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1.
Heart Fail Clin ; 20(3): 333-341, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38844304

ABSTRACT

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the myocardial extracellular deposition of amyloid fibrils formed from the dissociation of TTR tetramer into monomers. The rate-limiting step in TTR amyloidogenesis is the dissociation of the TTR tetramer into monomers: Tafamidis is an effective TTR-stabilizer in its native homotetrameric structure. Tafamidis is a safe and effective drug in reducing symptoms, hospitalization and mortality in accurately selected patients affected by hereditary and wild-type transthyretin amyloid cardiomyopathy.


Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Cardiomyopathies , Humans , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/complications , Amyloid Neuropathies, Familial/genetics , Cardiomyopathies/drug therapy , Cardiomyopathies/metabolism , Prealbumin/genetics , Prealbumin/metabolism
2.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2355-2363, 2024 May.
Article in Chinese | MEDLINE | ID: mdl-38812136

ABSTRACT

This study explored the effects of 4-hydroxy-2(3H)-benzoxazolone(HBOA) on the proliferation and apoptosis of pancreatic cancer cells and its molecular mechanism. The L3.6 cells cultured in vitro were treated with HBOA of 0-1.0 mmol·L~(-1). The cell viability was detected by the cell counting kit-8(CCK-8) method, and the half inhibitory concentration(IC_(50)) was analyzed to determine the drug concentration and time. The cell morphology was observed under an inverted microscope and by acridine orange(AO) staining. The ability of proliferation and self-renewal were evaluated through live cell counting and colony formation experiments. The cell cycle progression and cell apoptosis rate were detected by flow cytometry. The morphology of cell apoptosis was observed by scanning electron microscopy. The mRNA expression of proliferating cell nuclear antigen(PCNA), cyclinA1, cyclinA2, cyclin dependent kinase 2(CDK2), and cyclin dependent kinase inhibitor 1A(P21) were determined by qPCR. The level of reactive oxygen species(ROS), lipid peroxide, and mitochondrial membrane potential were measured by flow cytometry. The activity of protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway was detected by Western blot. Compared with the control group, the cells treated with HBOA exhibited a significant decrease in viability. Then the optimal concentration and intervention time of HBOA were determined to be 0.4 mmol·L~(-1), 0.6 mmol·L~(-1), and 48 h. Compared with the control group, groups with HBOA of 0.4 mmol·L~(-1 )and 0.6 mmol·L~(-1) showed a significant suppression in cell proliferation and colony formation ability, down-regulated mRNA of PCNA, cyclinA1, cyclinA2, and CDK2, up-regulated P21 mRNA, S-phase cell cycle arrest, and increased cell apoptosis rate. There was an appearance of apoptotic bodies, increased ROS and lipid peroxide, decreased mitochondrial membrane potential(with a significant decrease in 0.6 mmol·L~(-1) group), and down-regulated p-Akt and p-mTOR proteins. The results show that HBOA inhibits the proliferation of pancreatic cancer L3.6 cells and induces cell apoptosis, which may be related to the increase in reactive oxygen species and the inhibition of the Akt/mTOR pathway.


Subject(s)
Apoptosis , Cell Proliferation , Pancreatic Neoplasms , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Cell Proliferation/drug effects , Apoptosis/drug effects , Humans , Cell Line, Tumor , Benzoxazoles/pharmacology , Proliferating Cell Nuclear Antigen/genetics , Proliferating Cell Nuclear Antigen/metabolism , Cell Cycle/drug effects , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 2/metabolism , Cell Survival/drug effects , Reactive Oxygen Species/metabolism
3.
Bioorg Chem ; 148: 107426, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38733750

ABSTRACT

Taking advantage of key interactions between sulfoxide and heme cofactor, we used the sulfoxide as the anchor functional group to develop two series of indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitors: 2-benzylsulfinylbenzoxazoles (series 1) and 2-phenylsulfinylbenzoxazoles (series 2). In vitro enzymatic screening shows that both series can inhibit the activity of IDO1 in low micromolar (series 1) or nanomolar (series 2) levels. They also show inhibitory selectivity between IDO1 and tryptophan 2, 3-dioxygenase 2. Interestingly, although series 1 is less potent IDO1 inhibitors of these two series, it exhibited stronger inhibitory activity toward kynurenine production in interferon-γ stimulated BxPC-3 cells. Enzyme kinetics and binding studies demonstrated that 2-sulfinylbenzoxazoles are non-competitive inhibitors of tryptophan, and they interact with the ferrous form of heme. These results demonstrated 2-sulfinylbenzoxazoles as type II IDO1 inhibitors. Furthermore, molecular docking studies supports the sulfoxide being of the key functional group that interacts with the heme cofactor. Compound 22 (series 1) can inhibit NO production in a concentration dependent manner in lipopolysaccharides (LPS) stimulated RAW264.7 cells, and can relieve pulmonary edema and lung injury in LPS induced mouse acute lung injury models.


Subject(s)
Enzyme Inhibitors , Heme , Indoleamine-Pyrrole 2,3,-Dioxygenase , Animals , Humans , Mice , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Heme/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Benzoxazoles/pharmacology
4.
Chem Biodivers ; 21(5): e202400031, 2024 May.
Article in English | MEDLINE | ID: mdl-38448389

ABSTRACT

Ulcerative colitis has been widely concerned for its persistent upward trend, and the sustained overproduction of pro-inflammatory cytokines such as IL-6 remains a crucial factor in the development of UC. Therefore, the identification of new effective drugs to block inflammatory responses is an urgent and viable therapeutic strategy for UC. In our research, twenty-three 6-acylamino/sulfonamido benzoxazolone derivatives were synthesized, characterized, and evaluated for anti-inflammatory activity against NO and IL-6 production in LPS-induced RAW264.7 cells. The results demonstrated that most of the target compounds were capable of reducing the overexpression of NO and IL-6 to a certain degree. For the most active compounds 3i, 3j and 3 l, the inhibitory activities were superior or equivalent to those of the positive drug celecoxib with a dose-dependent relationship. Furthermore, animal experiments revealed that active derivatives 3i, 3j and 3 l exhibited definitive therapeutical effect on DSS induced ulcerative colitis in mice by mitigating weight loss and DAI score while decreasing levels of pro-inflammatory cytokines such as IL-6 and IFN-γ, simultaneously increasing production of anti-inflammatory cytokines IL-10. In addition, compounds 3i, 3j and 3 l could also inhibit the oxidative stress to alleviate ulcerative colitis by decreasing MDA and MPO levels. These finding demonstrated that compounds 3i, 3j and 3 l hold significant potential as novel therapeutic agents for ulcerative colitis.


Subject(s)
Benzoxazoles , Colitis, Ulcerative , Interleukin-6 , Animals , Colitis, Ulcerative/drug therapy , Mice , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Benzoxazoles/chemical synthesis , RAW 264.7 Cells , Structure-Activity Relationship , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/metabolism , Nitric Oxide/biosynthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Dextran Sulfate , Drug Discovery , Molecular Structure , Dose-Response Relationship, Drug
5.
Heart Vessels ; 39(6): 486-495, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38393377

ABSTRACT

This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.


Subject(s)
Benzoxazoles , Butyrates , Coronary Artery Disease , Cross-Over Studies , Hypertriglyceridemia , Insulin Resistance , Metabolic Syndrome , Humans , Male , Metabolic Syndrome/blood , Metabolic Syndrome/drug therapy , Metabolic Syndrome/complications , Metabolic Syndrome/diagnosis , Hypertriglyceridemia/blood , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/complications , Hypertriglyceridemia/diagnosis , Middle Aged , Coronary Artery Disease/blood , Coronary Artery Disease/drug therapy , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Butyrates/therapeutic use , Butyrates/pharmacology , Treatment Outcome , Aged , Triglycerides/blood , Hypolipidemic Agents/therapeutic use , Hypolipidemic Agents/pharmacology , Biomarkers/blood , PPAR alpha/agonists , Bezafibrate/therapeutic use , Bezafibrate/pharmacology
6.
Diabetes Metab J ; 48(3): 473-481, 2024 May.
Article in English | MEDLINE | ID: mdl-38419467

ABSTRACT

BACKGRUOUND: Fibrates have renal toxicity limiting their use in subjects with chronic kidney disease (CKD). However, pemafibrate has fewer toxic effects on renal function. In the present analysis, we evaluated the effects of pemafibrate on the renal function of diabetic subjects with or without CKD in a real-world clinical setting. METHODS: We performed a sub-analysis of data collected during a multi-center, prospective, observational study of the effects of pemafibrate on lipid metabolism in subjects with type 2 diabetes mellitus complicated by hypertriglyceridemia (the PARM-T2D study). The participants were allocated to add pemafibrate to their existing regimen (ADD-ON), switch from their existing fibrate to pemafibrate (SWITCH), or continue conventional therapy (CTRL). The changes in estimated glomerular filtration rate (eGFR) over 52 weeks were compared among these groups as well as among subgroups created according to CKD status. RESULTS: Data for 520 participants (ADD-ON, n=166; SWITCH, n=96; CTRL, n=258) were analyzed. Of them, 56.7% had CKD. The eGFR increased only in the SWITCH group, and this trend was also present in the CKD subgroup (P<0.001). On the other hand, eGFR was not affected by switching in participants with severe renal dysfunction (G3b or G4) and/or macroalbuminuria. Multivariate analysis showed that being older and a switch from fenofibrate were associated with elevation in eGFR (both P<0.05). CONCLUSION: A switch to pemafibrate may be associated with an elevation in eGFR, but to a lesser extent in patients with poor renal function.


Subject(s)
Butyrates , Diabetes Mellitus, Type 2 , Glomerular Filtration Rate , Hypolipidemic Agents , Renal Insufficiency, Chronic , Humans , Male , Female , Middle Aged , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/complications , Glomerular Filtration Rate/drug effects , Aged , Prospective Studies , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Hypolipidemic Agents/therapeutic use , Butyrates/therapeutic use , Butyrates/pharmacology , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/complications , Diabetic Nephropathies/drug therapy , Kidney/drug effects , Kidney/physiopathology
7.
Kurume Med J ; 69(3.4): 167-174, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38233183

ABSTRACT

OBJECTIVE: Oxidative damage is observed in the ischemic limbs of patients with arteriosclerosis obliterans. We investigated whether pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, reduced oxidative stress in ischemic limbs and consequently rescued limb damage in model mice. MATERIALS AND METHODS: We surgically induced hind-limb ischemia in mice and orally administered pemafibrate solution (P-05 group, 0.5 mg/kg/day; P-10 group, 1.0 mg/kg/day) or control solution (control group). Seven days after the surgery, differences in reactive oxygen species (ROS) contents, antioxidative enzyme and transcription factor expression, blood flow, and capillary density in ischemic limbs were assessed. RESULTS: Tissue ROS levels were lower in the P-05 and P-10 groups compared with those in the control group. Although the tissue expression levels of nuclear factor-erythroid 2-related factor 2 increased in the P-10 group compared with that in the control group, no corresponding changes were observed in the tissue expression of four antioxidative enzymes. The limb salvage rates and capillary densities in ischemic limbs were higher in the P-05 and P-10 groups than that in the control group. CONCLUSION: Pemafibrate treatment reduced oxidative stress and augmented angiogenesis in ischemic limbs, contributing to prevention of limb damage in mice.


Subject(s)
Benzoxazoles , Butyrates , Disease Models, Animal , Hindlimb , Ischemia , Neovascularization, Physiologic , Oxidative Stress , Reactive Oxygen Species , Animals , Oxidative Stress/drug effects , Benzoxazoles/pharmacology , Benzoxazoles/therapeutic use , Ischemia/drug therapy , Ischemia/metabolism , Neovascularization, Physiologic/drug effects , Male , Hindlimb/blood supply , Reactive Oxygen Species/metabolism , Butyrates/pharmacology , Butyrates/therapeutic use , Mice , Antioxidants/pharmacology , NF-E2-Related Factor 2/metabolism , Regional Blood Flow/drug effects , PPAR alpha/metabolism , Limb Salvage , Angiogenesis
8.
Behav Brain Res ; 459: 114772, 2024 02 29.
Article in English | MEDLINE | ID: mdl-37995966

ABSTRACT

Previous studies have shown that stressful stimuli induced an adaptive response of reduced nociception, known as stress-induced analgesia (SIA). Since orexin neuropeptides are involved in pain modulation, and orexin neurons, primarily located in the lateral hypothalamus (LH), project to various hippocampal regions, such as the dentate gyrus (DG), the current study aimed to examine the role of orexin receptors within the DG region in the restraint SIA in the animal model of chronic pain. One hundred-thirty adult male Wistar rats (230-250 g) were unilaterally implanted with a cannula above the DG region. Animals were given SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol, 0.5 µl/rat) into the DG region as orexin-1 receptor (OX1r) and orexin-2 receptor (OX2r) antagonists, respectively, five min before exposure to a 3-hour restraint stress (RS) period. Animals were then undergone the formalin test to assess pain-related behaviors as the animal model of chronic pain. The results showed that RS produces an analgesic response during the early and late phases of the formalin test. However, intra-DG microinjection of OX1r and OX2r antagonists attenuated the restraint SIA. OX2r antagonist was more potent than OX1r antagonist in the early phase of the formalin test, while OX1r antagonist was little more effective in the late phase. Predominantly, it could be concluded that the orexinergic system in the DG region might act as a potential endogenous pain control system and a novel target for treating stress-related disorders.


Subject(s)
Analgesia , Chronic Pain , Rats , Male , Animals , Orexin Receptors/metabolism , Orexins/pharmacology , Rats, Wistar , Carbachol/pharmacology , Hippocampus/metabolism , Dentate Gyrus/metabolism , Models, Animal , Orexin Receptor Antagonists/pharmacology , Urea/pharmacology , Benzoxazoles/pharmacology , Naphthyridines/pharmacology
9.
Chem Biodivers ; 20(12): e202301491, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37916892

ABSTRACT

To discover more effective antifungal candidates, 33 benzoxazole derivatives, were designed, synthesized, and evaluated for their antifungal activity against seven phytopathogenic fungi by the mycelium growth rate method. Among 33 benzoxazole derivatives had thirteen derivatives no reported, and new derivatives C17 exhibited good inhibitory activity against Phomopsis sp. with EC50 values of 3.26 µM. Structure-activity relationship (SAR) of these derivatives analysis indicated that the substituent played a key role in antifungal activity in ortho-, meta- and para- substituted acetophenones. The preliminary mechanistic exploration demonstrated that C17 might exert its antifungal activity by targeting the mycelia cell membrane, which was verified by the observed changes in mycelial morphology, the formation of extracellular polysaccharides, cellular contents, cell membrane permeability and integrity, among other effects. Furthermore, C17 had potent curative effect against Phomopsis sp. in vivo, which indicated that C17 may be as a novelty potent antifungal agent.


Subject(s)
Antifungal Agents , Fungi , Antifungal Agents/pharmacology , Structure-Activity Relationship , Benzoxazoles/pharmacology
10.
Z Naturforsch C J Biosci ; 78(11-12): 433-440, 2023 Nov 27.
Article in English | MEDLINE | ID: mdl-37903727

ABSTRACT

A series of new benzoxazole-hydrazone and benzoxazole-1,3,4-oxadiazole derivatives have been designed, synthesized and evaluated as cytotoxic agents toward human A549 lung cancer cells. Compounds 3d, 3e, 5b, 5c, 5d and 5e were the most potent compounds with IC50 values of <3.9, 10.33, 11.6, 5.00, <3.9 and 4.5 µg/mL, respectively, which are higher than reference drug cisplatin (IC50 = 19.00 µg/mL). The flow cytometry-based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. All tested compounds induced apoptosis in A549 cell line.


Subject(s)
Antineoplastic Agents , Lung Neoplasms , Humans , Benzoxazoles/pharmacology , Benzoxazoles/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Cisplatin/pharmacology , A549 Cells , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Cell Proliferation , Apoptosis , Cell Line, Tumor , Molecular Structure
11.
ChemMedChem ; 18(22): e202300352, 2023 11 16.
Article in English | MEDLINE | ID: mdl-37727903

ABSTRACT

The efficient synthesis of novel estradiol-based A-ring-fused oxazole derivatives, which can be considered as benzoxazole-steroid domain-integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2-aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection-based t-distributed stochastic neighbor embedding (t-SNE), the novel molecules were proved to represent a new chemical space among steroid drugs. They were characterized based on critical physicochemical parameters using in silico and experimental data. The performance of the compounds to inhibit cell proliferation was tested on four human cancer cell lines and non-cancerous cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency (LLE) values, cancer cell selectivity, and apoptosis-triggering features. Pharmacological tests and LLE metric revealed that some derivatives, especially the 2-(4-ethylpiperazin-1-yl)oxazole derivative exhibit strong anticancer activity and trigger the apoptosis of cancer cells with relatively low promiscuity risk similarly to the structurally most closely-related and intensively studied anticancer agent, 2-methoxy-estradiol.


Subject(s)
Antineoplastic Agents , Estradiol , Humans , Structure-Activity Relationship , Estradiol/pharmacology , Benzoxazoles/pharmacology , Drug Screening Assays, Antitumor , Antineoplastic Agents/chemistry , Oxazoles/pharmacology , Cell Proliferation , Molecular Structure , Cell Line, Tumor
12.
J Enzyme Inhib Med Chem ; 38(1): 2251712, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37664987

ABSTRACT

A series of pleuromutilin analogs containing substituted benzoxazole were designed, synthesised, and assessed for their antibacterial activity both in vivo and in vitro. The MIC of the synthesised derivatives was initially assessed using the broth dilution method against four strains of Staphylococcus aureus (MRSA ATCC 43300, S. aureus ATCC 29213, clinical isolation of S. aureus AD3 and S. aureus 144). Most of the synthesised derivatives displayed prominent in vitro activity (MIC ≤ 0.5 µg/mL). Compounds 50 and 57 exhibited the most effective antibacterial effect against MRSA (MIC = 0.125 µg/mL). Furthermore, the time-kill curves showed that compounds 50 and 57 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 50 was evaluated further using a murine thigh model infected with MRSA (-1.24 log10CFU/mL). Compound 50 exhibited superior antibacterial efficacy to tiamulin. It was also found that compound 50 did not display significant inhibitory effect on the proliferation of RAW 264.7 cells. Molecular docking study revealed that compound 50 can effectively bind to the active site of the 50S ribosome (the binding free energy -7.50 kcal/mol).


Subject(s)
Anti-Bacterial Agents , Staphylococcus aureus , Animals , Mice , Molecular Docking Simulation , Anti-Bacterial Agents/pharmacology , Benzoxazoles/pharmacology , Pleuromutilins
13.
Int J Mol Sci ; 24(13)2023 Jun 28.
Article in English | MEDLINE | ID: mdl-37445983

ABSTRACT

Benzoxazole and benzothiazole have a broad spectrum of agricultural biological activities, such as antibacterial, antiviral, and herbicidal activities, which are important fused heterocyclic scaffold structures in agrochemical discovery. In recent years, great progress has been made in the research of benzoxazoles and benzothiazoles, especially in the development of herbicides and insecticides. With the widespread use of benzoxazoles and benzothiazoles, there may be more new products containing benzoxazoles and benzothiazoles in the future. We systematically reviewed the application of benzoxazoles and benzothiazoles in discovering new agrochemicals in the past two decades and summarized the antibacterial, fungicidal, antiviral, herbicidal, and insecticidal activities of the active compounds. We also discussed the structural-activity relationship and mechanism of the active compounds. This work aims to provide inspiration and ideas for the discovery of new agrochemicals based on benzoxazole and benzothiazole.


Subject(s)
Agrochemicals , Benzoxazoles , Benzoxazoles/pharmacology , Benzoxazoles/chemistry , Benzothiazoles/chemistry , Anti-Bacterial Agents , Structure-Activity Relationship
15.
J Org Chem ; 88(13): 9469-9474, 2023 07 07.
Article in English | MEDLINE | ID: mdl-37276434

ABSTRACT

The metal-free cascade transformation of geldanamycin benzoquinone core is proposed at relatively mild conditions. This approach yields new benzoxazole ansamycin antibiotics and enables their functionalization in an atom-economic manner, irrespective of the type of amine used. The analysis of the heterocyclization course reveals the dependence of its rate on the nature of the para-substituent within the benzylamine moiety (EDG/EWG) and the strength of the base. The reduction of the ansamycin core enables an increase in anticancer potency and selectivity.


Subject(s)
Benzoxazoles , Rifabutin , Lactams, Macrocyclic/pharmacology , Benzoxazoles/pharmacology , Benzoquinones
16.
Arch Pharm (Weinheim) ; 356(9): e2300097, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37379240

ABSTRACT

Eleven novel benzoxazole/benzothiazole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3, and MCF-7 cells. Generally, the open analogs with semicarbazide and thiosemicarbazide moieties (10, 13a-c, 14, and 17a,b) exhibited higher cytotoxic activities than derivatives with closed glutarimide moiety (8a-d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, and 4.71 µM against HepG-2, HCT-116, PC3, and MCF-7, respectively) and 14 (IC50 = 7.93, 8.23, 12.37, and 5.43 µM, respectively) exhibited the highest anticancer activities against the four tested cell lines. The most active compounds 13a and 14 were further evaluated for their in vitro immunomodulatory activities on tumor necrosis factor-alpha (TNF-α), caspase-8 (CASP8), vascular endothelial growth factor (VEGF), and nuclear factor kappa-B p65 (NF-κB p65) in HCT-116 cells. Compounds 13a and 14 showed a remarkable and significant reduction in TNF-α. Furthermore, they showed significant elevation in CASP8 levels. Also, they significantly inhibited VEGF. In addition, compound 13a showed significant decreases in the level of NF-κB p65 while compound 14 demonstrated an insignificant decrease with respect to thalidomide. Moreover, our derivatives exhibited good in silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.


Subject(s)
Antineoplastic Agents , Immunomodulating Agents , Humans , Molecular Structure , Structure-Activity Relationship , Vascular Endothelial Growth Factor A/pharmacology , Thalidomide/pharmacology , Benzoxazoles/pharmacology , NF-kappa B , Tumor Necrosis Factor-alpha , Cell Proliferation , MCF-7 Cells , Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Cell Line, Tumor , Drug Design
17.
Eur J Pharmacol ; 950: 175763, 2023 Jul 05.
Article in English | MEDLINE | ID: mdl-37146705

ABSTRACT

Orexin is a neuromodulatory peptide produced by lateral hypothalamic orexin neurons and binds to G-protein-coupled orexin-1 receptor and orexin-2 receptors. Whether orexin modulates learning and memory is not fully understood. Orexin has biphasic effects on learning and memory: promoting learning and memory at homeostatic levels and inhibiting at supra- and sub-homeostatic levels. Hippocampal sharp wave-ripples encode memory information and are essential for memory consolidation and retrieval. The role of orexin on sharp wave-ripples in hippocampal CA1 remains unknown. Here, we used multi-electrode array recordings in acute ex vivo hippocampal slices to determine the effects of orexin receptor antagonists on sharp wave-ripples. Bath-application of either the orexin-1 receptor antagonist N-(2-Methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB-334867) or the orexin-2 receptor antagonist N-Ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA) reduced sharp wave and ripple incidence, sharp wave amplitude, and sharp wave duration. SB-334867 and EMPA effects on sharp wave amplitude and duration were equivalent, whereas EMPA exhibited a greater reduction of sharp wave and ripple incidence. EMPA also increased ripple duration, whereas SB-334867 had no effect. Inhibition of both orexin receptors with a dual orexin receptor antagonist N-[1,1'-Biphenyl]-2-yl-1-[2-[(1-methyl-1H-benzimidazol-2-yl)thio]acetyl-2-pyrrolidinedicarboxamide (TCS-1102) had effects similar to EMPA, however, sharp wave amplitude and duration were unaffected. Region-specific expression of orexin receptors suggests orexin may regulate sharp wave generation in CA3, dentate gyrus-mediated sharp wave modification, sharp wave propagation to CA1, and local ripple emergence in CA1. Our study indicates an orexin contribution to hippocampal sharp wave-ripple complexes and suggests a mechanism by which sub-homeostatic concentrations of orexin may inhibit learning and memory function.


Subject(s)
Benzoxazoles , Hippocampus , Orexin Receptors , Orexins/pharmacology , Benzoxazoles/pharmacology , Receptors, G-Protein-Coupled
18.
Chem Biodivers ; 20(6): e202201145, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37080925

ABSTRACT

Myeloid differentiation protein 2 (MD2), a key TLR4 adaptor protein for sensing LPS, plays an important role in inflammatory process and has been identified as a promising target for the treatment of a variety of inflammatory diseases. In our study, a series of benzoxazolone derivatives were synthesized, characterized and tested for anti-inflammatory activity in vitro. The compounds 3c, 3d and 3g demonstrated the greatest anti-inflammatory activity against IL-6 with IC50 values of 10.14±0.08, 5.43±0.51 and 5.09±0.88 µM, respectively. Furthermore, the bis-ANS displacement assay revealed that these compounds competitively inhibited the binding between the probe bis-ANS and the MD2 protein. The most active compound 3g, revealed a directly bind with MD2 protein via Arg90 binding and a dissociation constant value of 1.52×10-6  mol L-1 as determined by the biological layer interference (BLI) assay. Our finding suggested that compounds 3g could be a promising lead compound as MD2 inhibitor for further anti-inflammatory agent development.


Subject(s)
Anti-Inflammatory Agents , Benzoxazoles , Anti-Inflammatory Agents/chemistry , Anilino Naphthalenesulfonates , Benzoxazoles/pharmacology , Benzoxazoles/chemistry , Lipopolysaccharides/pharmacology
19.
Int J Mol Sci ; 24(4)2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36835453

ABSTRACT

The large Amino Acid Transporter 1 (LAT1) is an interesting target in drug discovery since this transporter is overexpressed in several human cancers. Furthermore, due to its location in the blood-brain barrier (BBB), LAT1 is interesting for delivering pro-drugs to the brain. In this work, we focused on defining the transport cycle of LAT1 using an in silico approach. So far, studies of the interaction of LAT1 with substrates and inhibitors have not considered that the transporter must undergo at least four different conformations to complete the transport cycle. We built outward-open and inward-occluded conformations of LAT1 using an optimized homology modelling procedure. We used these 3D models and the cryo-EM structures in outward-occluded and inward-open conformations to define the substrate/protein interaction during the transport cycle. We found that the binding scores for the substrate depend on the conformation, with the occluded states as the crucial steps affecting the substrate affinity. Finally, we analyzed the interaction of JPH203, a high-affinity inhibitor of LAT1. The results indicate that conformational states must be considered for in silico analyses and early-stage drug discovery. The two built models, together with the available cryo-EM 3D structures, provide important information on the LAT1 transport cycle, which could be used to speed up the identification of potential inhibitors through in silico screening.


Subject(s)
Benzoxazoles , Large Neutral Amino Acid-Transporter 1 , Tyrosine , Humans , Biological Transport , Blood-Brain Barrier/metabolism , Brain/metabolism , Large Neutral Amino Acid-Transporter 1/metabolism , Neoplasms/metabolism , Tyrosine/chemistry , Tyrosine/pharmacology , Benzoxazoles/chemistry , Benzoxazoles/pharmacology
20.
Bioorg Chem ; 134: 106437, 2023 05.
Article in English | MEDLINE | ID: mdl-36842320

ABSTRACT

Novel series of benzoxazole-appended piperidine derivatives were planned, synthesized and screened against two breast cancer cell lines. Considerable antiproliferative activity was observed for screened compounds (IC50 = 33.32 ± 0.2 µM to 7.31 ± 0.43 µM and 1.66 ± 0.08 µM to 12.10 ± 0.57 µM) against MCF-7 and MDA-MB-231 cell lines respectively being more potent than doxorubicin (IC50 = 8.20 ± 0.39 µM and 13.34 ± 0.63 µM respectively). Active compounds were submitted for enzyme inhibition assays when 4d and 7h demonstrated potent EGFR inhibition (0.08 ± 0.002 µM and 0.09 ± 0.002 µM respectively) compared to erlotinib (0.11 ± 0.003 µM). However, no one compound displayed effective ARO inhibition activity as tested compounds were less active than letrozole. Apoptosis inducing ability results implied that apoptosis was provoked by significant stimulation of caspase-9 protein levels (4.25-7.04-fold) upon treatment of MCF-7 cells with 4a, 7h, 9, 12e and 12f. Alternatively, MDA-MB-231 cells treated with 4d, 7a, 12b and 12c considerably increased caspase-9 levels (2.32-4.06-fold). Cell cycle arrest and annexin-V/Propidium iodide assays further confirmed apoptosis when tested compounds arrested cell cycle at various phases and demonstrated high annexin V binding affinity. Docking outcomes proved valuable binding affinities for compounds 4d and 7h to EGFR enzyme while compounds 4a and 12e, upon docking into the active site of ARO, failed to interact with heme, suggesting their inabilities to act as AIs. Therefore, these benzoxazoles can act as promising candidates exhibiting EGFR inhibition and apoptosis-promoting properties.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Humans , Female , Structure-Activity Relationship , Molecular Structure , Caspase 9 , Cell Line, Tumor , Breast Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Benzoxazoles/pharmacology , Benzoxazoles/chemistry , ErbB Receptors , Cell Proliferation , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Apoptosis
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