ABSTRACT
Twelve spiro thiazolidinone compounds (A-L) were synthesized via either conventional thermal or ultrasonication techniques using Fe2O3 nanoparticles. The modification of the traditional procedure by using Fe2O3 nanoparticles led to enhancement of the yield of the desired candidates to 78-93% in approximately half reaction time compared with 58-79% without catalyst. The products were fully characterized using different analytical and spectroscopic techniques. The structure of the two derivatives 4-phenyl-1-thia-4-azaspirodecan-3-one (A) and 4-(p-tolyl)-1-thia-4-azaspirodecan-3-one (B) were also determined using single crystal X-ray diffraction and Hirshfeld surface analysis. The two compounds (A and B) were crystallized in the orthorhombic system with Pbca and P212121 space groups, respectively. In addition, the crystal packing of compounds revealed the formation of supramolecular array with a net of intermolecular hydrogen bonding interactions. The energy optimized geometries of some selected derivatives were performed by density functional theory (DFT/B3LYP). The reactivity descriptors were also calculated and correlated with their biological properties. All the reported compounds were screened for antimicrobial inhibitions. The two derivatives, F and J, exhibited the highest levels of bacterial inhibition with an inhibition zone of 10-17 mm. Also, the two derivatives, F and J, displayed the most potent fungal inhibition with an inhibition zone of 15-23 mm. Molecular docking investigations of some selected derivatives were performed using a B-DNA (PDB: 1BNA) as a macromolecular target. Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial activities and the computed reactivity parameters.
Subject(s)
Molecular Docking Simulation , Thiazolidines , Catalysis , Thiazolidines/chemistry , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Crystallography, X-Ray/methods , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Density Functional Theory , Microbial Sensitivity Tests , Ferric Compounds/chemistry , Hydrogen BondingABSTRACT
Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.
Subject(s)
Apoptosis , Autophagic Cell Death , Liver Neoplasms , Neoplastic Stem Cells , Proto-Oncogene Proteins c-akt , Signal Transduction , TOR Serine-Threonine Kinases , Humans , Apoptosis/drug effects , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Signal Transduction/drug effects , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Hep G2 Cells , Autophagic Cell Death/drug effects , Thiazolidines/pharmacology , Animals , Mice , Cell Movement/drug effects , Antineoplastic Agents/pharmacology , Autophagy/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistryABSTRACT
A range of hybrid molecules incorporating the ciminalum moiety in the thiazolidinone ring demonstrate significant anticancer and antimicrobial properties. Therefore, the aim of our study was to evaluate the properties and mechanism of action of two 4-thiazolidinone-based derivatives, i.e., 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (Les-45) and 5-[2-chloro-3-(4-nitrophenyl)-2-propenylidene]-2-(3-hydroxyphenylamino)thiazol-4(5H)-one (Les-247). In our study, we analyzed the impact of Les-45 and Les-247 on metabolic activity, caspase-3 activity, and the expression of genes and proteins related to inflammatory and antioxidant defenses and cytoskeleton rearrangement in healthy human fibroblasts (BJ) and a human lung carcinoma cell line (A549). The cells were exposed to increasing concentrations (1 nM to 100 µM) of the studied compounds for 24 h and 48 h. A decrease in the metabolic activity in the BJ and A549 cell lines was induced by both compounds at a concentration range from 10 to 100 µM. Both compounds decreased the mRNA expression of NRF2 (nuclear factor erythroid 2-related factor 2) and ß-actin in the BJ cells. Interestingly, a significant decrease in the level of NF-κB gene and protein expression was detected in the BJ cell line, suggesting a direct impact of the studied compounds on the inhibition of inflammation. However, more studies are needed due to the ability of Les-45 and Les-247 to interfere with the tubulin/actin cytoskeleton, i.e., a critical system existing in eukaryotic cells.
Subject(s)
NF-kappa B , Signal Transduction , Thiazolidines , Humans , Thiazolidines/pharmacology , Thiazolidines/chemistry , NF-kappa B/metabolism , Signal Transduction/drug effects , A549 Cells , Fibroblasts/metabolism , Fibroblasts/drug effects , Antioxidants/pharmacology , Antioxidants/chemistryABSTRACT
Peptide ligation chemistries have revolutionized the synthesis of proteins with site-specific modifications or proteomimetics through assembly of multiple peptide segments. In order to prepare polypeptide chains consisting of 100-150 amino acid residues or larger generally assembled from three or more peptide segments, iterative purification process that decreases the product yield is usually demanded. Accordingly, methodologies for one-pot peptide ligation that omit the purification steps of intermediate peptide segments have been vigorously developed so far to improve the efficiency of chemical protein synthesis. In this chapter, we first outline the concept and recent advances of one-pot peptide ligation strategies. Then, the practical guideline for the preparation of peptide segments for one-pot peptide ligation is described with an emphasis on diketopiperazine thioester synthesis. Finally, we disclose the explicit protocols for one-pot four segment ligation via repetitive deprotection of N-terminal thiazolidine by a 2-aminobenzamide type aldehyde scavenger.
Subject(s)
Peptides , Thiazolidines , Thiazolidines/chemistry , Peptides/chemistry , Diketopiperazines/chemistryABSTRACT
PURPOSE: Cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer and the chemotherapeutic drugs available have high toxicity and have reported side effects hence, there is a need for the synthesis of novel drugs in the treatment of cancer. METHODS: The current research work dealt with the synthesis of a series of 3-(3-acetyl-2-oxoquinolin-1-(2H)-yl-2-(substitutedphenyl)thiazolidin-4-one (Va-j) derivatives and evaluation of their in-vitro anticancer activity. All the synthesized compounds were satisfactorily characterized by IR and NMR data. Compounds were further evaluated for their in-vitro anticancer activity against A-549 (lung cancer) cell lines. The in-vitro anticancer activity was based upon the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay method. RESULTS: The synthesized compounds exhibited satisfactory anticancer properties against the A-549 cell line. The compound (VH): showed the highest potency amongst the tested derivatives against the A-549 cell line with IC50 values of 100 µg/ml respectively and was also found to be more potent than Imatinib (150 µg/ml) which was used as a standard drug. Molecular docking studies of the titled compounds (Va-j) were carried out using AutoDock Vina/PyRx software. The synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of the EGFRK tyrosine kinase domain (PDB 1m17). CONCLUSION: Among all the synthesized analogues, the binding affinity of the compound (Vh) was found to be higher than other synthesized derivatives and a molecular dynamics simulation study explored the stability of the docked complex system.
Subject(s)
Antineoplastic Agents , ErbB Receptors , Lung Neoplasms , Molecular Docking Simulation , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Cell Line, Tumor , A549 Cells , Thiazolidines/pharmacology , Thiazolidines/chemistry , Thiazolidines/chemical synthesis , Drug Screening Assays, Antitumor , Cell Proliferation/drug effectsABSTRACT
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.
Subject(s)
Aldo-Keto Reductases , Curcumin , Non-alcoholic Fatty Liver Disease , Triglycerides , Curcumin/pharmacology , Curcumin/analogs & derivatives , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Animals , Humans , Hep G2 Cells , Aldo-Keto Reductases/metabolism , Rats , Male , Triglycerides/blood , Triglycerides/metabolism , Acetyl-CoA Carboxylase/metabolism , Aldehyde Reductase/metabolism , Aldehyde Reductase/antagonists & inhibitors , Diet, High-Fat/adverse effects , Molecular Docking Simulation , Liver/drug effects , Liver/metabolism , Metformin/pharmacology , Rats, Sprague-Dawley , Disease Models, Animal , Rhodanine/analogs & derivatives , ThiazolidinesABSTRACT
Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to bind peroxisome proliferator receptor γ (PPARγ), which has various effects on cancer and can inhibit cell proliferation. In this study, we investigated the effect of new 4-thiazolidinone (4-TZD) hybrids Les-4369 and Les-3467 and their effect on reactive oxygen species (ROS) production, metabolic activity, lactate dehydrogenase (LDH) release, caspase-3 activity, and gene and protein expression in human foreskin fibroblast (BJ) cells and lung adenocarcinoma (A549) cells. The ROS production and caspase-3 activity were mainly increased in the micromolar concentrations of the studied compounds in both cell lines. Les-3467 and Les-4369 increased the mRNA expression of PPARG, P53 (tumor protein P53), and ATM (ATM serine/threonine kinase) in the BJ cells, while the mRNA expression of these genes (except PPARG) was mainly decreased in the A549 cells treated with both of the tested compounds. Our results indicate a decrease in the protein expression of AhR, PPARγ, and PARP-1 in the BJ cells exposed to 1 µM Les-3467 and Les-4369. In the A549 cells, the protein expression of AhR, PPARγ, and PARP-1 increased in the treatment with 1 µM Les-3467 and Les-4369. We have also shown the PPARγ modulatory properties of Les-3467 and Les-4369. However, both compounds prove weak anticancer properties evidenced by their action at high concentrations and non-selective effects against BJ and A549 cells.
Subject(s)
PPAR gamma , Pyrazoles , Reactive Oxygen Species , Humans , A549 Cells , PPAR gamma/metabolism , PPAR gamma/genetics , Reactive Oxygen Species/metabolism , Pyrazoles/pharmacology , Thiazolidines/pharmacology , Indoles/pharmacology , Caspase 3/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins/metabolism , Apoptosis/drug effects , Fibroblasts/drug effects , Fibroblasts/metabolismABSTRACT
Based on the fact that substances with a ß-phenyl-α,ß-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1-8 were prepared as potential tyrosinase inhibitors. Four analogs (1-3 and 5) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1, 3, and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1, 3, and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.
Subject(s)
Agaricales , Antioxidants , Enzyme Inhibitors , Melanins , Molecular Docking Simulation , Monophenol Monooxygenase , Monophenol Monooxygenase/antagonists & inhibitors , Monophenol Monooxygenase/metabolism , Agaricales/enzymology , Animals , Antioxidants/pharmacology , Antioxidants/chemistry , Mice , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Melanins/antagonists & inhibitors , Melanins/biosynthesis , Thiazolidines/chemistry , Thiazolidines/pharmacology , Cell Line, Tumor , Kinetics , Melanoma, Experimental/drug therapy , Melanoma, Experimental/pathology , Benzylidene Compounds/pharmacology , Benzylidene Compounds/chemistry , PyronesABSTRACT
Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five.
Subject(s)
Molecular Conformation , Molecular Docking Simulation , Thiazolidines , Thiazolidines/chemistry , Thiazolidines/chemical synthesis , Isomerism , Animals , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Zebrafish , Magnetic Resonance Spectroscopy , Janus Kinase 3/antagonists & inhibitors , Janus Kinase 3/metabolism , Janus Kinase 3/chemistry , Molecular StructureABSTRACT
Root hair (RH) cells are important for the growth and survival of seedlings. They favor plant-microbe interactions and nutrients uptake. When invading the soil, RH cells have to penetrate a dense medium exhibiting a variety of physical properties, such as mechanical resistance, that impact the growth and survival of plants. Here we investigate the effect of the mechanical resistance of the culture medium on RH-physical and phenotypical parameters such as length, time, and speed of growth. We also analyze the impact of the environment on nuclear dynamics. We show that the RH growth rate and the nucleus speed decrease similarly as mechanical resistance increases while the time of growth of RH cells is invariable. Moreover, during RH growth, the nucleus-to-tip distance was found to decrease when the stiffness of the environment was increased. Along this line, using Latrunculin B treatment in liquid growth media, we could internally slow down RH growth to reach speeds similar to those observed in stiff solid media while the nucleus-to-tip distance was only slightly affected, supporting thus the idea of a specific effect of mechanical resistance of the environment on nucleus dynamics.
Subject(s)
Cell Nucleus , Plant Roots , Plant Roots/growth & development , Cell Nucleus/metabolism , Arabidopsis/growth & development , Arabidopsis/physiology , Culture Media , Thiazolidines/pharmacology , Seedlings/growth & development , Bridged Bicyclo Compounds, Heterocyclic/pharmacologyABSTRACT
We describe a simple and robust oxidation strategy for preparing N-terminal thiazolidine-containing peptide thioesters from peptide hydrazides. We find for the first time that l-thioproline can be used as a protective agent to prevent the nitrosation of N-terminal thiazolidine during peptide hydrazide oxidation. The thioproline-based oxidation strategy has been successfully applied to the chemical synthesis of CC chemokine ligand-2 (69aa) and omniligase-C (113aa), thereby demonstrating its utility in hydrazide-based native chemical ligation.
Subject(s)
Oxidation-Reduction , Peptides , Thiazolidines , Thiazolidines/chemistry , Thiazolidines/chemical synthesis , Molecular Structure , Peptides/chemistry , Peptides/chemical synthesis , Hydrazines/chemistry , Proline/chemistry , Esters/chemistry , Sulfhydryl Compounds/chemistryABSTRACT
AIMS: The skeletal effects of metformin monotherapy and in combination with teneligliptin are not well illustrated in patients with T2DM. To address this, we conducted an observational study to evaluate the effect of these oral hypoglycemic agents on bone turnover markers. METHODS: We recruited patients with T2DM and first-ever prescribed metformin monotherapy or metformin combined with teneligliptin from a tertiary care teaching hospital in New Delhi, North India. Both bone formation and resorption markers, IL-6 and PTD, were estimated along with glycated hemoglobin at baseline and 12 weeks. RESULTS: In both groups, hbA1c levels decreased significantly from baseline to 12 weeks. In the metformin-treated group, ß-CTX, sRANKL, IL-6, and PTD decreased significantly, and no significant changes were observed in P1NP, OC, BAP, or OPG at 12 weeks from baseline. In the metformin + teneligliptin group, BAP, ß-CTX, sRANKL, IL-6, and PTD decreased significantly, and no significant changes were observed in P1NP, OC, or OPG after 12 weeks from baseline. CONCLUSIONS: The positive bone outcome of metformin or teneligliptin was linked to bone resorption rather than bone formation and was independent of changes in HbA1c or PTD. However, these results must be confirmed with well-designed RCTs with more extended follow-up periods.
Subject(s)
Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Metformin , Pyrazoles , Thiazolidines , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood , Metformin/therapeutic use , Male , Thiazolidines/therapeutic use , Female , Middle Aged , Pyrazoles/therapeutic use , Hypoglycemic Agents/therapeutic use , Follow-Up Studies , Glycated Hemoglobin/metabolism , Glycated Hemoglobin/analysis , Drug Therapy, Combination , Adult , Interleukin-6/blood , Bone Remodeling/drug effects , Biomarkers/blood , Aged , Bone Resorption/drug therapyABSTRACT
With the aim of identifying novel neonicotinoid insecticides with low bee toxicity, a series of compounds bearing thiazolidine moiety, which has been shown to be low bee toxic, were rationally designed through substructure splicing strategy and evaluated insecticidal activities. The optimal compounds A24 and A29 exhibited LC50 values of 30.01 and 17.08 mg/L against Aphis craccivora, respectively. Electrophysiological studies performed on Xenopus oocytes indicated that compound A29 acted on insect nAChR, with EC50 value of 50.11 µM. Docking binding mode analysis demonstrated that A29 bound to Lymnaea stagnalis acetylcholine binding protein through H-bonds with the residues of D_Arg55, D_Leu102, and D_Val114. Quantum mechanics calculation showed that A29 had a higher highest occupied molecular orbit (HOMO) energy and lower vertical ionization potential (IP) value compared to the high bee toxic imidacloprid, showing potentially low bee toxicity. Bee toxicity predictive model also indicated that A29 was nontoxic to honeybees. Our present work identified an innovative insecticidal scaffold and might facilitate the further exploration of low bee toxic neonicotinoid insecticides.
Subject(s)
Insecticides , Neonicotinoids , Thiazolidines , Animals , Insecticides/chemistry , Insecticides/toxicity , Bees/drug effects , Neonicotinoids/chemistry , Neonicotinoids/toxicity , Thiazolidines/chemistry , Thiazolidines/toxicity , Molecular Docking Simulation , Insect Proteins/genetics , Insect Proteins/chemistry , Insect Proteins/metabolism , Insect Proteins/toxicity , Aphids/drug effects , Aphids/genetics , Structure-Activity Relationship , Molecular Structure , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Receptors, Nicotinic/chemistryABSTRACT
Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 µg/ml) and 7a (38.15 µg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 µg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 µg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.
Subject(s)
Alternaria , Benzaldehydes , Fusarium , Microbial Sensitivity Tests , Oxadiazoles , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Benzaldehydes/chemistry , Benzaldehydes/pharmacology , Molecular Structure , Fusarium/drug effects , Alternaria/drug effects , Thiazolidines/pharmacology , Thiazolidines/chemistry , Botrytis/drug effects , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Fungicides, Industrial/pharmacology , Fungicides, Industrial/chemistry , Humans , Structure-Activity RelationshipABSTRACT
Zoonoses such as ZIKV and SARS-CoV-2 pose a severe risk to global health. There is urgent need for broad antiviral strategies based on host-targets filling gaps between pathogen emergence and availability of therapeutic or preventive strategies. Significant reduction of pathogen titers decreases spread of infections and thereby ensures health systems not being overloaded and public life to continue. Based on previously observed interference with FGFR1/2-signaling dependent impact on interferon stimulated gene (ISG)-expression, we identified Pim kinases as promising druggable cellular target. We therefore focused on analyzing the potential of pan-Pim kinase inhibition to trigger a broad antiviral response. The pan-Pim kinase inhibitor AZD1208 exerted an extraordinarily high antiviral effect against various ZIKV isolates, SARS-CoV-2 and HBV. This was reflected by strong reduction in viral RNA, proteins and released infectious particles. Especially in case of SARS-CoV-2, AZD1208 led to a complete removal of viral traces in cells. Kinome-analysis revealed vast changes in kinase landscape upon AZD1208 treatment, especially for inflammation and the PI3K/Akt-pathway. For ZIKV, a clear correlation between antiviral effect and increase in ISG-expression was observed. Based on a cell culture model with impaired ISG-induction, activation of the PI3K-Akt-mTOR axis, leading to major changes in the endolysosomal equilibrium, was identified as second pillar of the antiviral effect triggered by AZD1208-dependent Pim kinase inhibition, also against HBV. We identified Pim-kinases as cellular target for a broad antiviral activity. The antiviral effect exerted by inhibition of Pim kinases is based on at least two pillars: innate immunity and modulation of the endolysosomal system.
Subject(s)
Antiviral Agents , Immunity, Innate , Proto-Oncogene Proteins c-akt , Proto-Oncogene Proteins c-pim-1 , SARS-CoV-2 , Signal Transduction , TOR Serine-Threonine Kinases , Humans , Immunity, Innate/drug effects , Antiviral Agents/pharmacology , TOR Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Lysosomes/drug effects , Lysosomes/metabolism , Zika Virus/drug effects , Protein Kinase Inhibitors/pharmacology , Animals , Hepatitis B virus/drug effects , Endosomes/drug effects , Endosomes/metabolism , Cell Line , COVID-19/immunology , COVID-19/virology , COVID-19 Drug Treatment , Virus Replication/drug effects , Biphenyl Compounds , ThiazolidinesABSTRACT
Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.
Subject(s)
Benzenesulfonamides , Carbonic Anhydrase II , Carbonic Anhydrase Inhibitors , Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Hypoglycemic Agents , Sulfonamides , Thiazolidines , alpha-Glucosidases , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase II/metabolism , Diabetes Mellitus, Type 2/drug therapy , alpha-Glucosidases/metabolism , Humans , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfonamides/chemical synthesis , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemical synthesis , Structure-Activity Relationship , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Animals , Ligands , Thiazolidines/chemistry , Thiazolidines/pharmacology , Thiazolidines/chemical synthesis , Molecular Structure , Rats , Dose-Response Relationship, Drug , Molecular Docking Simulation , Diabetes Mellitus, Experimental/drug therapy , Male , Rats, WistarABSTRACT
Aim: Breast cancer has been a leading cause of mortality among women worldwide in recent years. Targeting the lysophosphatidic acid (LPA)-LPA1 pathway using small molecules could improve breast cancer therapy. Materials & methods: Thiazolidin-4-ones were developed and tested on MCF-7 cancer cells, and active compounds were analyzed for their effects on apoptosis, migration angiogenesis and LPA1 protein and gene expression. Results & conclusion: Compounds TZ-4 and TZ-6 effectively reduced the migration of MCF-7 cells, and induced apoptosis. TZ-4, TZ-6, TZ-8 and TZ-14 significantly reduced the LPA1 protein, LPA1 and angiogenesis gene expression in treated MCF-7 cells. Molecular docking and molecular dynamic simulation studies reveal the ligand interactions and stability of the LPA1-ligand complex. Developed thiazolidin-4-ones showed great potential as an LPA1-targeted approach to combating breast cancer.
Breast cancer is a major cause of death for women worldwide. Using small molecules to target the lysophosphatidic acid (LPA)LPA1 pathway could improve breast cancer treatment. We tested a type of molecule called thiazolidin-4-ones on breast cancer cells in the lab. We looked at how these molecules affected cell death, movement, blood vessel growth and the activity of the LPA1 gene and protein. Some of these molecules, such as TZ-4 and TZ-6, reduced the movement of cancer cells and caused them to die. They also decreased the levels of LPA1 protein and gene activity in the cells. We used computer simulations to see how these molecules interacted with the LPA1 protein. Our findings suggest that thiazolidin-4-ones could be a promising treatment for breast cancer by targeting LPA1.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Drug Design , Receptors, Lysophosphatidic Acid , Thiazolidines , Humans , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Receptors, Lysophosphatidic Acid/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Female , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Thiazolidines/pharmacology , Thiazolidines/chemistry , Thiazolidines/chemical synthesis , Apoptosis/drug effects , Molecular Docking Simulation , MCF-7 Cells , Molecular Structure , Structure-Activity Relationship , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Cell Movement/drug effectsABSTRACT
Epilepsy is a chronic neurological disorder characterized by episodic dysfunction of central nervous system. The most basic mechanism of epilepsy falls to the imbalance between excitation and inhibition. In adults, GABAA receptor (GABAAR) is the main inhibitory receptor to prevent neurons from developing hyperexcitability, while its inhibition relies on the low intracellular chloride anion concentration ([Cl-]i). Neuronal-specific electroneutral K+-Cl- cotransporter (KCC2) can mediate chloride efflux to lower [Cl-]i for GABAAR mediated inhibition. Our previous study has revealed that the coordinated downregulation of KCC2 and GABAAR participates in epilepsy. According to a high-throughout screen for compounds that reduce [Cl-]i, CLP290 turns out to be a specific KCC2 functional modulator. In current study, we first confirmed that CLP290 could dose-dependently suppress convulsant-induced seizures in mice in vivo as well as the epileptiform burst activities in cultured hippocampal neurons in vitro. Then, we discovered that CLP290 functioned through preventing the downregulation of the KCC2 phosphorylation at Ser940 and hence the KCC2 membrane expression during convulsant stimulation, and consequently restored the GABA inhibition. In addition, while CLP290 was given in early epileptogenesis period, it also effectively decreased the spontaneous recurrent seizures. Generally, our current results demonstrated that CLP290, as a specific KCC2 modulator by enhancing KCC2 function, not only inhibits the occurrence of the ictal seizures, but also suppresses the epileptogenic process. Therefore, we believe KCC2 may be a suitable target for future anti-epileptic drug development.
Subject(s)
Anticonvulsants , Hippocampus , K Cl- Cotransporters , Neurons , Seizures , Symporters , Animals , Symporters/metabolism , Seizures/drug therapy , Seizures/metabolism , Mice , Hippocampus/drug effects , Hippocampus/metabolism , Male , Anticonvulsants/pharmacology , Neurons/drug effects , Neurons/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Receptors, GABA-A/metabolism , Dose-Response Relationship, Drug , Cells, Cultured , ThiazolidinesABSTRACT
BACKGROUND: Chemoresistance contributes to relapse in high-risk neuroblastoma. Cancer cells acquire resistance through multiple mechanisms, including drug efflux pumps. In neuroblastoma, multidrug resistance-associated protein-1 (MRP1/ABCC1) efflux pump expression correlates with worse outcomes. These pumps are regulated by PIM kinases, a family of serine-threonine kinases, overexpressed in neuroblastoma. We hypothesized PIM kinase inhibition would sensitize neuroblastoma cells by modulating MRP1. METHODS: Kocak database query evaluated ABCC1, PIM1, PIM2, and PIM3 expression in neuroblastoma patients. SK-N-AS and SK-N-BE(2) cells were treated with doxorubicin or the pan-PIM kinase inhibitor, AZD1208. Flow cytometry assessed intracellular doxorubicin accumulation. AlamarBlue assay measured viability. The lethal dose 50% (LD50) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. RESULTS: Kocak database query demonstrated positive correlation between PIM genes and ABCC1. PIM kinase inhibition increased intracellular doxorubicin accumulation in both cell lines, suggesting PIM kinase regulation of MRP1. Isobolograms showed synergy between AZD1208 and doxorubicin. CONCLUSIONS: The correlation between PIM and ABCC1 gene expression suggests PIM kinases may contribute to neuroblastoma chemotherapeutic resistance. PIM kinase inhibition increased intracellular doxorubicin accumulation. Combination treatment with AZD1208 and doxorubicin decreased neuroblastoma cell viability in a synergistic fashion. These findings support further investigations of PIM kinase inhibition in neuroblastoma. TYPE OF STUDY: Basic Science Research. LEVEL OF EVIDENCE: NA.
Subject(s)
Doxorubicin , Drug Resistance, Neoplasm , Multidrug Resistance-Associated Proteins , Neuroblastoma , Proto-Oncogene Proteins c-pim-1 , Humans , Neuroblastoma/drug therapy , Neuroblastoma/pathology , Neuroblastoma/genetics , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Cell Line, Tumor , Antibiotics, Antineoplastic/therapeutic use , Antibiotics, Antineoplastic/pharmacology , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Drug Synergism , Biphenyl Compounds , ThiazolidinesABSTRACT
Extracellular vesicles (EVs) play an important role in the development and function of mammalian ovarian follicles. However, the mechanisms by which they are taken up by the follicular granulosa cells remain unclear. In addition, while oocytes play a pivotal role in follicular development, the possible interactions between oocyte-derived paracrine factors (ODPFs) and EV signals are unknown. Therefore, this study aimed to elucidate the mechanism of EV uptake and the effects of ODPFs on EV uptake by follicular somatic mural granulosa cells in mice. Fluorescence-labeled transferrin (TRF) and cholera toxin B (CTB), substrates for clathrin- and caveolae-mediated endocytosis, respectively, were taken up by mural granulosa cells in vitro. Their uptake was inhibited by Pitstop 2 and genistein, inhibitors of clathrin and caveolae pathways, respectively. Mural granulosa cells took up EVs, and this uptake was suppressed by Pitstop 2 and genistein. Moreover, ODPFs promoted the uptake of EVs and CTB, but not TRF, by mural granulosa cells. These results suggest that mural granulosa cells take up EVs through both clathrin- and caveolae-mediated endocytosis and that oocytes may promote caveolae-mediated endocytosis to facilitate the uptake of EVs.