Compound D3 Research Articles

Design, synthesis, and in vivo and in vitro biological screening of pseudolaric acid B derivatives as potential anti-tumor agents

Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 μM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 μM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.

Design, synthesis, and evaluation of PD-1/PD-L1 small-molecule inhibitors bearing a rigid indane scaffold

Discovery of small-molecule inhibitors against programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis provides a promising alternative to overcome the inevitable defects of PD-1/PD-L1 monoclonal antibodies (mAbs). Here, we report a series of indanes as novel small-molecule inhibitors of PD-1/PD-L1 interaction. Thirty-one indanes were synthesized and the structure−activity relationships (SARs) demonstrated that conformational restriction with (S)-indane is superior in potency to inhibit the interaction of PD-1 and PD-L1. Compound D3 was found to be the most potent inhibitor with an IC50 value of 2.2 nM against PD-1/PD-L1 interaction. Cell-based assay showed that D3 significantly induced immune activity of peripheral blood mononuclear cells (PBMCs) against MDA-MB-231 cells and could restore the immune function of T cells by promoting secretion of the IFN-γ. The above results indicate that compound D3 is a promising PD-1/PD-L1 inhibitor that deserves further development.

Novel Benzothiazole Derivatives as Potential Anti-Quorum Sensing Agents for Managing Plant Bacterial Diseases: Synthesis, Antibacterial Activity Assessment, and SAR Study

As quorum sensing (QS) regulates bacterial pathogenicity, antiquorum sensing agents have powerful application potential for controlling bacterial infections and overcoming pesticide/drug resistance. Identifying anti-QS agents thus represents a promising approach in agrochemical development. In this study, the anti-QS potency of 53 newly prepared benzothiazole derivatives containing an isopropanolamine moiety was analyzed, and structure-activity relationships were examined. Compound D3 exhibited the strongest antibacterial activity, with an in vitro EC50 of 1.54 μg mL-1 against Xanthomonas oryzae pv oryzae (Xoo). Compound D3 suppressed QS-regulated virulence factors (e.g., biofilm, extracellular polysaccharides, extracellular enzymes, and flagella) to inhibit bacterial infection. In vivo anti-Xoo assays indicated good control efficiency (curative activity, 47.8%; protective activity, 48.7%) at 200 μg mL-1. Greater control efficiency was achieved with addition of 0.1% organic silicone or orange peel essential oil. The remarkable anti-QS potency of these benzothiazole derivatives could facilitate further novel bactericidal compound development.

Ion exchange pattern-based 18β-glycyrrhetinic acid containing pyridinium salts derivatives as novel antibacterial agents with low toxicity

Studies in the past few years have shown that simple salts, such as pyridinium salts and imidazole salts, have excellent antibacterial activity. However, their application in drugs and agrichemicals development has been limited due to their high toxicity. In this study, we found that synthesized target compounds with pyridinium salt unit A1 and B6 displayed excellent anti-Xac (Xanthomonas. axonopodis pv. citri) and Xoo (Xanthomonas oryzae pv. oryzae) activity, with EC50 values of 7.67 μg/mL and 1.37 μg/mL, respectively. On searching for a toxicity reduction strategy, an ion exchange method was adopted to obtain a new type of various organic acid-decorated pyridinium salt derivatives containing with glycyrrhetinic acid framework, and their structure was characterized by FTIR and 1H NMR. Furthermore, bioassays and toxicity tests were used to show that these organic acid-exchanged compounds not only exhibited lower toxicity to plants but also had excellent antibacterial activity towards virulent phytopathogenic bacteria, especially compound D3, which provided an EC50 of 1.60 μg/mL toward Xoo. Subsequently, the pot experiments determined that compound D3 exhibited suitable protective and curative activities for the management of rice bacterial leaf blight at 200 μg/mL, with control efficacies of 54.09% and 38.50%, respectively. In addition, studies evaluating potential antibacterial mechanisms suggested that apoptosis was responsible for the antibacterial behavior of the target compounds. Overall, this study proved that the ion exchange method was a feasible strategy to reduce the toxicity of pyridinium salts and was promising for use in the development of novel antimicrobial agents.

1,2,4-Triazole and benzimidazole fused dihydropyrimidine derivatives: Design, green synthesis, antibacterial, antitubercular, and antimalarial activities.

This study reports the design and synthesis of novel 1,2,4-triazolo/benzimidazolo-pyrimidine linked 1-benzyl-4-[(p-tolyloxy)methyl]-1,2,3-triazole derivatives as potent antimicrobial agents according to their in vitro antibacterial, antifungal, antitubercular as well as antimalarial activities. An efficient, ecologically benign, and facile multicomponent synthesis wasemployed to synthesize these derivatives. The synthesis is accelerated with the mild and eco-friendly organocatalyst tetrabutylammonium bromide, providing a yield of 82%-96% within the short reaction time of 0.5-1.5 h. Compared with the MIC values of ciprofloxacin and ampicillin on the respective strains, compound d2 showed better activity against Escherichia coli and Streptococcus pyogenes and compound d8 showed better MIC against Staphylococcus aureus. Additionally, compounds d3, d4, and d5 showed potent MIC values against Pseudomonas aeruginosa. All triazolo-pyrimidine derivatives d1-d8 showed potent inhibitory action against Gram-positive strains. Compound e3 showed good potency against Mycobacterium tuberculosis H37Rv. The IC50 values of d3 and e2 indicated better activity against Plasmodium falciparum. Collectively, these derivatives depict potent multifaceted activity and provide promising access for further antimicrobial and antimalarial investigations.

Design, synthesis, and bioactivity study on Lissodendrins B derivatives as PARP1 inhibitor

Poly(ADP-ribose) polymerase-1 (PARP1) is an enzyme that catalyzes the polymerization of ADP-ribose units to target proteins, and it is a potential target for anti-cancer drug discovery, especially for BRAC1/2 mutated tumors. In this study, a series of 2-aminoimidazole Lissodendrins B derivatives were designed, synthesized, and evaluated as PARP1 inhibitors. We found that compound D3 is better due to its PARP enzyme inhibitory activity and in vitro anti-cancer activity compared with other tested compounds. It could inhibit PARP1 enzymatic activity (IC50 = 17.46 µM) in the non-cell system and BRCA1-deficient HCC1937 and MDA-MB-436 cells growth (IC50 = 17.81 and 12.63 µM, respectively). Further study demonstrated that compound D3 inhibits tumor growth through multiple mechanisms, such as reduction of PARylation, accumulation of cellular DNA double-strand breaks, induction of G2/M cell cycle arrest, and subsequent apoptosis of BRCA1-deficient cells. Besides, the molecular docking study also confirmed that compound D3 could effectively occupy the active pocket of PARP1. Our findings provide a new skeleton structure for PARP1 inhibitor, and the results suggested that the compound D3 may serve as a potential lead compound to develop novel PARP1 inhibitors for cancer therapy.

Design, synthesis, and bioactivity of ferulic acid derivatives containing an β-amino alcohol

BackgroundPlant diseases caused by viruses and bacteria cause huge economic losses due to the lack of effective control agents. New potential pesticides can be discovered through biomimetic synthesis and structural modification of natural products. A series of ferulic acid derivatives containing an β-amino alcohol were designed and synthesized, and their biological activities were evaluated.ResultBioassays results showed that the EC50 values of compound D24 against Xanthomonas oryzae pv. oryzae (Xoo) was 14.5 μg/mL, which was better than that of bismerthiazol (BT, EC50 = 16.2 μg/mL) and thiodiazole copper (TC, EC50 = 44.5 μg/mL). The in vivo curative and protective activities of compound D24 against Xoo were 50.5% and 50.1%, respectively. The inactivation activities of compounds D2, D3 and D4 against tobacco mosaic virus (TMV) at 500 μg/mL were 89.1, 93.7 and 89.5%, respectively, superior to ningnanmycin (93.2%) and ribavirin (73.5%). In particular, the EC50 value of compound D3 was 38.1 μg/mL, and its molecular docking results showed that compound D3 had a strong affinity for TMV-CP with a binding energy of − 7.54 kcal/mol, which was superior to that of ningnanmycin (− 6.88 kcal /mol).ConclusionsThe preliminary mechanism research results indicated that compound D3 may disrupt the three-dimensional structure of the TMV coat protein, making TMV particles unable to self-assemble, which may provide potential lead compounds for the discovery of novel plant antiviral agents.Graphical

SYNTHESIS, MOLECULAR BIOINFORMATICS MODELLING, AND ANTIMICROBIAL EVALUATION OF SOME NOVEL OXADIAZOLE FLUOROQUINOLONE DERIVATIVES

Objective: The present study envisages a series of oxadiazole fluoroquinolone derivatives that were synthesized (D1–D12) with added derivatives such as phenyl, aminophenyl, amino hydroxyphenyl along with cyclopropyl, ethyl, piperazine, and imidazole. Methods: All of the newly produced molecules were characterized by infrared, 1H nuclear magnetic resonance, mass spectrometry, and elemental analysis technique and screened for docking stimulation to find out binding modes of synthesized derivatives with 3FV5, 5IMW, and 5ESE and evaluated for in vitro antimicrobial activity. Results: From this study, it was found that the compound D8 showed good antibacterial activity against Gram-positive (Staphylococcus aureus), compound D9 showed good antibacterial activity against Gram-negative (Escherichia coli), and compound D3 showed good antifungal activity against fungi (Saccharomyces cerevisiae) in comparison with standard drugs (Ciprofloxacin and fluconazole). The zone of inhibition and minimum inhibitory concentration studies was performed on synthesized compounds. Conclusion: The analogs of oxadiazole flouroquinolone are suggested to be potent inhibitors with sufficient scope for further exploration.

Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist.

Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a dominant role in inflammation, autoimmunity, and host defense. RORγt is a key transcription factor mediating T helper 17 (Th17) cell differentiation and IL-17 production, which is able to activate CD8+ T cells and elicit antitumor efficacy. A series of sulfonamide derivatives as novel RORγt inverse agonists were designed and synthesized. Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

Quantitative analysis of total methenolone in animal source food by liquid chromatography-tandem mass spectrometry.

Methenolone, an anabolic androgenic steroid, has been applied to improve the quality and protein content of meat in animal husbandry. However, the usage of methenolone in sports is banned for its doping effects. Several methods have been reported to monitor the content of methenolone in serum and urine samples, but a highly sensitive detection system has not been developed for the determination of methenolone in animal source food due to its constituent complexity. In this study, a novel detection system was developed to quantify the contents of both free and conjugated methenolone in animal source food including pork, beef, mutton, milk, and eggs by using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) coupled with delicate pretreatment procedures. The conjugated methenolone in the above food samples was released by dual enzyme digestion, and the total methenolone was extracted by 1% formic acid in acetonitrile, followed by the purification using a PRiME HLB column or QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) salt. The compound d3 -methyltestosterone was used as an internal standard to minimize matrix interference. Finally, a wide linear range (0.5-20 μg/kg), low limit of detection (LOD) (0.3 μg/kg), good precision (<7% relative standard deviation), and high recovery (>90%) were obtained in the study of method validation. In summary, this analytical method provides a practicable monitoring tool for the quantification of methenolone in animal source food.

A study of the biological activity of 4-(Para-Substituted phenyl)-1,2,3-Selenadiazole derivatives as anti-oxidant and anti-breast cancer

In present work, five ligands of substituted 1,2,3-selenadiazole have been synthesized and characterized and they tested as possible anti-oxidant and anti-breast cancer. The synthesized compounds were prepared by the reaction of selenium dioxide with a series of semicabazone derivatives in glacial acetic acid. The prepared compounds have been characterized using different methods. The biological activity of 1,2,3-selenadiazole compounds were examined against the growth of two types of bacterial strains (E.coli and staphylococcus aureus). Also this study included determined the activity of 1,2,3-selenadiazole derivatives as antioxidants, and measured their ability toward α, α-diphenyl-β-picrylhydrazyl (DPPH) free radical scavenging. It has been found that they have a good activity to reduce free radical’s effects. Inhibition of 1,2,3-selenadiazole derivatives was carried out against human breast cancer cells (MCF-7) growth by MTT , the measurements showed that the derivatives had a higher inhibition rate than the complexes , the IC50 of compounds D3 and D4 was ( 89.5 and 44.3) µg/ ml respectively

Synthesis and Biological Evaluation of (+)-Usnic Acid Derivatives as Potential Anti-Toxoplasma gondii Agents.

Six series of (+)-usnic acid derivatives were synthesized. The IC50 values of these compounds were determined in T. gondii infected HeLa cells (μM) and in HeLa cells (μM), and their selectivity indexes (SI) were calculated. In vitro, most of the derivatives tested in this study exhibited more anti activity than that of the parent compound (+)-usnic acid and the positive control drugs. Among these derivatives, methyl (E)-(1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)phenylalaninate (D3) showed the most effective anti-T. gondii activity (selectivity >2.77). In comparison with the clinically used positive control drugs sulfadiazine (selectivity 1.15), pyrimethamine (selectivity 0.89), spiramycin (selectivity 0.72), and the lead compound (+)-usnic acid (selectivity 0.96), D3 showed better results in vitro. Furthermore, D3 and (E)-6-acetyl-7,9-dihydroxy-8,9b-dimethyl-2-(1-(quinolin-6-ylamino)ethylidene)dibenzo[b,d]furan-1,3(2H,9bH)-dione (F3) had greater inhibitory effects on T. gondii (inhibition rates 76.0% and 64.6%) in vivo in comparison to spiramycin (inhibition rate 55.2%); in the peritoneal cavity of mice, the number of tachyzoites was significantly reduced (p < 0.001) in vivo. Additionally, some biochemical parameters were measured and spleen indexes were comprehensively evaluated, and the results indicated that mice treated with both compound D3 and compound F3 showed reduced hepatotoxicity and significantly enhanced antioxidative effects in comparison to the normal group. Granuloma and cyst formation were effected by the inhibition of compound D3 and compound F3 in liver sections. Overall, these results indicated that D3 and F3 for use as anti-T. gondii agents are promising lead compounds.

The A\u03b2 oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology

While amyloid-β protein (Aβ) aggregation into insoluble plaques is one of the pathological hallmarks of Alzheimer’s disease (AD), soluble oligomeric Aβ has been hypothesized to be responsible for synapse damage, neurodegeneration, learning, and memory deficits in AD. Here, we investigate the in vitro and in vivo efficacy of the d-enantiomeric peptide RD2, a rationally designed derivative of the previously described lead compound D3, which has been developed to efficiently eliminate toxic Aβ42 oligomers as a promising treatment strategy for AD. Besides the detailed in vitro characterization of RD2, we also report the results of a treatment study of APP/PS1 mice with RD2. After 28 days of treatment we observed enhancement of cognition and learning behaviour. Analysis on brain plaque load did not reveal significant changes, but a significant reduction of insoluble Aβ42. Our findings demonstrate that RD2 was significantly more efficient in Aβ oligomer elimination in vitro compared to D3. Enhanced cognition without reduction of plaque pathology in parallel suggests that synaptic malfunction due to Aβ oligomers rather than plaque pathology is decisive for disease development and progression. Thus, Aβ oligomer elimination by RD2 treatment may be also beneficial for AD patients.

Contribution of excited state absorption to optical limiting properties in multi-branched structures

A series of multi-branched compounds D1–D3 combining a triphenylamine core with one, two or three benzylidene cyclopentylidene malononitrile branches, respectively, were synthesized. The linear photophysical property, photochemical stability, thermal stability, and nonlinear absorption under 1064nm pulsed lasers with pulse durations in both nanosecond and femtosecond regimes of D1–D3 were investigated. The results showed that the main optical limiting mechanism of D1–D3 under femtosecond pulses was two-photon absorption (2PA), but their excited state absorption (ESA) became the main contributor for their optical limiting behaviors under nanosecond pulses. Meanwhile, introducing a multi-branched structure has much stronger impact on the ESA spectrum of D3 than on its linear absorption spectrum compared with the monomer D1. The largest ESA cross-section of D3 was the main contributor to its enhancement of effective 2PA in nanosecond regime. Combining with its best thermal and photochemical stability, the three-branched compound D3 was proved as a good optical limiting material for 1064nm nanosecond pulsed lasers.

Synthesis and evaluation of adenosine containing 3-arylfuran-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors

Tyrosyl-tRNA synthetase (TyrRS) is an aminoacyl-tRNA synthetase family protein that possesses an essential role in bacterial protein synthesis. The synthesis, structure-activity relationship, and evolution of a novel series of adenosine-containing 3-arylfuran-2(5H)-ones as TyrRS inhibitors are described. Advanced compound d3 from this series exhibited excellent affinity for TyrRS with IC50 of 0.61 ± 0.04 μM. Bacterial growth inhibition assays demonstrated that d3 showed submicromolar antibacterial potency against Escherichia coli and Pseudomonas aeruginosa, and compared to the marketed antibiotics ciprofloxacin.

Identification of para-Substituted Benzoic Acid Derivatives as Potent Inhibitors of the Protein Phosphatase Slingshot.

Slingshot proteins form a small group of dual-specific phosphatases that modulate cytoskeleton dynamics through dephosphorylation of cofilin and Lim kinases (LIMK). Small chemical compounds with Slingshot-inhibiting activities have therapeutic potential against cancers or infectious diseases. However, only a few Slingshot inhibitors have been investigated and reported, and their cellular activities have not been examined. In this study, we identified two rhodanine-scaffold-based para-substituted benzoic acid derivatives as competitive Slingshot inhibitors. The top compound, (Z)-4-((4-((4-oxo-2-thioxo-3-(o-tolyl)thiazolidin-5-ylidene)methyl)phenoxy)methyl)benzoic acid (D3) had an inhibition constant (Ki) of around 4 μm and displayed selectivity over a panel of other phosphatases. Moreover, compound D3 inhibited cell migration and cofilin dephosphorylation after nerve growth factor (NGF) or angiotensin II stimulation. Therefore, our newly identified Slingshot inhibitors provide a starting point for developing Slingshot-targeted therapies.

Synthesis and Herbicidal Activity ofN-Acyl-N-(m-fluoro-benzyl)-6-amino-coumarin

以N-间氟苄基-6-氨基香豆素为先导,利用活性亚结构拼接原理,设计、合成了一系列N-酰基-N-间氟苄基-6-氨基香豆素衍生物,其结构用1H NMR、ESI-MS和元素分析表征,N-三氟乙酰基取代的化合物d5结构经X-ray单晶衍射进一步确证.采用琼脂小杯法和盆栽法对合成化合物的除草活性进行了初步研究.结果表明,100 mg/L分别为N-氯乙酰基、N-溴乙酰基、N-三氟乙酰基、N-（2,4-二氯苯氧乙酰基）取代的化合物d2,d3,d5和d17对反枝苋根、茎的抑制率大于75%,优于乙草胺EC;1500 g/ha分别为N-溴乙酰基、N-（2,4-二氯苯氧乙酰基）取代的化合物d3和d17对反枝苋等双子叶杂草茎叶处理的抑制率达76%以上;同剂量化合物d17对单子叶作物小麦、玉米和水稻安全.

Synthesis and Antitumor Activity in Vitro of 5-Fluorouracil-1-alkylaxgphenyl-tetra m-Chlorophenyl Porphyrin Compounds

To search for more potential antitumor agents,five new porphyrin-5-fluorouracil compounds were designed and synthesized.The reaction conditions were optimized and the separation method of the target products was explored.The compositions and structures of these compounds were confirmed by IR,UV-Vis,1H NMR and MS.Their cytotoxicity against five human cancer cell lines in vitro was evaluated by MTT assay.Biological screening results demonstrate that some tested compounds exhibit potential antitumor activity,particularly,compound D3 shows more potential cytotoxic activities than the control 5-fluorouracil against Sk-ov-3 cells.

Distinct effects of dinuclear ruthenium(III) complexes on cell proliferation and on cell cycle regulation in human and murine tumor cell lines.

We have examined the biological and antitumor activity of a series of dinuclear ruthenium complexes. The aim of this study was to compare the in vitro effects of these new compounds on cell proliferation, cell distribution among cell cycle phases, and the expression of some proteins involved in cell cycle regulation. Results obtained show a mild cytotoxic activity against human and murine cell lines, more evident after prolonged exposure of cell challenge. Two of the eight dinuclear complexes [namely, compounds D3 (Na(2)[(RuCl(4)(dmso-S))(2)(mu-bipy)]) and D7 ([NH(4)][(RuCl(4)(dmso-S))(mu-pyz)(RuCl(3)(dmso-S)(dmso-O))]) modify cell cycle distribution similarly to imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate (NAMI-A), whereas the others have a low or negligible effect on this parameter. If we correlate the induction of cell cycle modifications with ruthenium uptake by tumor cells and with the modulation of proteins regulating cell cycle, we may stress that the induction of G(2)-M cell cycle arrest is related to the achievement of a threshold concentration of ruthenium inside the cells, which is dependent on the cell line being used, and that only cyclin B, among cell cycle regulating proteins examined by immunoblotting assays, appears to be significantly modified. This in vitro study shows that dinuclear ruthenium complexes may have a behavior similar to that of the monomer NAMI-A. These results encourage the future experimentation of their pharmacological properties in in vivo models.

Determination of low molecular weight silicones in plasma and blood of women after exposure to silicone breast implants by GC/MS.

A sensitive, one-step sample preparation method for detection of volatile, low molecular weight (LMW) cyclic silicones hexamethylcyclotrisiloxane (D3), octamethyl-cyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) in plasma and blood using gas chromatography coupled with mass spectrometry (GC/MS, SIM mode) is presented. In spiked experiments, extraction efficiencies for these siloxanes (100-20 000 ng/mL) were approximately 90% for plasma and approximately 80% for blood; only in the case of D3 was the recovery very low. Plasma and blood of women who are or were exposed to silicone gel-filled implants and of control subjects were analyzed for low molecular weight silicones. D3-D6 were not detectable in control plasma or blood. Although the investigated numbers of patients samples are very limited, and thus, no statistical analysis is possible, our data clearly show a general increase in the amount of LMW cyclic siloxanes in the bodies of women with silicone implants. In particular, several years after ruptured silicone implants were removed, siloxanes could still be found in blood samples from several women. Siloxane compound D3 varied between 6 and 12 ng/mL (plasma) and between 20 and 28 ng/mL (blood), whereas the concentration range of D4 was 14-50 ng/mL (plasma) and 79-92 ng/mL (blood). D5 and D6, with one exception, could not be detected.