Compounds 4d Research Articles

Synthesis, characterization and thrombolytic activity evaluation of novel pyrazolo[3,4-b]pyridine-4-carbohydrazide derivatives

Thrombosis, a leading cause of numerous fatalities, particularly in developed nations, accounts for thousands of deaths. The contemporary lifestyle inevitably leads to occurrences of venous thrombosis, including deep vein thrombosis and thromboembolism. This article presents a groundbreaking study where a novel series of N′-(arylmethylidene)-6-(p-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b] pyridine-4-carbohydrazide derivatives were efficiently synthesized and screened for thrombolytic activities. Compounds 4a, 4c, 4d, and 4h demonstrated the best antiplatelet activities when using different agonists such as arachidonic acid and collagen. These compounds showed >50 % activity by using agonist collagen and inhibited >50 % platelet aggregation in whole human blood. Compounds 4c and 4d showed the greatest inhibitory effect of 97.98 % and 98.97 %, respectively as compared to other synthesized compounds and aspirin. For platelet aggregation using arachidonic acid, all the synthesized compounds 4a, 4c, 4d and 4h shown >93 % inhibition than that of aspirin. In computational studies, ligands 4c(ap) and 4d(ap) exhibited potent interaction with the COX-1 active site, suggesting inhibitory potential against thrombolytic activities. Ligand 4c(ap) scored 8896 and ACE of -418.31 kcal/mol, while 4d(ap) scored 8742 and ACE of -417.43 kcal/mol. Similarly, ligands 4c(ap) and 4h(ap) displayed outstanding docking scores at the COX-2 active site, with 4c(ap) scoring 8574 (ACE:301.49 kcal/mol) and 4h(ap) scoring 8424 (ACE:276.16 kcal/mol). Synthesized compounds particularly 4c and 4d have the potential to be used for clinical trials and could be beneficial for the designing and development of novel therapeutics for cardiovascular and thromboembolic ailments.

The new pattern for dual NOTCH pathway involving nuclear transcription and mitochondrial regulation supports therapeutic mechanism of 4-butyl benzophenone derivatives against SIRS

The systemic inflammatory response syndrome (SIRS) represents a self-amplifying cascade of inflammatory reactions and pathophysiological states triggered by infectious or non-infectious factors. The identification of disease targets and differential proteins in the liver (the unique and important immune organ) of SIRS mice treated with the lead compound D1 was conducted using the Genecards database and proteomic analysis, respectively. Subsequently, NOTCH1 was identified as the potential hub target via an intersection analysis between the aforementioned differentially expressed proteins and disease targets. Based on our previous research on the structure-activity relationship, we designed and synthesized a series of SIRS-related derivatives, wherein butyl, halogen, and ester groups were incorporated into benzophenone, aiming at exploring the anti-inflammatory protective action from the perspective of macrophage polarization. Notably, these derivatives exhibited a direct binding capability to the O-glucosylation site (SER496) or its vicinities (such as SER492, VAL485) of NOTCH1 using docking, SPR, DARTS, and CETSA techniques. Mechanistically, derivative D6 exerted anti-inflammatory effects via the dual NOTCH pathway. Firstly, it could inhibit NOTCH1 nuclear transcriptional activity, attenuate the interaction between NICD and RBPJK, concurrently suppress NF-κB and NLRP3 inflammasome (NLRP3, ASC, and cleaved CASP1) activation, and promote NICD (NOTCH1 active fragments) ubiquitination metabolism (the nuclear transcriptional pathway). Secondly, it might possess the ability to increase PGC1α level, subsequently, enhance ATP and MMP levels, mitigate ROS production, increase mitochondrial numbers, and ameliorate mitochondrial inflammatory damage (the mitochondrial pathway). Importantly, the activator Jagged1 could effectively reverse the aforementioned effects, while the inhibitor DAPT exhibited a synergistic effect, suggesting that the nuclear transcriptional regulation and mitochondrial regulation were both in a NOTCH1-dependent manner. Subsequently, it effectively alleviated the inflammatory response and preserved organ function as evidenced by up-regulating M2-type macrophage-related anti-inflammatory cytokines (IL10, TGFβ, CD206, and ARG1) and down-regulating M1-type macrophage-related pro-inflammatory cytokines (NO, IL6, IL18, iNOS, TNFα, CD86, and IL1β). In a word, derivative D6 modulated macrophage polarization and effectively mitigated SIRS by targeting inhibition of the dual NOTCH pathway.

Acyl hydrazone derivatives with trifluoromethylpyridine as potential agrochemical for controlling plant diseases.

Crops are consistently under siege by a multitude of pathogens. These pathogenic microorganisms, including viruses and bacteria, result in substantial reductions in quality and yield globally by inducing detrimental crop diseases, thus posing a significant challenge to global food security. However, the biological activity sepectrumof commercially available pesticides is limitedand the pesticide efficacy is poor, necessitating the urgent development of broad-spectrum and efficient strategies for crop disease prevention and control. The bioassay results revealed that certain target compounds demonstrated outstanding in vivo antiviral efficacy against cucumber mosaic virus and tobacco mosaic virus. In particular, compound D6 showed remarkable antiviral activity against CMV, significantly higher than that of the control agent ningnanmycin. Mechanism of action studies have shown that compound D6 could enhance the activity of defense enzymes and upregulate the expression of genes related to disease resistance, thereby enhancing the antiviral effects in plants. In addition, these compounds displayed superior inhibitory activity against plant bacterial diseases. For Xoo, compound D10 showed an excellent inhibitory effect that was better than that of the control agent bismerthiazol. Scanning electron microscopy and fluorescence double-staining experiments revealed that compound D10 effectively inhibited bacterial growth by disrupting the cell membrane. A series of trifluoromethyl hydrazone derivatives were designed and synthesized, and it was found that they have control effects on plant viruses and bacterial diseases. In addition, this study revealed the mechanism of action of the active compounds and demonstrated their potential as multifunctional crop protectants. © 2024 Society of Chemical Industry.

Exploration of cytotoxicity of iodoquinazoline derivatives as inhibitors of both VEGFR-2 and EGFRT790M: Molecular docking, ADMET, design, and syntheses.

Novel inhibitors of epidermal growth factor receptor (EGFR)T790M/vascular endothelial growth factor receptor-2 (VEGFR-2) were synthesized based on the iodoquinazoline scaffold linked to different heteroaromatic, aromatic, and/or aliphatic moieties. The novel derivatives were in vitro examined for anticancer activities against A549, HCT116, michigan cancer foundation-7 (MCF-7), and HepG2 cells. Molecular modeling was applied to discover their orientation of binding with both VEGFR-2 and EGFR active sites. Compounds 8d, 8c, 6d, and 6c indicated the highest cytotoxicity with IC50 = 6.00, 6.90, 6.12 and 6.24 µM, 7.05, 7.35, 6.80, and 6.80 µM, 5.75, 7.50, 6.90, and 6.95 µM, and 6.55, 7.88, 7.44, and 7.10 µM against the A549, HepG2, HCT116, and MCF-7 cell lines, correspondingly. The cytotoxicity against normal VERO (normal african green monkey kidney cells) of the extremely active eight compounds 6a-d and 8a-d was evaluated. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 45.66-51.83 μM. Furthermore, inhibition assays for both the EGFRT790M and VEGFR-2 enzymes were done for all compounds. Remarkable inhibition of EGFRT790M activity was achieved with compounds 6d, 8d, 6c, and 8c at IC50 = 0.35, 0.42, 0.48, and 0.50 µM correspondingly. Moreover, remarkable inhibition of VEGFR-2 activity was achieved with compounds 8d, 8c, 6d, and 6c at IC50 = 0.92, 0.95, 1.00, and 1.20 µM correspondingly. As planned, derivatives 6d, 8d, 6c, and 8c presented exceptional inhibition of both EGFRT790M/VEGFR-2 activities. Finally, in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were made for the highly active four compounds 6c, 6d, 8c, and 8d in comparison with erlotinib and sorafenib as reference standards.

A Rational Approach To Antitubercular Drug Design: Molecular Docking, Prediction of ADME Properties and Evaluation of Antitubercular Activity of Novel Isonicotinamide Scaffold.

One of the most devastating and leading diseases is Tuberculosis (TB), caused by Mycobacterium tuberculosis. Even though many synthetic drugs are available in the market, to increase the therapeutic efficacy and reduce toxicity. Isoniazid is the primary drug used in the treatment of tuberculosis. The main objective of the study is to perform molecular docking studies and synthesize the derivatives of isonicotinamide along with the anti-tubercular activity. The isonicotinamide derivatives (a-j) are prepared using isoniazid, carbon disulphate, methyl cyanide, and benzaldehyde derivatives and characterized by TLC, IR, 1HNMR, and Mass spectroscopy. The enzyme decaprenylphosphoryl-D-ribose oxidase (DprE1) of M. tuberculosis had good binding capacity with all the ligands revealed in molecular docking studies. In-vitro studies indicated that all the ligands showed anti-tuberculosis with strain M. tuberculosis. The analysis was based on the binding energy and minimum inhibitory concentration (MIC). The highest and lowest binding energy is -4.22 Kcal/mol (f) and -8.45 Kcal/mol (d), and the MIC for compound d was found to be 644.22 nM. Among all the ligands, compound 5d has the most cytotoxic effect and lower IC50 values and better bioavailability. This investigation helps in the development of better anti-tubercular therapy.

Synthesis, Characterization, and Evaluation of Antioxidant Activities of 2-(1-(Substituted phenyl)ethylidene)-1-(4,6-dimethylpyrimidin-2-yl)hydrazines

Background: Pyrimidine and hydrazones are well known for their therapeutic applications. Objective: To investigate the antioxidant activities of compounds having pyrimidine and hydrazone motifs in hope of finding molecules with robust antioxidant activities. Methods: Hydrazones were obtained by condensing pyrimidine hydrazine with aromatic ketones. The structures of these compounds were established on the basis of NMR, FTIR and mass spectral data analysis. Results: All compounds were assessed for their antioxidant potential against DPPH, hydrogen peroxide, nitric oxide and superoxide free radicals. Conclusion: A series of twelve 2-(1-(substituted phenyl)ethylidene)-1-(4,6-dimethylpyrimidin-2-yl)hydrazines was synthesized and compounds 6d, 6e, 6h, and 6j found to have good antioxidant activities.

Development of novel antibiotics derived from pyridazine: Synthesis, spectroscopic characterization, in vitro antimicrobial activity and molecular docking studies

In light of the increasing antibiotic resistance, it is crucial to discover new antimicrobial medications. Pyridazines are frequently investigated in research for the development of new chemical entities with enhanced therapeutic properties. Their structure allows for significant flexibility in the attachment of various functional groups, which is essential for drug discovery.Our work focuses on synthesizing new pyridazine derivatives (7a, 7b, 7c and 7d) through coupling reactions with various amino esters. The structures of these compounds have been analyzed using spectroscopic measurements including 1H, 13C NMR, IR, and mass spectroscopy. The compounds showed positive effects against two bacterial strains: Escherichia coli: ATCC25922 and Staphylococcus aureus: CIP543154. Molecular docking results of the protein 7AZ5 indicated significant affinities with these molecules through hydrogen bonds. Compounds 7a and 7d demonstrated the highest binding energies and the best antimicrobial activity, suggesting their potential as a model for creating novel and potent antimicrobial compounds.

Design, Antimicrobial Testing, and Molecular Docking Studies of New Chalcone and Pyrimidine Derivatives based on 2-phenyl-1H-pyrazol-3(2H)-one

Background & Objectives: Heterocyclic pyrimidine and pyrazole rings have attracted the interest of medicinal chemists because of their pharmacological potential including antimicrobial activity. Based on molecular hybridization, new chalcones 6a-g and pyrimidines 7a-g based on a pyrazole scaffold were designed. Methods: The synthesis of these compounds involved mild condensation reactions between compound 4 and various aromatic aldehydes in a mixture of ethanol/NaOH (95:5 v/v) to give the corresponding chalcones 6a-g. These chalcones were further reacted with urea in the presence of a base in ethanol to produce the pyrimidine derivatives 7a-g. These new candidates were screened for their in vitro antimicrobial activities and molecular docking studies were evaluated. Results: The antibacterial and antifungal studies of all synthesized compounds against the strains tested showed that compounds 6c, d, and 7c, d exhibited the highest antibacterial and antifungal activities. In addition, the structure-activity relationship and docking studies are discussed. Conclusion: The synthesized compounds 6c, 6d, 7c, and 7d showed the highest antibacterial and antifungal activities against the tested strains.

Design, Synthesis and Cytotoxic Studies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer

Background: The pre-existing EGFR (Epidermal Growth Factor Receptors) inhibitors (Gefitinib, Afatinib and osimertinib) show significant resistance after one year of EGFR therapy in NSCLC (Non-small cell lung cancer) patients. With the aim of overcoming the resistance problem associated with a current therapeutic regimen, there is an imperative need for the development of novel 4- anilinoquinazoline derivatives that are specifically designed for resistance cases of NSCLC patients. Objective: We designed and synthesized eighteen 4-anilinoquinazolines derivatives as a novel scaffold and evaluated their anti-cancer potential against different NSCLC cell lines. Methods: Molecular docking study of designed compounds were performed on Glide v5.8 (Schrodinger, LLC, New York, NY). Synthesis of 4-anilinoquinazoline derivatives were performed, based on the docking score and was characterized by various spectroscopic methods. Further, in vitro anti-cancer activity was performed using MTT assay on different cancer cell lines. Results: Molecular docking analysis [EGFRT790M mutant (4I22)] indicated that most of these analogs (6g, 6j, 6l, 6m and 6o) were found to be higher docking scores than gefitinib. Furthermore, spectral analysis revealed that the designed compounds were synthesized successfully. The compounds 6a, 6d, 6g, 6i, 6j and 6m were identified as the potent inhibitors against (A431, H1975, A549) cell lines as compared to reference standard gefitinib. Excitingly, compound 6j (with IC50 values of 4.88 ± 0.13, 4.38 ± 0.08 & 11.97 ± 0.14 μM) was identified as the most potent inhibitor for (A431, H1975, A549) cell lines. Conclusion: The study suggested that the six derivatives showed significant therapeutic potential against different NSCLC cell lines as compared to reference standard gefitinib.

Synthesis, anti-microbial, and docking studies of functionalized chromenyl phosphonates using ionic liquid catalyst.

Synthesis of functionalized chromenyl phosphonates by the reaction among 2-hydorxybenzaldehydes, dicyanoethane, and dialkyl phosphonates that was promoted by choline hydroxide ionic liquid catalyzes the simultaneous, Knoevenagel, Pinner, and phospha-Michael reactions, under neat condition at room temperature. Important phosphorus-containing compounds can be produced at a reasonable cost because of the mild reaction conditions and the inexpensive promoter choline hydroxide. Furthermore, the desired products can be obtained without the need for any extraction or chromatography steps. An alternate technique for the simple and high-yield synthesis of functionalized chromenyl phosphonates is offered by this protocol. The synthesized compounds were studied by anti-microbial activity and docking studies. The title compounds molecular docking investigations demonstrated their efficacy as therapeutic agents against DNA Gyrase B and Aspergillus niger endoglucanase in both antibacterial and antifungal inhibition, and they identified compounds 4a, 4d, 4l, 4p, and 4q as promising candidates for microbial treatment, with binding affinities ranging from -6.9 to -7.4kcal/mol.

Design, Synthesis, Anti-Cancer, Anti-inflammatory and In Silico Studies of 3-Substituted-2-Oxindole Derivatives.

This study focuses on the design and synthesis of 3-substituted-2-oxindole derivatives aimed at developing dual-active molecules with anti-cancer and anti-inflammatory properties. The molecules were designed with diverse structural and functional features while adhering to Lipinski, Veber, and Leeson criteria. Physicochemical properties were assessed using SWISSADME to ensure drug-likeness and favourable pharmacokinetics. Multistep synthetic procedures were employed for molecule synthesis. In vitro evaluations confirmed the dual activity of the derivatives, with specific emphasis on the significance of dialkyl aminomethyl substitutions for potency against various cell lines. 4 a exhibited GI50 value 3.00E-05 against MDA-MB-231, 4 b has shown GI50 value 2E-05 against MDA-MB-231, 4 c has shown GI50 value 6E-05 against VERO, 4 d has shown GI50 value 8E-05 each against both the MDA-MB-231 and MCF-7 and 4 e has shown GI50 values 2E-05 and 5E-05 each against both the MCF-7 and VERO. The analysis indicates that compounds 3 c (71.19 %), 3 e (66.84 %), and 3 g (63.04 %) exhibited significant anti-inflammatory activity. Additionally, in silico binding free energy analysis and interaction studies revealed significant correlations between in vitro and computational data, identifying compounds 4 d, 4 e, 3 b, 3 i, and 3 e as promising candidates. Key residues such as Glu917, Cys919, Lys920, Glu850, Lys838, and Asp1046 were found to play critical roles in ligand binding and kinase inhibition, providing valuable insights for designing potent VEGFR2 inhibitors. The Quantum Mechanics-based Independent Gradient Model analysis further highlighted the electronic interaction landscape, showing larger attractive peaks and higher electron density gradients for compounds 4 d and 4 e compared to Sunitinib, suggesting stronger and more diverse attractive forces. These findings support the potential of these compounds for further development and optimization in anticancer drug design.

Derivatization of Abietane Acids by Peptide-like Substituents Leads to Submicromolar Cytotoxicity at NCI-60 Panel.

Natural compounds, including diterpenoids, play a critical role in various biological processes and are recognized as valuable components in cancer treatment. Isocyanides multicomponent reactions (IsMCRs) are one of the effective methods to obtain adducts at the carboxyl group with a peptide-like substituent. In this study, dehydroabietic acid and levopimaric acid diene adducts as the starting scaffolds were modified by the multicomponent Passerini (P-3CR) and Ugi (U-4CR) reactions to afford α-acyloxycarboxamides and α-acylaminocarboxamides. A group of twenty novel diterpene hybrids was subjected to NCI in vitro assessment, and a consistent structure-activity relationship was established. Eleven of the synthesized derivatives inhibited the growth of cancer cells of 4 to 39 cell lines in one dose assay, and the most active were derivatives 3d, 9d, and 10d holding a fragment of 1a,4a-dehydroquinopimaric acid. They were selected for a five-dose analysis and demonstrated a significant antiproliferative effect towards human cancer cell lines. The outstanding cytotoxic activity was observed for the P-3CR product 3d with growth inhibitory at submicromolar and micromolar concentrations (GI50 = 0.42-3 μM) against the most sensitive cell lines. The U-4CR products 9d and 10d showed selective activity against all leukemia cell lines with GI50 in the range of 1-17 µM and selectivity indexes of 5.49 and 4.72, respectively. Matrix COMPARE analysis using the GI50 vector showed a moderate positive correlation of compound 3d with standard anticancer agents that can influence kinase receptors and epidermal growth factor receptors (EGFRs). The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents. The obtained results indicate that these new hybrids could be useful for the further development of anticancer drugs, and 1a,4a-dehydroquinopimaric acid derivatives could be recommended for in-depth studies and the synthesis of new antitumor analogs on their basis.

Emerging therapeutics: The imidazo[1,2-b]pyridazine scaffold as a novel drug candidate for eumycetoma, a neglected tropical disease

Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2-b]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis, the prime causative agent of eumycetoma, with IC50 ≤ 5 μM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC50 of 0.9 μM, in the same order then itraconazole (IC50 = 1.1 μM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies.

Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents

Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC50 of 2.60 μM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.

Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers.

Ferroptosis is a promising therapeutic target for injury-related diseases, yet diversity in ferroptosis inhibitors remains limited. In this study, initial structure optimization led us to focus on the bond dissociation enthalpy (BDE) of the N-H bond and the residency time of radical scavengers in a phospholipid bilayer, which may play an important role in ferroptosis inhibition potency. This led to the discovery of compound D1, exhibiting potent ferroptosis inhibition, high radical scavenging, and moderate membrane permeability. D1 demonstrated significant neuroprotection in an oxygen glucose deprivation/reoxygenation (OGD/R) model and reduced infarct volume in an in vivo stroke model upon intravenous treatment. Further screening based on this strategy identified NecroX-7 and Eriodictyol-7-O-glucoside as novel ferroptosis inhibitors with highly polar structural characteristics. This approach bridges the gap between free radical scavengers and ferroptosis inhibitors, providing a foundation for research and insights into novel ferroptosis inhibitor development.

Synthesis, Antimicrobial Evaluation, and In Silico Studies of 2-Substituted-Phenyl-3-(5-Aryl/Heteroaryl Substituted Thiazol-2-yl) Thiazolidin-4-One Derivatives.

In a one-pot reaction involving 3-(2-aminothiazol-5-yl)-2H-chromen-2-one/5-(naphthalen-1-yl)thiazol-2-amines 5-6 with various substituted aldehydes and mercaptoacetic acid, we obtained the corresponding 2-(4-substituted-phenyl)-3-[5-(2-oxo-2H-chromen-3-yl)thiazol-2-yl] thiazolidin-4-ones 8(a-h) and 2-(4-substituted-phenyl)-3-[5-(naphthalen-1-yl)thiazol-2-yl] thiazolidin-4-ones 9(a-h). The antimicrobial activity of all compounds was evaluated against Pseudomonas aeruginosa (MTCC-424), Salmonella typhi (MTCC-531), Staphylococcus aureus (MTCC-737), and Candida albican (MTCC-227). Molecular docking further supported the findings, which showed that the compounds 8d and 9d had excellent antibacterial action against all tested pathogens.

Novel Thiazole-Hydrazide Derivatives and Their Anticancer Properties

Objective: Cancer is described as uncontrolled cell division, and it is a major problem in Türkiye, as well as around the world. Current treatment options are insufficient in some cases, particularly the treatment rate for lung cancer cases, which is very low. Meanwhile, current pharmaceuticals have several side effects, such as drug-drug interactions, and cognitive disorders. Additionally, developing drug resistance is a major problem for current and future management of the disease. Accordingly, the search for new molecules or alternative treatment options is actively achieved. Methods: In this study, eight novel thiazole-hydrazide analogs were designed and synthesized, and their structural elucidation was performed via HRMS, 1H-NMR, and 13C-NMR. Their biological activity profile was investigated on A549 lung carcinoma and MCF7 breast adenocarcinoma cells. To determine the selective cytotoxicity on cancer cells, they were also tested against NIH/3T3 healthy cell line. Besides that, an in silico study was performed to understand the binding modes of the compounds. Results: The results showed that in the serial 4f and 4g, the most bulky analogues, showed no inhibition against any cell type, even at the highest concentration tested. On the other hand, 4a, 4b, 4d, 4e, and 4h showed less cytotoxicity on healthy cells than A549 cells, so they exhibited significant cytotoxicity and a selective profile against A549 cancer cells. While they also inhibited MCF7 cells. The major point is that para-chlorophenyl analogs at the fourth position on thiazole (4a and 4d) displayed a better anticancer profile than ortho-chlorophenyl analogs. These two compounds were also investigated for their apoptotic effects using in silico studies. Both experimental and in silicon studies revealed that the combination of thiazole and hydrazinoacetyl has a significant impact against cancer cells, and in silico study also suggested that tri-substitute thiazole ring has anticancer potential that induced cancer cell death via apoptosis. Conclusion: Results of this study was presented that compound 4a was the most potent compound against lung cancer cells (A549) and 4d was the most potent compound against breast cancer cells (MCF-7). Furthermore, analyzing the molecular docking study for promising compounds (4a and 4d) suggested that interactions with the loop region residues have a pivotal role in inducing caspase-3 enzyme activity. It was concluded that hybridization of thiazole and hydrazinoacetyl moieties is responsible for the anticancer activity.

Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Triflic acid-promoted Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives: Synthesis and photophysical studies of novel 9,10-dihydrophenanthrenes

An efficient metal-free, triflic acid-promoted intramolecular Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives is discussed. This method provides an elegant route for the construction of 9,10-dihydrophenanthrenes of biological significance in good to excellent yields. The carbocyclization reaction is likely to proceeds via activation of terminal CC bond of alkenylated biphenyl derivatives followed by subsequent aromatic electrophilic substitution to give desired carbocyclic products. Single crystal X-ray diffraction analysis of compound 10d revealed that the crystals are packed in AB-AB layer packing, where the molecules are aligned in anti-parallel fashion. Notably, all of the synthesized 9,10-dihydrophenanthrenes exhibited blue to greenish yellow fluorescence with λmax = 418–481 nm range. The stokes shift, quantum yield and optical band gap of tricyclic products were computed using their absorption and emission spectra. A significant positive solvatochromic effect was observed for 9,10-dihydrophenanthrene derivative 10l, which is a characteristic of ICT interactions.

Design, Synthesis, and Evaluation of the Selective and Orally Active LSD1 Inhibitor with the Potential of Treating Heart Failure.

LSD1 has become an appealing target for the development of new pharmacologic agents to treat cardiovascular diseases, including heart failure. Herein, we reported the design, synthesis, and structure-activity relationship of a series of TCP-based derivatives targeting LSD1. Docking studies were employed to successfully elucidate the SAR. Particularly, compound 7d, characterized by low toxicity, demonstrated a high affinity for LSD1 at molecular and cellular levels. It also displayed favorable pharmacokinetic properties for oral dosing (e.g., F = 77.61%), effectively alleviating Ang II-induced NRCFs activation in vitro and reducing pathological myocardial remodeling in TAC-induced cardiac remodeling and heart failure in vivo. Additionally, mechanism studies revealed that suppression of myocardial dysfunction by compound 7d is related to LSD1 inhibition-induced TGFβ signaling pathway repressing. In summary, the current report presents compound 7d as a potent LSD1 inhibitor with the potential for further development as a therapeutic agent for pressure overload-related heart failure.