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The excessive use of pesticides (an important group of chemicals) in the agricultural as well as public sectors raises a health concern. Pesticides affect humans and other living organisms via the food chain. Therefore, it is very necessary to calculate the dissipation half-life of pesticides in plants. Experimental prediction of pesticide dissipation half-lives requires complex environmental conditions, high cost, and a long time. Thus, in-silico half-life predictions are suitable and the best alternative. Herein, a total of six PLS (partial least squares) models namely, M1 (overall), M2 (fruit), M3 (plant interior), M4 (leaf), M5 (plant surface), and M6 (whole plant) alongside two MLR (multiple linear regression) models i.e. M7 (fruit surface) and model M8 (straw) were generated using dissipation half-lives (log10(T1/2)) of pesticides in plants and their different parts. Models were constructed in strict accordance with the guidelines outlined by the Organization for Economic Co-operation and Development (OECD) and extensively validated using globally accepted validation metrics (determination coefficient (R2) = 0.610-0.795, leave-one-out (LOO) cross-validated correlation coefficient (Q2LOO) = 0.520-0.660, MAE-FITTED TRAIN (mean absolute error fitted train) = 0.119-0.148, MAE-LOOTRAIN = 0.132-0.177, predictive R2 or Q2F1 = 0.538-0.567, Q2F2 = 0.500-0.565, MAETEST = 0.122-0.232), confirming their accuracy, reliability, predictivity, and robustness. Lipophilicity, the presence of a cyclomatic ring, suphur, aromatic amine fragments, and chlorine atom fragments are responsible (+ve contribution) for high dissipation half-lives of pesticides in plants. In contrast, hydrophilicity, pyrazine fragments, and rotatable bonds reduce (-ve negative contribution) the dissipation half-lives of pesticides in plants. To address the real-world applicability, the models were employed to screen the PPDB (Pesticide Properties Database) database, which revealed the top 10 pesticides with the highest log(T1/2) in the whole plant and respective parts of the plant body. The present work will aid in developing safer and novel pesticides, regulatory risk assessment, various risk assessments for the sustenance of public health, screening of databases, and data-gap filling.
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Organic cation transporter 1 (OCT1, gene symbol: SLC22A1) is mainly responsible for the hepatic uptake of various cationic drugs, closely associated with drug-induced liver injury (DILI). Screening and identifying potent OCT1 inhibitors with little toxicity in natural products is of great value in alleviating OCT1-mediated liver injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions (FDIs). Our objective was to investigate potential inhibitors of OCT1 from 96 flavonoids, evaluate the hepatoprotective effects on retrorsine-induced liver injury, and clarify the structure-activity relationships of flavonoids with OCT1. Thirteen flavonoids exhibited significant inhibition (>50%) on OCT1 in OCT1-HEK293 cells. Among them, the five strongest flavonoid inhibitors (IC50 < 10 µM), including α-naphthoflavone, apigenin, 6-hydroxyflavone, luteolin, and isosilybin markedly decreased oxaliplatin-induced cytotoxicity. In retrorsine-induced liver injury models, they also reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to different levels, the best of which was 6-hydroxyflavone. The pharmacophore model clarified that hydrogen bond acceptors at the 4,8,5' position might play a vital role in the inhibitory effect of flavonoids on OCT1. Taken together, our findings would pave the way to predicting the potential risks of flavonoid-related FDIs in humans and optimizing flavonoid structure to alleviate OCT1-mediated liver injury.
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We designed and synthesized 27 new amide and dipeptide derivatives containing a substituted phenylalanine as negative allosteric modulators (NAMs) for the beta-2 adrenergic receptor (ß2AR). These analogs aimed to improve the activity of our lead compound, Cmpd-15, by introducing variations in three key regions: the meta-bromobenzyl methylbenzamide (S1), para-formamidophenylalanine (S2), and 1-cyclohexyl-1-phenylacetyl (S3) groups. The synthesis involved the Pd-catalyzed ß-C(sp3)-H arylation of N-acetylglycine with 1-iodo-4-substituent-benzenes as the key step. GloSensor cAMP accumulation assay revealed that six analogs (A1, C5, C6, C13, C15 and C17) surpass Cmpd-15 in ß2AR allosteric function. This highlights the crucial role of the S1 region (meta-bromobenzyl methylbenzamide) in ß2AR allostery while suggesting potential replaceability of the S2 region (para-formamidophenylalanine). These findings serve as a valuable springboard for further optimizing Cmpd-15, potentially leading to smaller, more active, and more stable ß2AR-targeting NAMs.
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The unique and complex structure of papain-like protease (PLpro) of the SARS-CoV-2 virus represents a difficult challenge for antiviral development, yet it offers a compelling validated target for effective therapy of COVID-19. The surge in scientific interest in inhibiting this cysteine protease emerged after its demonstrated connection to the cytokine storm in patients with COVID-19 disease. Furthermore, the development of new inhibitors against PLpro may also be beneficial for the treatment of respiratory infections caused by emerging coronavirus variants of concern. This review article provides a comprehensive overview of PLpro inhibitors, focusing on the structural framework of the known inhibitor GRL0617 and its analogs. We categorize PLpro inhibitors on the basis of their structures and binding site: Glu167 containing site, BL2 groove, Val70Ub site, and Cys111 containing catalytic site. We summarize and evaluate the majority of GRL0617-like inhibitors synthesized so far, highlighting their published biochemical parameters, which reflect their efficacy. Published research has shown that strategic modifications to GRL0617, such as decorating the naphthalene ring, extending the aromatic amino group or the orthomethyl group, can substantially decrease the IC50 from micromolar up to nanomolar concentration range. Some advantageous modifications significantly enhance inhibitory activity, paving the way for the development of new potent compounds. Our review places special emphasis on structures that involve direct modifications to the GRL0617 scaffold, including piperidine carboxamides and modified benzylmethylnaphthylethanamines (Jun9 scaffold). All these compounds are believed to inhibit the proteolytic, deubiquitination, and deISGylation activity of PLpro, biochemical processes linked to the severe progression of COVID-19. Finally, we summarize the development efforts for SARS-CoV-2 PLpro inhibitors, in detailed structure-activity relationships diagrams. This aims to inform and inspire future research in the search for potent antiviral agents against PLpro of current and emerging coronavirus threats.
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Marine bioactive peptides (MBPs) are a type of natural compound with a variety of bioactivities, such as anticancer, antimicrobial, antioxidant, and antihypertensive. Due to a wide range of sources, low toxicity, and high specificity, MBPs have now received extensive attention in the fields of food, medicine, and cosmetics. The structure of MBPs determines their biological activities. Therefore, it is essential to analyze the relationship between the structure and bioactivity of MBPs. Because of the advantages of mild conditions, high specificity, safety, and environmental friendliness, enzymatic hydrolysis has become the most commonly used method to produce MBPs. However, the high cost and low yield of enzymatic methods have motivated researchers to search for alternative technologies. Novel pretreatments like ultrasound, microwave, high hydrostatic pressure, and pulsed electric fields have been employed in the production of MBPs. By inducing protein unfolding and increasing enzymatic cleavage sites, these techniques have been demonstrated to accelerate protein hydrolysis and enhance the biological activity of MBPs. This article reviews recent research advances on marine-derived protein hydrolysates and peptides, discusses the relationship between their biological activity and structure, and compares the mechanisms of action of different novel technologies used to promote protein hydrolysis and enhance the biological activity of MBPs. In addition, the current challenges facing the development and application of MBPs are outlined and possible future work in tackling these challenges is also suggested in the current review. It is hoped that this review can promote further development and application of marine active substances.
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2D metal-organic frameworks (2D MOFs) offer promising electrocatalytic potential for urea synthesis, yet the underlying reaction mechanisms and structure-activity relationships remain unclear. Using Cu-BDC as a model, density functional theory (DFT) calculations to elucidate these aspects are conducted. The results reveal a novel coupling mechanism involving *NOâCO and *NOâ*ONCO, emphasizing the impact of linker modifications on Cu spin states and charge distribution. Notably, Cu-BDC-NH2 and CuâBDCâOH emerge as promising catalysts. Additionally, structure-activity relationships through descriptors like d-band center, IE ratio, and L(CuâO), providing insights for rational catalyst design is established. These findings pave the way for optimized catalysts and sustainable urea production, opening avenues for future research and technological advancements.
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1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate (donor substrate) and d-glyceraldehyde 3-phosphate (d-GAP, acceptor substrate) in bacterial central metabolism. DXPS uses a ligand-gated mechanism in which binding of a small molecule "trigger" activates the first enzyme-bound intermediate, C2α-lactylThDP (LThDP), to form the reactive carbanion via LThDP decarboxylation. d-GAP is the natural acceptor substrate for DXPS and also serves a role as a trigger to induce LThDP decarboxylation in the gated step. Additionally, we have shown that O2 and d-glyceraldehyde (d-GA) can induce LThDP decarboxylation. We hypothesize this ligand-gated mechanism poises DXPS to sense and respond to cellular cues in metabolic remodeling during bacterial adaptation. Here we sought to characterize features of small molecule inducers of LThDP decarboxylation. Using a combination of CD, NMR and biochemical methods, we demonstrate that the α-hydroxy aldehyde moiety of d-GAP is sufficient to induce LThDP decarboxylation en route to DXP formation. A variety of aliphatic aldehydes also induce LThDP decarboxylation. The study highlights the capacity of DXPS to respond to different molecular cues, lending support to potential multifunctionality of DXPS and its metabolic regulation by this mechanism.
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Rhein, as a plant antibiotic, demonstrates a broad spectrum of pharmacological effects. Nevertheless, its limited water solubility, low bioavailability, and potential hepatotoxicity and nephrotoxicity making it difficult to directly become a medicine, thereby imposing significant constraints on its clinical application. In recent decades, extensive researches have been proceeded on the multifaceted structural modifications of rhein, resulting in notable improvements on pharmacological activities and druggabilities. This review offers a comprehensive overview and advanced update on the biological potential and structural-activity relationships (SARs) of various rhein derivatives, delineating the sites of structural modification and corresponding activity trends of rhein derivatives for future.
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Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.
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Acetofenonas , Enfermedad de Alzheimer , Diseño de Fármacos , Imidazoles , Fármacos Neuroprotectores , Oximas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Animales , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Estructura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/químicaRESUMEN
Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, a nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb. Complete loss of activity was observed for this compound in Mtb mutants affected in enzyme cofactor F420 biosynthesis (fbiC), suggesting that 1 undergoes prodrug activation in a manner similar to anti-tuberculosis prodrug pretomanid. Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease.
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BACKGROUND: Plant diseases seriously decrease the yield and quality of agricultural crops. Fungicide treatments remain the main means of field fungi control. However, the residual activity of fungicides is rapidly reduced due to various factors in the natural environment, therefore the development of agents with novel modes of action is desirable. It is highly required to design and develop new fungicides to address the resistance issue. Designing low impact chemicals to safely and sustainably address needs of agriculture. RESULTS: In this work, we used the highly active fluxapyroxad and flutolanil as parent structures, to design and synthesize a series of pyrazole-4-carboxamide derivatives. Some of the pyrazole-4-carboxamide derivatives exhibit fungicidal activities that are comparable to or higher than those of the commercialized fungicides fluxapyroxad and bixafen. In particular, compounds TM-1, TM-2, TM-3, TM-4, TM-5, TM-7 and TM-8 showed excellent fungicidal activities against corn rust that were 2-4 times higher than those of fluxapyroxad and bixafen. Field trial results demonstrated that at the same dosage levels, compound TM-2 exhibited comparable field control efficacy against wheat rust as compared to triadimefon and pyrazophenamide. Molecular docking simulations reveal that compound TM-2 interacts with TRP 173 of succinate dehydrogenase (SDH) through hydrogen bonding, which could explain the probable mechanism of action between compound TM-2 and the target protein. CONCLUSION: These results indicate that compound TM-2 may be a promising fungicide candidate and provide valuable reference for further investigation. © 2024 Society of Chemical Industry.
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Obesity is acknowledged as a significant risk factor for various metabolic diseases, and the inhibition of human pancreatic lipase (hPL) can impede lipid digestion and absorption, thereby offering potential benefits for obesity treatment. Anthraquinones is a kind of natural and synthetic compounds with wide application. In this study, the inhibitory effects of 31 anthraquinones on hPL were evaluated. The data shows that AQ7, AQ26, and AQ27 demonstrated significant inhibitory activity against hPL, and exhibited selectivity towards other known serine hydrolases. Then the structure-activity relationship between anthraquinones and hPL was further analysed. AQ7 was found to be a mixed inhibition of hPL through inhibition kinetics, while AQ26 and AQ27 were effective non-competitive inhibition of hPL. Molecular docking data revealed that AQ7, AQ26, and AQ27 all could associate with the site of hPL. Developing hPL inhibitors for obesity prevention and treatment could be simplified with this novel and promising lead compound.
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Antraquinonas , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Inhibidores Enzimáticos , Lipasa , Páncreas , Relación Estructura-Actividad , Antraquinonas/farmacología , Antraquinonas/química , Antraquinonas/síntesis química , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Páncreas/enzimología , Simulación del Acoplamiento Molecular , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis químicaRESUMEN
Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor.
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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.
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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.
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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.
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Antineoplásicos , Piridazinas , Piridazinas/química , Piridazinas/farmacología , Piridazinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Humanos , Relación Estructura-Actividad , Química Farmacéutica , Estructura Molecular , Neoplasias/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
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.
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Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Pirimidinas , Pirroles , Peptidasa Específica de Ubiquitina 7 , Humanos , Peptidasa Específica de Ubiquitina 7/antagonistas & inhibidores , Peptidasa Específica de Ubiquitina 7/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Pirroles/farmacología , Pirroles/química , Pirroles/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Línea Celular Tumoral , Estructura Molecular , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Descubrimiento de Drogas , Pirimidinonas/farmacología , Pirimidinonas/química , Pirimidinonas/síntesis química , Ciclo Celular/efectos de los fármacosRESUMEN
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.
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Bacteriocinas , Bacteriocinas/química , Bacteriocinas/farmacología , Relación Estructura-Actividad , Secuencia de Aminoácidos , Enlace de Hidrógeno , Antibacterianos/química , Antibacterianos/farmacología , Modelos MolecularesRESUMEN
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.
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Receptores Acoplados a Proteínas G , Receptores de la Hormona Gastrointestinal , Tiadiazoles , Humanos , Relación Estructura-Actividad , Tiadiazoles/farmacología , Tiadiazoles/química , Receptores de la Hormona Gastrointestinal/agonistas , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Animales , Células CHO , Cricetulus , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacosRESUMEN
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.