Structure-activity Relationship Research Articles

Discovery of benzimidazole-2-amide BNZ-111 as new tubulin inhibitor

Methyl benzimidazole-2-carbamate anthelmintics are a class of oral drugs to treat parasitic worm infections via microtubule disruption for non-systemic indications and currently in use. In order to use for anticancer treatment, the new benzimidazoles needs to improve solubility and pharmacokinetic parameters while maintaining its cellular potency as for systemic drug. Structure–activity-relationship on the benzimidazole is thoroughly examined and a novel benzimidazole-2 propionamide BNZ-111 is identified having good oral exposure and bioavailability in rat. Molecular docking study suggests BNZ-111 have a specific binding mode to the β subunit of curved tubulin. BNZ-111 is potent to cancer cells and possesses good drug-like properties as oral drug. Especially, BNZ-111 is not a P-gp substrate and it demonstrates its efficacy over Paclitaxel-resistance tumor in vivo.

Discovery Process Chemistry: An Innovation Hub at the Interface of Academia, the Pharmaceutical Industry, and Contract Research Organizations

AbstractDiscovery Process Chemistry (DPC) is an emerging intersectoral space that is characterized by the development of new chemical reactions or syntheses that enable the efficient elucidation of structure-activity relationships (SARs) and structure-property relationships (SPRs) as well as a rapid transition to process development. Drug discovery and development are accelerated by such efforts and this has led chemists in academia and industry alike to place an increasing importance on these aims. In this Short Review, we explore recent advances in DPC and the impact that it can have on SAR/SPR interrogation and downstream drug development efforts.1 Introduction2 Enabling SAR/SPR Interrogation with Bioisosteres3 Couplings of Diversifiable Reaction Partners4 Late-Stage Functionalization5 Conclusion and Outlook

Leveraging In Silico Structure-Activity Models to Predict Acute Honey Bee (Apis mellifera) Toxicity for Agrochemicals.

In the realm of crop protection products, ensuring the safety of pollinators stands as a pivotal aspect of advancing sustainable solutions. Extensive research has been dedicated to this crucial topic as well as new approach methodologies in toxicity testing. Hence, within the agricultural and chemical industries, prioritizing pollinator safety remains a constant objective during the development of predictive tools. One of these tools includes computational models like quantitative structure-activity relationships (QSARs) that are valuable in predicting the toxicity of chemicals. This research uses bee toxicity data to develop artificial neural network classification models for predicting honey bee acute toxicity. Bee toxicity data from 1542 compounds were used to develop models; the sensitivity and specificity of the best model were 0.90 and 0.91, respectively. These in silico models can aid in the discovery of next-generation crop protection products. These tools can guide the screening and selection of next-generation crop protection molecules with high margins of safety to pollinators, and candidates with favorable sustainability profiles can be identified at the early discovery stage as precursors to in vivo data generation.

Nickel-Catalyzed C-C Activation of Vinylcyclobutane with Visible Light: Scope, Mechanism, and Application to Chemically Recyclable Polyolefins.

N-heterocyclic carbene (NHC)-supported nickel complexes were investigated for the oxidative ring-opening of vinylcyclobutane (VCB) and photocatalytic activity. Addition of VCB to in situ generated [(NHC)Ni(0)] compounds furnished (NHC)Ni(VCB)2 that underwent oxidative addition and conversion to the corresponding Ni(II) alkyl, allyl-metallacycles. The (NHC)Ni(C6H10) metallacycles were isolated, characterized, and exhibited high thermal and chemical stability. Irradiation with visible light at ambient temperature produced a mixture of ethylene and 4-vinylcyclohexene and 1,5-cyclooctadiene, cycloaddition dimers of butadiene, arising from formal retro-[2 + 2] cycloaddition. A mixture of hexadiene products arising from β-H elimination from the metallacycle was also observed. Free ethylene also underwent a secondary reaction to form cyclopropane products through formal [2 + 1] cycloaddition. A series of sterically and electronically modified NHC ligands was evaluated to establish the structure-activity relationship governing the rate of photocatalytic conversion of VCB and the resulting product distribution. Isotopic labeling experiments, resting state analysis, and independent synthesis of a range of nickel bis(olefin) complexes provided insight into the mechanism of the reaction and origins of the organic product mixture. (NHC)Ni-catalysis was also applied toward the retro-[2 + 2] depolymerization of (1,n'-divinyl)-oligocyclobutane to butadiene dimers.

12-Nor-rotenoids and other cytotoxic constituents of Pachyrhizus erosus seeds

Five previously undescribed compounds, including three 12-nor-rotenoids, were isolated from Pachyrhizus erosus seeds. A brief survey on the dealkylation of selected rotenoids with BBr3 was undertaken. Spectroscopic data of these previously undescribed compounds and reaction products are reported. The proposal of absolute configurations at stereocenters in the isolates and reaction products was based on NMR and ECD data. Most of the isolates and reaction products were evaluated for their growth inhibitory activities against four cancer cell lines and a Vero cell line. Many compounds exhibited strong to moderate activities with IC50 values ranging from 0.06 to 20.9 μM, and their structure-activity relationships were evaluated.

Quantitative and mechanistic elucidation of the reactive oxygen species for effective sulfamethoxazole removal in heterogeneous peroxymonosulfate activated by MOFs-derived cladding structure CoZn/NC@UiO

In cobalt-based catalyst/peroxymonosulfate (PMS) systems, the key issues are the leaching of metals and the stability of catalysts. In this study, a NH2-UiO-66 cladded CoZn/NC catalyst was synthesized for efficient degradation of sulfamethoxazole (SMX) using activated PMS. The removal efficiency of SMX could achieve 100% within 30 min. The leaching of Co2+ was inhibited to 0.05 ppm and the anti-interference and cyclic stability of the catalyst were enhanced by the NH2-UiO-66 shell. In addition, the quenching experiment, electron paramagnetic resonance (EPR) technique and probe experiment were used to analyze the reactive oxygen species (ROSs) qualitatively and quantitatively. The findings demonstrated that singlet oxygen (1O2) had the highest steady-state and cumulative concentration. However, 1O2 could only participate in the degradation of SMX through single electron transfer or addition reaction, resulting in a lower second-order rate constant of the SMX reaction with 1O2. Sulfate radical (SO4·-) contributed the most to the degradation of SMX due to the high reactivity of the sulfonamide structure in SMX to SO4·-. Finally, possible pathways for SMX degradation were proposed. The two primary mechanisms of SMX degradation were S-N cleavage and amino hydroxylation/oxidation. The toxicity of most of the intermediates was less than that of SMX through ecological structure–activity relationship analysis. Overall, a novel approach to synthesize low leaching and efficient cobalt based catalyst was put forward, and the activation mechanism of PMS was also revealed.

In-silico screening of Staphylococcus aureus antibacterial agents based on Isatin scaffold: QSAR, molecular docking, molecular dynamics simulation and DFT analysis

The design of novel antimicrobial drugs is necessary due to the increasing resistance to many existing antibiotics. Considering that the drug discovery process requires a lot of time and resources, computational chemistry and molecular docking as the basic components in the drug discovery process, can help the acceleration of this prolonged process and minimise the research costs. In this study, 64 molecules containing the Isatin scaffold were subjected to quantitative structure–activity relationship analysis to identify the necessary features for designing effective antimicrobial agents. Three chemometrics methods were employed to establish a connection between structural parameters and antibacterial effects. MLR was identified as the best model, demonstrating high accuracy compared to the other models. Based on the obtained model, ten novel lead compounds were designed, and their antibacterial potency of these compounds was assessed. The outputs of the molecular docking study revealed that compound S4 fits well in the ATP-binding site and blocks ATPase activity. Additionally, it was observed that compound S4 exhibited adequate binding affinity against the DNA gyrase target. An appropriate relationship was observed between QSAR, DFT and molecular modelling approaches. Therefore, compound S4 can be considered as a promising candidate for further development as an antibacterial agent.

Pyrazolines inhibiting the activity of the early growth response-1 DNA-binding domain

To identify compounds inhibiting the activity of the Early Growth Response (EGR)-1 DNA-binding domain, thirty-seven pyrazolines were prepared and their EGR-1 DNA-binding activities were measured. Pharmacophores were derived based on quantitative structure–activity relationship calculations. As compound 2, 1-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-2-ol, showed the best inhibitory effects against the activity of the EGR-1 DNA-binding domain, the binding mode between compound 2 and EGR-1 was elucidated using in silico docking. The pharmacophores were matched to the binding modes. Electrophoretic mobility shift assays confirmed that compound 2 dose-dependently inhibited TNFα-induced EGR-1-DNA complex formation in HaCaT cells. Reverse transcription-polymerase chain reaction demonstrated that compound 2 effectively reduced the mRNA expression of EGR-1-regulated inflammatory genes, including thymic stromal lymphopoietin (TSLP), interleukin (IL)-1β, IL-6, and IL-31, in TNFα-stimulated HaCaT cells. Therefore, compound 2 could be developed as an agent that inhibits the activity of the EGR-1 DNA-binding domain.

An arabinan from Citrus grandis fruits alleviates ischemia/reperfusion-induced myocardial cell apoptosis via the Nrf2/Keap1 and IRE1/GRP78 signaling pathways

Citrus grandis fruit is a famous traditional Chinese medicine with various bioactivities, including cardioprotective effects. Polysaccharides are one of the key active ingredients responsible for its cardioprotective effects. This study aimed to investigate the structure and cardioprotective effect of a homogeneous polysaccharide from C. grandis fruit (CGP80-1) and explore its mechanism against myocardial ischemia-reperfusion (MI/R) injury. Structure analysis showed that CGP80-1 (11,917 Da) is an arabinan with compact coil chain conformation, containing →5)-α-L-Araf-(1→, →3,5)-α-L-Araf-(1→, and →2,3,5)-α-L-Araf-(1→ as the backbone, as well as →5)-α-L-Araf-(1→ and t-α-L-Araf as side-chains substituted at the C2 and C3 positions. Pharmacological experiments showed that pre-treatment with CGP80-1 could effectively alleviate MI/R injury by improving endogenous antioxidant enzymes and cardiac enzymes, reducing reactive oxygen species levels, and regulating apoptosis-related proteins such as caspase-3, Bax, and Bcl-2. The protective effects were correlated with the Nrf2/Keap1 and IRE1/GRP78 signaling pathways. Further analysis of structure-activity relationships revealed that the myocardial protection effects of CGP80-1 might be attributed to its appropriate molecular weight, high arabinose content, and unique compact coil chain conformation. Overall, our results provide insight into the chemical structure of CGP80-1 and its mechanism of action, suggesting that CGP80-1 could be a candidate drug for myocardial protection.

Structure-Activity Relationship of Inositol Thiophosphate Analogs as Allosteric Activators of Clostridioides difficile Toxin B.

Clostridioides difficile is a bacterium that causes life-threatening intestinal infections. Infection symptoms are mediated by a toxin secreted by the bacterium. Toxin pathogenesis is modulated by the intracellular molecule, inositol-hexakisphosphate (IP6). IP6 binds to a cysteine protease domain (CPD) on the toxin, inducing autoproteolysis, which liberates a virulence factor in the cell cytosol. We developed second-generation IP6 analogs designed to induce autoproteolysis in the gut lumen, prior to toxin uptake, circumventing pathogenesis. We synthesized a panel of thiophosphate-/sulfate-containing IP6 analogs and characterized their toxin binding affinity, autoproteolysis induction, and cation interactions. Our top candidate was soluble in extracellular cation concentrations, unlike IP6. The IP6 analogs were more negatively charged than IP6, which improved affinity and stabilization of the CPD, enhancing toxin autoproteolysis. Our data illustrate the optimization of IP6 with thiophosphate biomimetic which are more capable of inducing toxin autoproteolysis than the native ligand, warranting further studies in vivo.

Design and Synthesis of 3-(Phenylsulfonamido)benzamide Derivatives as Potent Carbonic Anhydrase IX Inhibitors: Biological Evaluations and Molecular Modeling Studies

Introduction: Carbonic anhydrase IX (CAIX) is known to be overexpressed in various tumors and plays a significant role in tumor development and progression. Methods: A series of 3-(benzylsulfonamido)benzamides derivatives was synthesized and tested for their CAIX inhibitory activities. The two most active compounds were subjected to cytotoxicity testing against a panel of 60 cancer cell lines. Results: Many of the synthesized compounds successfully inhibited CAIX activities, exhibiting IC50 values in the low nanomolar range. The most potent CAIX inhibitor was compound 14, with an IC50 of 140 nM. Structure-activity relationship analysis of the synthesized compounds supported with molecular docking revealed strong coordination of sulfonamide moiety with the catalytic Zn2+ metal, hydrophobic interactions of the benzylsulfonamido ring with a hydrophobic pocket, and π- stacking interactions of the aryl ring with an aromatic surface. The two most active analogues (10 and 14) were further tested for their antiproliferative activities in the NCI-60 human tumor cell lines. Notably, compound 14 demonstrated potent growth inhibitory effects against several cancer cell lines. Conclusion: The synthesized analogues represent a novel scaffold for the treatment of different types of cancer by targeting CAIX.

Regulating reaction kinetics used for the preparation of ethylene-vinyl acetate copolymer with high grafting ratio

A feasible and innovative reaction kinetics control method was proposed to reduce the degradation, cross-linking and other side reactions during the melt grafting process. The components in the melt grafting system were firstly blended at a temperature lower than the half-life (170 °C) of the radical initiator. After the system was homogeneous, the temperature was raised to the half-life temperature for high-temperature melting reaction. By regulating the reaction kinetics of silane grafted EVA system, the collision probability between macromolecular free radicals and grafted monomers was effectively increased. The efficiency and grafting rate of EVA grafted by silane were significantly improved, which reached a maximum of 74.45 % and 4.81 wt%, respectively. The thermal behavior, crystallographic, mechanical and electrical properties of the grafts were further characterized, which made the structure-activity relationship of polymers construct and investigate.

Medicinal Perspective of 2,4-Thiazolidinediones Derivatives: An Insight into Recent Advancements.

2,4-Thiazolidinedione derivatives represent nitrogen-containing heterocyclic compounds utilized in type 2 diabetes mellitus management. Recent advances in medicinal chemistry have unveiled diverse therapeutic potentials and structural modifications of these derivatives. This review delves into novel TZD derivatives, encompassing their synthesis, structure-activity relationships, and pharmacokinetic profiles. Various therapeutic potentials of TZDs are explored, including anticancer, antimicrobial, anti-inflammatory, antioxidant, anticonvulsant, antihyperlipidemic, anticorrosive, and antitubercular activities. Additionally, it addresses mitigating side effects associated with marketed TZD derivatives such as weight gain, oedema, fractures, and congestive heart failure in type 2 diabetes mellitus management. The review elaborates on in vivo, in vitro, and ex vivo studies supporting different biological activities, alongside predicting ADME and drug-likeness properties of TZDs. Computational studies are also integrated to elucidate binding modes and affinities of novel TZD derivatives. Furthermore, a plethora of novel TZD derivatives with varied and enhanced therapeutic potentials are presented, warranting further evaluation of their biological activities.

Leveraging new approach methodologies: ecotoxicological modelling of endocrine disrupting chemicals to Danio rerio through machine learning and toxicity studies

New approach methodologies (NAMs) offer information tailored to the intended application while reducing the use of animals. NAMs aim to develop quantitative structure-activity relationship (QSAR) and quantitive-Read-Across structure-activity relationship (q-RASAR) models to predict and categorize the acute toxicity of known and unknown endocrine-disrupting chemicals (EDCs) against zebrafish. EDCs are a diverse group of toxic substances that disrupt the endocrine system of humans and animals. The q-RASAR model was constructed and verified using validation metrics (R 2 = 0.886 and Q 2 = 0.814) which found to be more reliable model compare to QSAR model. The substructure fingerprint was well-fitted for the classification model and it was validated using 10-fold average accuracy (Q = 86.88%), specificity (Sp = 88.89%), Matthew’s correlation curve (MCC = 0.621) and receiver operating characteristics (ROC = 0.828). The dataset of unknown substances revealed that phenolphthalein (Php) exhibited a significant level of toxicity based on q-RASAR model. The docking and simulation study indicated that the computationally derived important features successfully bound to the target zebrafish sex hormone binding globulin (zfSHBG). The experimental LC50 value of 0.790 mg L−1 was very close to the predicted value of 0.763 mg L−1, which provides high confidence to the developed model.

Design, synthesis, and structure–activity relationships of oil-soluble fluorinated surfactants with fluorocarbon/hydrocarbon hybrid chain

Design, synthesis, and structure–activity relationships of oil-soluble fluorinated surfactants with fluorocarbon/hydrocarbon hybrid chain

Identification of Tunable, Environmentally Responsive Fluorogenic Dyes by High-Throughput Screening.

Small molecule dyes remain essential biological tools, yet only a handful of environmentally responsive fluorogenic small molecules are available for routine characterization of protein state. Here, we report the development and execution of a high throughput screen to identify compounds that increase in fluorescence in response to binding of lipophilic sites of proteins. This effort yielded two small molecules that potently indicate the presence of a range of common proteins and outperform common dyes in differential scanning fluorimetry experiments. Structure activity relationship studies revealed that these two scaffolds can be tuned both for their quantum yields and emission wavelengths. This work affords a straightforward framework for the discovery of new fluorophores and adds two fluorogenic probes to the toolbox for studying protein state.

Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1.

Protein arginine N-methyltransferases (PRMT) are a family of S-adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers. Accordingly, many groups have targeted PRMT1 using small molecules and peptide inhibitors. In this Perspective, we discuss the structure and function of selected peptide and small molecule inhibitors of PRMT1. We examine inhibitors that target the substrate arginyl peptide, SAM, or both binding sites, and the type of inhibition that results. Small molecules, and peptides that are bisubstrate, and/or PRMT transition state mimic inhibitors as well as inhibitors that alkylate PRMTs will be discussed. We define a structure-activity relationship for the aromatic/heteroaromatic N-methylethylenediamine inhibitors of PRMT1 and review current progress of PRMT1 inhibitors in clinical trials.

Phenotypic-Based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium tuberculosis.

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, 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.

Assessing the inhibitory effects of some secondary amines, thioureas and 1,3-dimethyluracil conjugates of (-)-cytisine and thermopsine on the RNA-dependent RNA polymerase of SARS-CoV-1 and SARS-CoV-2

SARS-CoV-2 causes COVID-19, with symptoms ranging from mild to severe, including pneumonia and death. This beta coronavirus has a 30-kilobase RNA genome and shares about 80 % of its nucleotide sequence with SARS-CoV-1. The replication/transcription complex, essential for viral RNA synthesis, includes RNA-dependent RNA polymerase (RdRp, nsp12) enhanced by nsp7 and nsp8. Antivirals like molnupiravir and remdesivir, which are RdRp inhibitors, treat severe COVID-19 but have limitations, highlighting the need for new therapies. This study assessed (-)-cytisine, methylcytisine, and thermopsine derivatives against SARS-CoV-1 and SARS-CoV-2 in vitro, focusing on their RdRp inhibition. Selected compounds from a previous study were evaluated using a SARS-CoV-2 RNA polymerase assay kit to investigate their structure–activity relationships. Compound 17 (1,3-dimethyluracil conjugate with (-)-cytisine and thermopsine) emerged as a potent inhibitor of SARS-CoV-1 and SARS-CoV-2 RdRp, with an IC50 value of 7.8 μM against SARS-CoV-2 RdRp. It showed a dose-dependent reduction in cytopathic effects in cells infected with SARS-CoV-1 and SARS-CoV-2 replicon-based single-round infectious particles (SRIPs) and significantly inhibited SARS-CoV N protein expression, with EC50 values of 0.12 µM for SARS-CoV-1 and 1.47 µM for SARS-CoV-2 SRIPs. Additionally, compound 17 reduced viral subgenomic RNA levels in a concentration-dependent manner in SRIP-infected cells. The structure–activity relationships of compound 17 with SARS-CoV-1 and SARS-CoV-2 RdRp were also investigated, highlighting it as a promising lead for developing antiviral agents against SARS and COVID-19.

Effects of papain hydrolysate of Pseudosciaena crocea roe on the physical and oxidative stability of water-in-oil emulsions

This study investigates the effects of hydrolysates from Pseudosciaena crocea roe on the physical and oxidative stability of oil-in-water emulsions, emphasizing the structure-activity relationship between peptide structure and emulsifying properties. The results showed that, compared to other proteases, hydrolysates prepared with papain (PCRHs) at moderate degrees of hydrolysis (DH 4.68% and 6.8%) exhibited superior emulsifying activity index (EAI) and emulsifying stability index (ESI). PCRHs with DH of 4.68%, 6.8% formed smaller particle sizes (89.8 ± 3.52 nm, 112 ± 2.65 nm) and more stable emulsions. EAI and ESI of PCRHs were significantly negatively correlated with emulsion particle size and significantly positively correlated with surface hydrophobicity, amino acid composition, relative molecular mass, random coil content and total sulfhydryl groups. Additionally, although PCRHs with DH of 4.68% produced smaller and more stable emulsion particles, PCRHs with DH of 6.8% significantly inhibited primary and secondary lipid oxidation products formation. Correlation analysis revealed that emulsions with smaller particle sizes exhibited poorer oxidative stability, and secondary volatile oxidation products better reflected the oxidative stability of emulsions. Therefore, hydrolysates from Pseudosciaena crocea roe protein with moderate hydrolysis, particularly PCRHs with DH of 6.8%, demonstrate potential as natural emulsifiers to maintain the physical and oxidative stability of oil-in-water emulsions.