3-triazole, and tacrine, have been explored for their potential to combat AD. Key reactions used for synthesis of chromenone hybrids include Perkin and Pechmann condensation. The activity of chromenone hybrids has been reported against several drug targets, including AChE, BuChE, BACE-1, and MAO-A/B. This review comprehensively explores natural, semisynthetic, and synthetic chromenone, elucidating their synthetic routes, possible mode of action/drug targets and structure-activity relationships (SAR). The acquired knowledge provides valuable insights for the development of new chromenone hybrids against AD.

Toxicity reference values (TRVs) for force health protection: Gap identification and TRV prediction.

The mission of the Force Health Protection (FHP) program of the U.S. Air Force (USAF), sustaining the readiness of warfighters, relies on determinations of acceptable levels of exposure to a wide array of substances that USAF personnel may encounter. In many cases, exposure details are limited or authoritative toxicity reference values (TRVs) are unavailable. To address some of the TRV gaps, we are integrating several approaches to generate health protective exposure guidelines. Descriptions are provided for identification of chemicals of interest for USAF FHP (467 to date), synthesis of multiple TRVs to derive Operational Exposure Limits (OpELs), and strategies for identifying and developing candidate values for provisional OpELs when authoritative TRVs are lacking. Rodent bioassay-derived long-term Derived No Effect Levels (DNELs) for workers were available only for a minority of the substances with occupational TRV gaps (19 of 84). Additional occupational TRV estimation approaches were found to be straightforward to implement: Tier 1 Occupational Exposure Bands, cheminformatics approaches (multiple linear regression and novel nearest-neighbor approaches), and empirical adjustment of short term TRVs. Risk assessors working in similar contexts may benefit from application of the resources referenced and developed in this work.

Discovery of pyrrolo[2,3-d]pyrimidin-4-one derivative YCH3124 as a potent USP7 inhibitor for cancer therapy.

USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds. The representative compound Z33 (YCH3124) exhibited highly potent USP7 inhibition activity as well as anti-proliferative activity against four kinds of cancer cell lines. Further study revealed that YCH3124 effectively inhibited the downstream USP7 pathway and resulted in the accumulation of both p53 and p21 in a dose-dependent manner. Notably, YCH3124 disrupted cell cycle progression through restricting G1 phase and induced significant apoptosis in CHP-212 cells. In summary, our efforts provided a series of novel pyrrole[2,3-d]pyrimidin-4-one analogs as potent USP7 inhibitors with excellent anti-cancer activity.

Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents.

Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.

Discovery, Optimization, and Biological Evaluation of Novel Pyrazol-5-yl-phenoxybenzamide Derivatives as Potent Succinate Dehydrogenase Inhibitors.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali, Gaeumannomyces graminis, and Botrytis cinerea, with EC50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC50 = 0.82 mg/L) and Rhizoctonia solani (EC50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum, respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (ΔGcal = -46.8 kcal/mol, IC50 = 1.22 mg/L, compared to ΔGcal = -41.1 kcal/mol, IC50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

Microbial-derived peptides with anti-mycobacterial potential.

Tuberculosis (TB), an airborne infectious disease caused by Mycobacterium tuberculosis, has become the leading cause of death. The subsequent emergence of multidrug-resistant, extensively drug-resistant and totally drug-resistant strains, brings an urgent need to discover novel anti-TB drugs. Among them, microbial-derived anti-mycobacterial peptides, including ribosomally synthesized and post-translationally modified peptides (RiPPs) and multimodular nonribosomal peptides (NRPs), now arise as promising candidates for TB treatment. This review presents 96 natural RiPP and NRP families from bacteria and fungi that have broad spectrum in vitro activities against non-resistant and drug-resistant mycobacteria. In addition, intracellular targets of 22 molecules are the subject of much attention. Meanwhile, chemical features of 38 families could be modified in order to improve properties. In final, structure-activity relationships suggest that the modifications of various groups, especially the peptide side chains, the amino acid moieties, the cyclic peptide skeletons, various special groups, stereochemistry and entire peptide chain length are important for increasing the potency.

Navigating pharmacophore space to identify activity discontinuities: A case study with BCR-ABL.

The exploration of chemical space is a fundamental aspect of chemoinformatics, particularly when one explores a large compound data set to relate chemical structures with molecular properties. In this study, we extend our previous work on chemical space visualization at the pharmacophoric level. Instead of using conventional binary classification of affinity (active vs inactive), we introduce a refined approach that categorizes compounds into four distinct classes based on their activity levels: super active, very active, active, and inactive. This classification enriches the color scheme applied to pharmacophore space, where the color representation of a pharmacophore hypothesis is driven by the associated compounds. Using the BCR-ABL tyrosine kinase as a case study, we identified intriguing regions corresponding to pharmacophore activity discontinuities, providing valuable insights for structure-activity relationships analysis.

Synthesis and evaluation of 3,4,5-trisubstituted triazoles as G protein-biased kappa opioid receptor agonists.

Kappa opioid receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu opioid receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing -S- → -CH2- replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure-activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1.

A review of the polysaccharides against fatigue and the underlying mechanism.

Fatigue is a common physiological state that affects normal human activities. Prolonged fatigue induces a variety of diseases and seriously affects human health, so it is imperative to discover nutritional dietary supplements and treatments without side effects, among which natural anti-fatigue polysaccharides have shown great potential. Polysaccharides, a class of biomolecules produced by a variety of organisms such as plants, animals, bacteria and algae, have attracted much attention in recent years due to their anti-fatigue activity and fewer side effects. This review summarizes the classification, dosage and experimental models of polysaccharides with anti-fatigue activity obtained from different natural sources. We also review the fatigue-relieving effects of these polysaccharides through mechanisms such as modulating oxidative damage, regulating energy metabolism and influencing intestinal flora, as well as the effects of molecular weights, monosaccharide compositions, structural features and chemical modifications of the polysaccharides on their anti-fatigue activities to support their potential application value in functional foods and pharmaceuticals. New valuable insights for future research on natural polysaccharides are also presented in the field of natural production of bio-based functional materials, functional foods and therapeutic agents.

A comparative study of two α-L-rhamnosidases with high sequence identity.

The GH78 α-L-rhamnosidase from Aspergillus tubingensis (AT-Rha) was proved to be a new clade of Aspergillus α-L-rhamnosidases in the previous study. A putative α-L-rhamnosidase from A. kawachii IFO 4308 (AK-Rha) has 92 % identity in amino acid sequence with AT-Rha. In this study, AK-Rha was expressed in P. pastoris and characterized. Similar to AT-rRha, the recombinant AK-Rha (AK-rRha) showed a narrow substrate specificity to naringin. Interestingly, the enzyme activity of AK-rRha was 0.816 U/mg toward naringin, significantly lower than 125.142 U/mg of AT-rRha. Their large differences in catalytic efficiency was mainly due to their differences in kcat values between AK-rRha (0.67 s-1) and AT-rRha (4.89 × 104 s-1). The molecular dynamics simulation exhibited that the overall conformation of AK-Rha was rigid and that of AT-Rha was flexible; the Loop Y-L located above the catalytic domain formed different steric hindrances to naringin, and interacted with the flavonoid matrices at different strengths. The polar solvation energy analysis implied that the glycosidic bond was more easily hydrolysed in AT-Rha. The comparative study verified that the main feature of AK-Rha and AT-Rha represented Aspergillus α-L-rhamnosidase was the narrow substrate specificity toward naringin, and provided an insight of the relationships between their catalytic abilities and structures.

Advancements in inhibitors of crucial enzymes in the cysteine biosynthetic pathway: Serine acetyltransferase and O-acetylserine sulfhydrylase.

Infectious diseases have been jeopardized problem that threaten public health over a long period of time. The growing prevalence of drug-resistant pathogens and infectious cases have led to a decrease in the number of effective antibiotics, which highlights the urgent need for the development of new antibacterial agents. Serine acetyltransferase (SAT), also known as CysE in certain bacterial species, and O-acetylserine sulfhydrylase (OASS), also known as CysK in select bacteria, are indispensable enzymes within the cysteine biosynthesis pathway of various pathogenic microorganisms. These enzymes play a crucial role in the survival of these pathogens, making SAT and OASS promising targets for the development of novel anti-infective agents. In this comprehensive review, we present an introduction to the structure and function of SAT and OASS, along with an overview of existing inhibitors for SAT and OASS as potential antibacterial agents. Our primary focus is on elucidating the inhibitory activities, structure-activity relationships, and mechanisms of action of these inhibitors. Through this exploration, we aim to provide insights into promising strategies and prospects in the development of antibacterial agents that target these essential enzymes.

Degradation of ß-lactam antibiotics by Fe(III)/HSO3- system and their quantitative structure-activity relationship.

ß-lactam antibiotics, extensively used worldwide, pose significant risks to human health and ecological safety due to their accumulation in the environment. Recent studies have demonstrated the efficacy of transition metal-activated sulfite systems, like Fe(Ⅲ)/HSO3-, in removing PPCPs from water. However, research on their capability to degrade ß-lactam antibiotics remains sparse. This paper evaluates the degradation of 14 types of ß-lactam antibiotics in Fe(Ⅲ)/HSO3- system and establishes a QSAR model correlating molecular descriptors with degradation rates using the MLR method. Using cefazolin as a case study, this research predicts degradation pathways through NPA charge and Fukui function analysis, corroborated by UPLC-MS product analysis. The investigation further explores the influence of variables such as HSO3- dosage, substrate concentration, Fe(Ⅲ) dosage, initial pH and the presence of common seen water matrices including humic acid and bicarbonate on the degradation efficiency. Optimal conditions for cefazolin degradation in Fe(Ⅲ)/HSO3- system were determined to be 93.3 µM HSO3-, 8.12 µM Fe(Ⅲ) and an initial pH of 3.61, under which the interaction of Fe(Ⅲ) dosage with initial pH was found to significantly affect the degradation efficiency. This study not only provides a novel degradation approach for ß-lactam antibiotics but also expands the theoretical application horizon of the Fe(Ⅲ)/HSO3- system.