ABSTRACT
The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.
Subject(s)
Antineoplastic Agents , ErbB Receptors , Molecular Docking Simulation , Naproxen , Oxadiazoles , ErbB Receptors/antagonists & inhibitors , Humans , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesis , Naproxen/pharmacology , Naproxen/analogs & derivatives , Naproxen/chemistry , Naproxen/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Apoptosis/drug effects , Erlotinib Hydrochloride/pharmacology , Erlotinib Hydrochloride/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Cell Proliferation/drug effectsABSTRACT
The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74-1.51 GBq/µmol, 20-41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity.
Subject(s)
Fluorine Radioisotopes , Histone Deacetylase Inhibitors , Radiopharmaceuticals , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Fluorine Radioisotopes/chemistry , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Drug Design , Humans , Radiochemistry/methods , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesisABSTRACT
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO (NtPPO) and herbicidal activity were evaluated. Among them, compounds B11 (Ki = 9.05 nM) and B20 (Ki = 10.23 nM) showed significantly better inhibitory activity against NtPPO than that against flumiclorac-pentyl (Ki = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds (Abutilon theophrasti, Amaranthus retroflexus, and Portulaca oleracea) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to NtPPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.
Subject(s)
Amaranthus , Drug Design , Enzyme Inhibitors , Herbicides , Molecular Docking Simulation , Oxadiazoles , Phthalimides , Plant Weeds , Protoporphyrinogen Oxidase , Thiadiazoles , Herbicides/chemistry , Herbicides/pharmacology , Herbicides/chemical synthesis , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Thiadiazoles/chemical synthesis , Plant Weeds/drug effects , Plant Weeds/enzymology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Structure-Activity Relationship , Phthalimides/chemistry , Phthalimides/pharmacology , Phthalimides/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemical synthesis , Protoporphyrinogen Oxidase/antagonists & inhibitors , Protoporphyrinogen Oxidase/chemistry , Protoporphyrinogen Oxidase/metabolism , Amaranthus/chemistry , Amaranthus/drug effects , Plant Proteins/chemistry , Plant Proteins/antagonists & inhibitors , Molecular Structure , Nicotiana/chemistryABSTRACT
We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).
Subject(s)
Antineoplastic Agents , Benzimidazoles , Molecular Docking Simulation , Oxadiazoles , Vascular Endothelial Growth Factor Receptor-2 , Humans , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Cell Line, Tumor , Structure-Activity Relationship , Drug Screening Assays, Antitumor , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Cell Proliferation/drug effectsABSTRACT
Papain-like protease (PLpro) is a promising therapeutic target for its pivotal role in the life cycle of SARS-CoV-2. A series of 1,2,4-oxadiazole derivatives was designed and synthesized via a ring formation strategy based on SARS-CoV-2 PLpro-GRL0617 complex structure. Systematic structure-activity relationship studies revealed that introducing oxadiazole and aryl carboxylic acid moieties to GRL0617 enhanced the enzymatic inhibition activity, affinity, and deubiquitination capacity toward PLpro. 1,2,4-Oxadiazole compounds 13f and 26r, which had PLpro inhibition activity (IC50 = 1.8 and 1.0 µM) and antiviral activity against SARS-CoV-2 (EC50 = 5.4 and 4.3 µM), exhibited good metabolic stability (t1/2 > 93.2 min) and higher plasma exposure (AUC0-t = 17,380.08 and 24,289.76 ng·h/mL) in mice. Especially, compound 26r with moderate oral bioavailability of 39.1% and potent antiviral activity is worthy of further studies in vivo. Our findings provide a new insight for the discovery of antiviral agents targeting PLpro.
Subject(s)
Antiviral Agents , Drug Design , Oxadiazoles , SARS-CoV-2 , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Animals , Antiviral Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Structure-Activity Relationship , SARS-CoV-2/drug effects , Mice , Humans , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Carboxylic Acids/chemical synthesis , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , COVID-19 Drug Treatment , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/metabolismABSTRACT
To find novel inhibitors of α-glucosidase and α-amylase, a series of new carbazole-oxadiazole derivatives (6a-6n) were prepared, and screened for their anti-α-glucosidase and anti-α-amylase effects. Most of the tested derivatives showed different degrees of α-glucosidase and α-amylase inhibitory activity (IC50: 21.39 ± 0.69-92.05 ± 1.54 µM, 45.53 ± 1.50-126.14 ± 6.33 µM, respectively) compared to the standard acarbose (IC50: 427.00 ± 9.56 µM, 24.68 ± 1.10 µM, respectively). Thereinto, 6c (IC50 = 21.39 ± 0.69 µM) displayed the most effective anti-α-glucosidase activity and 6e presented the best anti-α-amylase activity with an IC50 value of 45.53 ± 1.50 µM. Lineweaver-Burk plot analysis suggested that 6c and 6e behaved as mixed α-glucosidase inhibitor and mixed α-amylase inhibitor, respectively. The results of circular dichroism, atomic force microscope, and molecular docking simulation exposed interaction mechanisms between two preferred compounds (6c and 6e) and their corresponding enzymes. Combined with the possible properties of reducing the elevation in postprandial blood glucose, oral activity, positive bioavailability, and low cytotoxicity of 6c and 6e, it could be concluded that the target derivatives may be able to act as lead molecules for the development of new hypoglycemic agents.
Subject(s)
Carbazoles , Drug Design , Glycoside Hydrolase Inhibitors , Molecular Docking Simulation , Oxadiazoles , alpha-Amylases , alpha-Glucosidases , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , alpha-Glucosidases/metabolism , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , alpha-Amylases/antagonists & inhibitors , alpha-Amylases/metabolism , Carbazoles/chemistry , Carbazoles/pharmacology , Carbazoles/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Humans , Animals , Dose-Response Relationship, Drug , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/chemical synthesis , Rats , MaleABSTRACT
Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem. 2009, 7 (21), 4337-4348). Compound SL44 exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC50 = 1.30 µM) and inhibited the proliferation of HCCLM3 cells (IC50 = 3.1 µM, 21.4-fold higher than hit ADX-47273). Mechanistically, SL44 induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. In vivo results demonstrated that SL44 has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Cell Proliferation , Liver Neoplasms , Oxadiazoles , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Animals , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/therapeutic use , Oxadiazoles/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Mice , Structure-Activity Relationship , Cell Line, Tumor , Drug Discovery , Mice, Nude , Apoptosis/drug effects , MaleABSTRACT
The NAD+-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from Schistosoma mansoni (SmSirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and SmSirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.
Subject(s)
Oxadiazoles , Sirtuin 2 , Sirtuin 2/antagonists & inhibitors , Sirtuin 2/metabolism , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesis , Humans , Structure-Activity Relationship , Molecular Docking Simulation , Animals , Cell Line, Tumor , Cell Survival/drug effects , Schistosoma mansoni/drug effects , Schistosoma mansoni/enzymology , Cell Movement/drug effectsABSTRACT
A series of new indole-oxadiazole derivatives was designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited significant inhibitory activity with IC50 values ranging from 1.78 to 19.74 µM against ER-positive human breast cancer (BC) cell lines T-47D and MCF-7. Among them, compounds (5a, 5c, 5e-5h, 5j-5o) displayed superior activity against ER-α dominant (ratio of ER-α/ER-ß is 9/1) T-47D cells compared to the standard drug bazedoxifene (IC50 = 12.78 ± 0.92 µM). Compounds 5c and 5o exhibited remarkable anti-proliferative activity with IC50 values of 3.24 ± 0.46 and 1.72 ± 1.67 µM against T-47D cells, respectively. Further, compound 5o manifested 1589-fold higher ER-α binding affinity (213.4 pM) relative to bazedoxifene (339.2 nM) in a competitive ER-α binding assay, while compound 5c showed a binding affinity of 446.6 nM. The Western blot analysis proved that both compounds influenced the ER-α protein's expression, impeding its subsequent transactivation and signalling pathway within T-47D cells. Additionally, a molecular docking study suggests that compounds 5c and 5o bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Also, pharmacokinetic profiles showed that all compounds have drug-like properties. Further, molecular dynamic (MD) simulations and density functional theory (DFT) analysis confirmed the stability, conformational behaviour, reactivity, and biological feasibility of compounds 5c and 5o. In conclusion, based on our findings, compounds 5c and 5o, which exhibit significant ER-α antagonistic activity, can act as potential lead compounds for developing anti-breast cancer agents.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Estrogen Receptor alpha , Indoles , Oxadiazoles , Humans , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacology , Indoles/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Molecular Structure , Molecular Docking Simulation , Cell Line, TumorABSTRACT
Selective inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15-25, 29-30 with IC50 values in the range of 5.6-82.3 nM in a cell-free assay of prostaglandin (PG)E2 formation. We also demonstrate that 20 (TG554, IC50 = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE2 and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE2 formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development.
Subject(s)
Dose-Response Relationship, Drug , Oxadiazoles , Prostaglandin-E Synthases , Prostaglandin-E Synthases/antagonists & inhibitors , Prostaglandin-E Synthases/metabolism , Humans , Structure-Activity Relationship , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Microsomes/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesisABSTRACT
This paper describes the in vitro inhibition potential of bisoxadiazole-substituted sulfonamide derivatives (6a-t) against bovine carbonic anhydrase (bCA) after they were designed through computational analyses and evaluated the predicted interaction via molecular docking. First, in silico ADMET predictions and physicochemical property analysis of the compounds provided insights into solubility and permeability, then density functional theory (DFT) calculations were performed to analyse their ionization energies, nucleophilicity, in vitro electron affinity, dipole moments and molecular interactions under vacuum and dimethyl sulfoxide (DMSO) conditions. After calculating the theoretical inhibition constants, IC50 values determined from enzymatic inhibition were found between 12.93 and 45.77 µM. Molecular docking evaluation revealed favorable hydrogen bonding and π-interactions of the compounds within the bCA active site. The experimentally most active compound, 6p, exhibited the strongest inhibitory activity with a theoretical inhibition constant value of 9.41 nM and H-bonds with Gln91, Thr198, and Trp4 residues and His63 Pi-cation interactions with His63 residues. Overall, the study reveals promising bCA blocking potential for the synthesized derivatives, similar to acetazolamide.
Subject(s)
Carbonic Anhydrase Inhibitors , Molecular Docking Simulation , Oxadiazoles , Sulfonamides , Cattle , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/pharmacology , Animals , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Carbonic Anhydrases/chemistry , Carbonic Anhydrases/metabolism , Hydrogen Bonding , Structure-Activity Relationship , Catalytic DomainABSTRACT
This study examines the synthesis and evaluation of 11 newly developed compounds as potential anti-Alzheimer's agents that occur via cholinesterase and ß-secretase inhibition. The compounds were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the modified Ellman method. The results showed that several compounds exhibited significant inhibition of AChE, particularly compounds 6d, 7a, and 7e, which demonstrated high inhibitory activity at lower concentrations, with IC50 values of 0.120, 0.039, and 0.063 µM, respectively. However, the compounds showed limited effectiveness against BChE, with only a few compounds exhibiting moderate inhibition. Compound 7e showed an inhibitory effect against BACE-1 close to that of the standard drug. Structural analysis revealed that the compounds with substituted benzothiazole and thiazole moieties exhibited the most promising inhibitory activity. This study provides valuable insights into the potential of these synthesized derivatives as a treatment against Alzheimer's disease. Moreover, the structure, stability, and properties of the active compounds were further investigated using density functional theory calculations. As a final note, the utilization of molecular docking and molecular dynamics simulation studies allowed us to elucidate the action mechanism of the active compounds and gain insights into the structure-activity relationship against AChE and ß-secretase proteins. These computational techniques provide valuable information on the binding modes, interactions with target enzymes, dynamic behavior, and conformational changes of the compounds, enabling a comprehensive understanding of their biological activity.
Subject(s)
Acetylcholinesterase , Alzheimer Disease , Amyloid Precursor Protein Secretases , Butyrylcholinesterase , Cholinesterase Inhibitors , Drug Design , Molecular Docking Simulation , Oxadiazoles , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Structure-Activity Relationship , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Butyrylcholinesterase/metabolism , Acetylcholinesterase/metabolism , Humans , Molecular Structure , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Molecular Dynamics Simulation , Dose-Response Relationship, Drug , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolismABSTRACT
Aim: BCRP plays a major role in the efflux of cytotoxic molecules, limiting their antiproliferative activity. We aimed to design and synthesize new BCRP inhibitors to render cancerous tumors more sensitive toward anticancer agents. Materials & methods: Based on our previous work, we conceived potential BCRP inhibitors derived from 1,3,4-oxadiazoles bearing two substituted phenyl rings. Results: Evaluating 19 derivatives, we found that 2,5-diaryl-1,3,4-oxadiazoles possessing methoxy groups were the most active. The highest activity was recorded with derivatives bearing three methoxy groups. The most active compound (3j) was selective in inhibiting BCRP and nontoxic as evidenced by cellular tests. Conclusion: 3j is a promising BCRP inhibitor thanks to its synthetic accessibility and biological profile.
[Box: see text].
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Antineoplastic Agents , Neoplasm Proteins , Oxadiazoles , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Humans , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxadiazoles/chemical synthesis , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Cell Proliferation/drug effects , Molecular Structure , Cell Line, Tumor , Drug Screening Assays, AntitumorABSTRACT
The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) etâ al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compoundsâ 21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43â nM and 47.71â nM, respectively, which were stronger than that of ISRIB (IC50=67.90â nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70â nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.
Subject(s)
Activating Transcription Factor 4 , Drug Design , Eukaryotic Initiation Factor-2B , Humans , Activating Transcription Factor 4/metabolism , HeLa Cells , Structure-Activity Relationship , Eukaryotic Initiation Factor-2B/metabolism , Eukaryotic Initiation Factor-2B/antagonists & inhibitors , Molecular Structure , Dose-Response Relationship, Drug , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesisABSTRACT
BACKGROUND: Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies. AIM: The aim of the present study was to investigate the potential of new anti-inflammatory oxadiazole derivatives of Diclofenac as an anti-lymphoma agent through in vitro and in silico approaches. METHODS: Anti-lymphoma potential was evaluated by alamar blue technique. MTT assay employed for cytotoxicity. Gene and protein expression studies was performed by qRT-PCR and ELISA respectively. Docking studies was performed by using MOE program. RESULTS: Among five diclofenac derivatives, (II) showed promising anti-lymphoma effects, where it inhibited the expression of BCL-2, p-38 MAPK and TGF-ß in both follicular and Burkitt's lymphoma cells and was non-toxic against normal human fibroblast cells. The in silico studies against BCL-2 revealed that the unsubstituted Sulphur group in (II) is involved in the crucial interactions with the binding site residue. CONCLUSION: The compound (II) can be a potential therapeutic candidate for B-cell non-Hodgkin lymphoma and deserves further development as a novel anti-lymphoma agent.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Diclofenac , Molecular Docking Simulation , Oxadiazoles , Humans , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesis , Diclofenac/pharmacology , Diclofenac/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Proto-Oncogene Proteins c-bcl-2/metabolism , Cell Line, Tumor , Computer Simulation , Molecular Structure , Structure-Activity Relationship , Drug Screening Assays, Antitumor , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Plant diseases that are caused by fungi and nematodes have become increasingly serious in recent years. However, there are few pesticide chemicals that can be used for the joint control of fungi and nematodes on the market. To solve this problem, a series of novel 1,2,4-oxadiazole derivatives containing amide fragments were designed and synthesized. Additionally, the bioassays revealed that the compound F15 demonstrated excellent antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum) in vitro, and the EC50 value of that was 2.9 µg/mL, which is comparable with commonly used fungicides thifluzamide and fluopyram. Meanwhile, F15 demonstrated excellent curative and protective activity against S. sclerotiorum-infected cole in vivo. The scanning electron microscopy results showed that the hyphae of S. sclerotiorum treated with F15 became abnormally collapsed and shriveled, thereby inhibiting the growth of the hyphae. Furthermore, F15 exhibited favorable inhibition against the succinate dehydrogenase (SDH) of the S. sclerotiorum (IC50 = 12.5 µg/mL), and the combination mode and binding ability between compound F15 and SDH were confirmed by molecular docking. In addition, compound F11 showed excellent nematicidal activity against Meloidogyne incognita at 200 µg/mL, the corrected mortality rate was 93.2%, which is higher than that of tioxazafen.
Subject(s)
Antifungal Agents/chemical synthesis , Ascomycota/growth & development , Oxadiazoles/chemical synthesis , Succinate Dehydrogenase/metabolism , Amides/chemistry , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Ascomycota/drug effects , Ascomycota/metabolism , Cell Line , Drug Design , Fungal Proteins/chemistry , Fungal Proteins/metabolism , Humans , Hyphae/drug effects , Hyphae/growth & development , Hyphae/metabolism , Microbial Viability/drug effects , Models, Molecular , Molecular Structure , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Plants/drug effects , Plants/microbiology , Plants/parasitology , Protein Conformation , Structure-Activity Relationship , Succinate Dehydrogenase/chemistryABSTRACT
Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-ß-alanine 1,3,4-oxadiazole hybrids (4a-l), characterized by 1H- and 13C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-ß-alanine 1,3,4-oxadiazole derivatives 4a-l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC50 value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II.
Subject(s)
Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Alanine/analogs & derivatives , Alanine/chemical synthesis , Alanine/pharmacology , Carbonic Anhydrase II/chemistry , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Catalytic Domain/drug effects , Drug Design , Humans , Molecular Docking Simulation , Oxadiazoles/chemical synthesisABSTRACT
Ultrasound- and microwave-assisted green synthetic strategies were applied to furnish benzofuran-oxadiazole 5a-g and benzofuran-triazole 7a-h derivatives in good to excellent yields (60-96%), in comparison with conventional methods (36-80% yield). These synthesized derivatives were screened for hemolysis, thrombolysis and anticancer therapeutic potential against an A549 lung cancer cell line using an MTT assay. Derivatives 7b (0.1%) and 5e (0.5%) showed the least toxicity against RBCs. Hybrid 7f showed excellent thrombolysis activity (61.4%) when compared against reference ABTS. The highest anticancer activity was displayed by the 5d structural hybridwith cell viability 27.49 ± 1.90 and IC50 6.3 ± 0.7 µM values, which were considerably lower than the reference drug crizotinib (IC50 8.54 ± 0.84 µM). Conformational analysis revealed the spatial arrangement of compound 5d, which demonstrated its significant potency in comparison with crizotinib; therefore, scaffold 5d would be a promising anticancer agent on the basis of cytotoxicity studies, as well as in silico modeling studies.
Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Oxadiazoles/pharmacology , Triazoles/pharmacology , A549 Cells , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cell Survival/drug effects , Chemistry Techniques, Synthetic , Hemolysis/drug effects , Humans , Microwaves , Molecular Docking Simulation , Neoplasms/drug therapy , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Neuraminidase (NA) is an important target in the development of anti-influenza virus drugs. Compounds containing 1,3, 4-oxadiazole heterocycles have good biological activity and have been proved to have wide applications in antibacterial and antiviral drugs. In this paper, a series of novel 1, 3, 4-oxadiazole neuraminidase inhibitors (6a-6l) were designed and synthesized and their inhibitory activities of NA was tested in vitro. The results displayed that compound 6d exerts the best inhibitory activity (IC50 = 0.027 µM), which was obviously lower than that of oseltamivir carboxylate (OSC) (IC50 = 0.082 µM). Molecular docking analysis showed that the 1, 3, 4-oxadiazole heterocycle plays crucial part in compound 6d, and it can interact with the key arginine triad (Arg118, Arg292 and Arg 371) at the NA S1 site. The good efficacy of 6d may also be attributed to the extension of the substituted aniline ring to the 150-cavitiy. The theoretical and experimental results may provide reference for development of new anti-influenza drugs.
Subject(s)
Antiviral Agents/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Neuraminidase/antagonists & inhibitors , Orthomyxoviridae/drug effects , Oxadiazoles/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Neuraminidase/metabolism , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Structure-Activity RelationshipABSTRACT
Assessment of sphingosine-1-phosphate receptor 1 (S1PR1) expression could be a unique tool to determine the neuroinflammatory status for central nervous system (CNS) disorders. Our preclinical results indicate that PET imaging with [11C]CS1P1 radiotracer can quantitatively measure S1PR1 expression changes in different animal models of inflammatory diseases. Here we developed a multiple step F-18 labeling strategy to synthesize the radiotracer [18F]FS1P1, sharing the same structure with [11C]CS1P1. We explored a wide range of reaction conditions for the nucleophilic radiofluorination starting with the key ortho-nitrobenzaldehyde precursor 10. The tertiary amine additive TMEDA proved crucial to achieve high radiochemical yield of ortho-[18F]fluorobenzaldehyde [18F]12 starting with a small amount of precursor. Based on [18F]12, a further four-step modification was applied in one-pot to generate the target radiotracer [18F]FS1P1 with 30-50% radiochemical yield, >95% chemical and radiochemical purity, and a high molar activity (37-166.5 GBq µmol-1, decay corrected to end of synthesis, EOS). Subsequently, tissue distribution of [18F]FS1P1 in rats showed a high brain uptake (ID% g-1) of 0.48 ± 0.06 at 5 min, and bone uptake of 0.27 ± 0.03, 0.11 ± 0.02 at 5, and 120 min respectively, suggesting no in vivo defluorination. MicroPET studies showed [18F]FS1P1 has high macaque brain uptake with a standard uptake value (SUV) of â¼2.3 at 120 min. Radiometabolite analysis of macaque plasma samples indicated that [18F]FS1P1 has good metabolic stability, and no major radiometabolite confounded PET measurements of S1PR1 in nonhuman primate brain. Overall, [18F]FS1P1 is a promising F-18 S1PR1 radiotracer worthy of further clinical investigation for human use.