Compound 3c Research Articles

Discovery and structure − activity relationships of 2,4,5-trimethoxyphenyl pyrimidine derivatives as selective D5 receptor partial agonists

Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson’s and Alzheimer’s. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound 5c (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, 5j, 5h, and 5e. The most potent compound of this series 5j (4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine), exhibited EC50 of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that 5j is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of 5j (20 mg/kg, p.o) in C57BL/6j mice showed that 5j is readily absorbed via oral route of dosing and also enters into the brain (plasma Tmax: 1 h, Cmax: 51.10 ± 13.51 ng/ml; Brain Tmax: 0.5 h, Cmax: 22.54 ± 4.08 ng/ml). We further determined the in-vivo effect of 5j on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that 5j (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, i.p.). Furthermore, 5j did not exhibit any cytotoxicity (up to 10 µM) or in vivo acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that 5j could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.

Some heterocycles connected to substituted piperazine by 1,3,4-oxadiazole linker: Design, synthesis, anticholinesterase and antioxidant activity

AD is a multifactorial neurodegenerative disease that has caused morbidity and mortality on a global scale. Currently, there are only a few drugs used in the treatment of AD. Although many compounds that aim at new targets have reached clinical trials, none have been approved. However, discovering efficient drugs for AD treatment is one of the biggest challenges for pharmaceutical research and requires strong support. In this paper, we aim to design a series of indole, benzothiophene, and thiophene bearing 1,3,4-oxadiazole linker to the piperazine basic center and evaluate for their antioxidant and inhibitory activity against both cholinesterase enzymes. Among the compounds, 6a, 7b, and 8b exhibited moderate cationic radical scavenging activities with IC50 values ranging from 20.39 to 30.10 μM. The inhibitory activity results revealed that compounds 5c (IC50 for AChE = 53.91 μM and for BChE = 55.81 μM) and 6c (IC50 for AChE = 54.42 μM and BChE = 45.82 μM) bearing 2-fluorophenyl piperazine moiety showed both AChE and BChE inhibition with moderate IC50 values. To explore the binding properties of the target compounds into the active site of the enzyme, a molecular docking study was carried out using MOE software. The docking study showed that compound 6c targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE/BChE and formed important interactions with key residues. Moreover, theoretical physicochemical properties of the best active compound 6c were calculated by the SwissADME web service. It obeyed Lipinski's rule of five and had high GI absorption (gastrointestinal absorption) and good permeating to the blood-brain barrier (BBB). The compound 6c can be considered a promising compound and provides us directions for further research of anti-AD agent development.

Synthesis and Biological Evaluation of Novel Furopyridone Derivatives as Potent Cytotoxic Agents against Esophageal Cancer.

Cancer continues to be a major global health issue, ranking among the top causes of death worldwide. To develop novel antitumor agents, this study focused on the synthesis of a series of 21 novel furanopyridinone derivatives through structural modifications and functional enhancements. The in vitro anti-tumor activities of these compounds were investigated through the cytotoxicity against KYSE70 and KYSE150 and led to the identification of compound 4c as the most potent compound. At a concentration of 20 µg/mL, compound 4c demonstrated a remarkable 99% inhibition of KYSE70 and KYSE150 cell growth after 48 h. IC50 was 0.655 µg/mL after 24 h. Additionally, potential anti-tumor cellular mechanisms were explored through molecular docking, which was used to predict the binding mode of 4c with METAP2 and EGFR, suggesting that the C=O part of the pyridone moiety likely played a crucial role in binding. This study provided valuable insights and guidance for the development of novel anticancer drugs with novel structural scaffolds.

Flexible green synthesis of 2-benzyl-3‑hydroxy-1H-pyrazolo([1,2-b]phthalazine and [1,2-a]pyridazine)‑dione derivatives using CuI@KSF nanocatalyst under solvent-free conditions

In the frame of research that examines the use of task CuI@KSF nanoparticles as an efficient catalyst, new 1H-pyrazolo[1,2-b]phthalazine-5,10‑dione (HPPhD) and 1H-pyrazolo[1,2-a]pyridazine-5,8‑dione (HPPyD) derivatives were prepared. Using the four-multicomponent condensation reaction (4MCRs) of phthalic anhydride, hydrazine monohydrate, aromatic aldehydes, and ethyl 3-oxo-3-phenylpropanoate under solvent free conditions at 80 °C. This method has several advantages, including, operational, simplicity, mild conditions, and maximum product yield. To monitor the progress of the reactions, new organic salty catalysts were used. New catalysts are cheap, benign, recyclable, and environmentally friendly. In addition, they are easy to prepare and use. They also showed good catalytic activity, which in conclusion led to the synthesis of new phthalazine derivatives with good to excellent yields. The new catalysts were characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR), thermal gravimetric analysis (TGA), and scanning electron microscopy (SEM). To check the possible effect of these compounds in anticancer therapy, two types of proteins were selected and examined through docking calculations. In the case of 1DHT as an oxidoreductase enzyme compound 7e with the score of amount -8.99 represent the highest tendency toward interaction with the desired enzyme, while in the case of 6LQA by the dominance hydrophobic character, compound 7c seems likely to be more efficient.

New 6-nitro-4-substituted quinazoline derivatives targeting epidermal growth factor receptor: design, synthesis and in vitro anticancer studies.

Aim: Twenty compounds of 6-nitro-4-substituted quinazolines were synthesized.Materials & methods: The new derivatives were evaluated for their epidermal growth factor receptor (EGFR) inhibitory activity. The most potent derivatives were assessed for their cytotoxicity against colon cancer and lung cancer cells, in addition to normal fibroblast cells.Results & discussion: compound 6c showed a superior to nearly equal cytotoxicity in comparison to gefitinib, it also revealed a good safety profile. Compound 6c caused a cell cycle arrest at G2/M phase in additionto induction of apoptosis. A molecular docking study was conducted on the most active compounds to gain insights of their binding mode in the active site of EGFR enzyme besides ADME prediction of their physicochemical properties and drug likeness profile.

Design, synthesis, characterization and antidiabetic evaluation of 3,5-substituted thiazolidinediones: Evidenced by network pharmacology, Molecular docking, dynamic simulation, in vitro and in vivo assessment

In search of new antidiabetic agents, heterocyclic compounds containing 3,5-Substituted thiazolidinedione moieties were synthesized through a concise three-step reaction process. The synthesis involved Knoevenagel condensation at the 5th position of the 3,5-Substituted thiazolidinedione ring-system (6a-6c). Comprehensive physicochemical and spectral analyses, including FTIR, HR-MS, 1H NMR and 13C NMR, were performed to characterize the synthesized compounds. The synthesized derivatives were subjected to evaluation for their In vivo anti-diabetic activity against diabetes induced wistar rats and In vitro activity against α-amylase, α-glucosidase and glucose uptake by yeast cells. On the basis of the combined results of network pharmacology, In vitro and animal study experiments revealed that the compounds 6c predicted to have the greatest effect out of the compounds (6a-6c), showing interactions with targets exhibited potential binding patterns against the active site of target α-amylase, α-glucosidase with modulating AMY2A, GAA, PPARG, PIK3CA, PRKCB, INSR, and PRKCB signalling pathways and this is evidenced by molecular docking, dynamics simulation (MD) studies. Further, compound 6c showed In vitro α-amylase, α-glucosidase inhibitory activity with IC50 value of 86.06 ± 1.1 μM and 74.97 ± 1.23 μM as opposed to standard acarbose (IC50 value of 26.89 ± 3.12 and 29.25 ± 0.15 μM) and 58.23 ± 0.13 % of glucose uptake and also exhibited significant reduction (p < 0.001) in blood glucose levels (114 ± 1.17 mg/dL) comparable to the effect of pioglitazone (102.2 ± 0.79 mg/dL). The present study suggests that modified thiazolidinediones act as potential lead compounds to carter the need of antidiabetic agents.

Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.

Monocarbonyl curcuminoids as potential photosensitizers in photodynamic therapy against skin cancer

Two monocarbonyl dimethylamino curcuminoids, one derived from acetone (C3) and the second one from cyclohexane (C6), were synthesized aiming to study their photophysical properties and anticancer photodynamic potential. Compound C6 exhibited lower absorbance and fluorescence than C3. Photobleaching studies showed that C3 and C6 photostability behavior in DMSO differ significantly. C3 was completely photoconverted into a new species absorbing at lower wavelength than the parent compound, whereas, C6, upon a 30 min irradiation at λ = 440 nm with 15 mW/cm2 reached a photostationary phase where a smaller amount of the initial compound coexists with some photoproducts of higher and lower absorbance. Both compounds were able to generate significant amounts of ROS upon irradiation in an aqueous environment and exhibited successful intracellular localization in skin cancer cells (A431 cells). After dark cytotoxicity studies the concentrations of 5 μM and 1 μM for C3 and C6, respectively, were selected for the PDT assessment. C3 presented light dose-dependent photodynamic activity against A431 cells, resulting in 40 % cell viability after 12 min of light irradiation (440 nm, 15 mW/cm2). On the other side, C6 showed a biphasic light dose PDT effect with cell viability gradually decreasing up to 50 % after 5 min of light exposure, and then increasing again after 8 and 12 min of light exposure. The photodynamic performance of C6 may provide a new insight into the development of PSs with reduced prolonged photosensitivity.

Design and synthesis of Thieno[3, 2-b]pyridinone derivatives exhibiting potent activities against Mycobacterium tuberculosis in vivo by targeting Enoyl-ACP reductase

In this study, a series of novel thieno [3, 2-b]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5–1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T1/2 value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome sequencing of spontaneously compound 6c-resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2-b]pyridinone derivatives. Overall, this study identified thieno [3, 2-b]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents.

Therapeutic Effect of 1,3‐Thiazin‐6‐One for the Treatment of Brain Cancer Through Increased Accumulation in the Brain Glioblastoma Cells

AbstractIn the present study a library of five (2‐(amino)‐1,3‐thiazin‐6‐one) compounds was synthesized and investigated as against glioblastoma cells in vitro and in vivo in the mice model. The results revealed that all of the five 1,3‐thiazin‐6‐one compounds (4a, 4b, 4c, 4d and 4e) exhibited cytotoxicity against U87MG and 9 L brain cancer cell lines. Moreover, it was found that 9 L cells showed slightly higher sensitivity towards the compounds 4a, 4b, 4c, 4d and 4e compared to U87MG cells. It was observed that the compounds 4a, 4b, 4c, 4d and 4e showed a time‐dependent increase in uptake efficiency by U87MG and 9 L cells. Furthermore, the data revealed that uptake of the compounds and therefore internalization was maximum during initial 1 h of the treatment. Among the synthesized compounds, compound 4c containing trifluoromethyl moiety showed higher uptake efficiency compared to the compound 4a, 4b, 4d and 4e. Treatment of U87MG and 9 L cell tumor spheroids with compound 4c significantly (P&lt;0.05) inhibited the tumor growth compared to the control spheroids. In vivo data revealed that treatment with compound 4c led to a significant (P&lt;0.05) decrease in glioblastoma growth in mice in dose‐dependent manner. Growth of glioblastoma in mice was almost completely inhibited after 28 days of treatment with 2 mg/kg dose of compound 4c. Pharmacokinetic studies showed that compound 4c remained in circulation for longer duration in mice and its terminal half‐life was found to be 6.5 h. Treatment of U87MG and 9 L cells with compound 4c led to a prominent decrease in expression of CYR61 protein. In conclusion, findings of the present study suggest that compound 4c acts as a potential therapeutic agent for the treatment of advanced brain cancer through activation of Hippo pathway. Therefore, more studies need to be performed to investigate the detailed mechanism underlying the inhibitory effect of compound 4c against the glioblastoma.

Design, Synthesis, and Anticancer and Antibacterial Activities of Quinoline-5-Sulfonamides.

A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a-f and 6a-f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a-h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a-d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a-f and 6a-f and 1,2,3-triazole derivatives 7a-h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a-f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 µM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.

An Eco-Friendly Method to Synthesize Potent Antimicrobial Tricyclic Flavonoids.

The rapid emergence and spread of multidrug-resistant microorganisms is threatening our ability to treat common infections, with serious medical, social, and economic consequences. Despite substantial progress in the global fight against antibiotic resistance, the number of effective antibiotics is rapidly decreasing, underlying the urgent need to develop novel antimicrobials. In the present study, the green synthesis of novel iodine-substituted tricyclic flavonoids has been accomplished using an eco-friendly reagent, HPW-SiO2, as a cyclization agent for the precursor 3-dithiocarmamic flavanones. In vitro antimicrobial activity of the new compounds was evaluated using minimum inhibitory concentration (MIC) and minimum bactericidal/fungicidal concentrations. All tested compounds displayed potent inhibitory activity against all tested microbial strains, with the lowest MIC values of 0.12 µg/mL and 0.48 µg/mL recorded for compound 5c against Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus. Higher MIC values (7.81 µg/mL) were registered for several flavonoids against Gram-negative bacteria Escherichia coli and Acinetobacter pittii. No inhibitory activity was evidenced against Pseudomonas aeruginosa strain. The highest antifungal activity was displayed by flavonoid 5d against Candida krusei (MIC = 3.9 µg/mL). The same compound also exhibited the most potent bactericidal and fungicidal activity against Bacillus subtilis (0.9 µg/mL) and Staphylococcus aureus (1.97 µg/mL), Candida albicans, and Candida krusei (7.81 µg/mL). Based on the reported results, we believe that the novel iodine-substituted tricyclic flavonoids have good potential to become new antimicrobial agents effective against bacterial and fungal strains, including WHO-priority pathogens.

Expeditious assembly of N-heteroaryl substituted quercetin derivatives as potent anticancer agents

The synthesis of a small library of N-heteroaryl substituted quercetin derivatives (28 compounds) at the C8 position applying Suzuki-Miyaura cross-coupling reaction between 8-iodoquercetin methyl ether and various pyridylboronic acids or quinolylboronic acids is reported. The obtained quercetin derivatives 2a-2n and 3a-3n were well characterized by the 1H NMR, 13C NMR and HRMS data. Preliminary biological evaluations showed that some of the synthesized 8-heteroarylated quercetin derivatives possessed very high anti-cancer cell proliferation activity in HCC827 cancer cell line (IC50< 5.0 µmol/L) in vitro. Among these synthesized compounds, quinolin-7-yl substituted compound 2m exhibited best activity in HCC827 (IC50 = 3.20 µmol/L), while quinolin-3-yl substituted compound 2i showed best activity in MGC-803 cells (IC50 = 14.92 µmol/L). The 3-pyridyl compound 3c with ortho-fluorine showed best activity in OVCAR-3 cells (IC50 = 10.67 µmol/L). The disclosed structure-activity relationship provides hints that large steric hindrance at the C8 position of quercetin alter the anticancer activities and also offers new examples for new application of electronic and steric modifications as versatile tools in drug discovery.

Novel 1,3,4-trisubstituted Pyrazolopyrimidine Derivatives Show Potent Antiproliferative Activity in Mantle Cell Lymphoma

Background: Pyrazolopyrimidine scaffold is an important pharmacophore in drug discovery. This pharmacophore has been reported to produce numerous biological activities, of which anticancer is an important one. The development of novel pyrazolopyrimidine derivatives is of great importance for antitumor drug research. Objective: Compound 6, a pyrazolopyrimidine derivative reported by our group, showed weak antiproliferative activity with IC50 values of over 30 μM against mantle cell lymphoma (MCL) cell lines. In this study, we will further perform the structural optimization of compound 6 to screen highly active pyrazolopyrimidine derivatives. Methods: A novel series of 1,3,4-trisubstituted pyrazolopyrimidine derivatives were synthesized and their structures were elucidated by 1H-NMR, 13C-NMR, and HRMS. The antiproliferative activities of target compounds against MCL cell lines (Mino, Jeko-1, and Z138) were evaluated by the CellTiter-Glo luminescent cell viability assay. The effect of representative compounds to induce apoptosis was evaluated by Annexin V/Propidium Iodide (PI)-binding assay. Mitochondrial membrane potential and reactive oxygen species (ROS) levels in 15c-treated Z138 cells were tested by JC-1 and DCFH-DA probes, respectively. Results: Most compounds demonstrated improved antiproliferative activity against MCL cell lines compared to the lead compound 6, especially 15c, 15f, 15g, 15j, and 15o, with IC50 values at low micromolar levels. In addition, compound 15c could induce apoptosis in a dose-dependent manner in Z138 cells through reduction of mitochondrial membrane potential and enhancing reactive oxygen species production. Conclusion: The results showed that 1,3,4-trisubstituted pyrazolopyrimidine derivatives could be valuable lead compounds for the further development of anti-lymphoma agents.

Discovery of novel arylpyridine derivatives for motile ciliogenesis

Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies.

Efficient synthesis of novel 1,10 phenanthroline-substituted imidazolium salts: Exploring their anticancer applications

This study reports a new series of 1,10-phenanthroline-substituted imidazolium salts (1a–f), examining their design, synthesis, structure and anticancer activities. The structures of these salts (1a–f) were characterized using 1H, 13C NMR, elemental analysis, mass spectrometry and Fourier transform infrared (FT-IR) spectroscopies. The salts' cytotoxic activities were tested against cancer cell lines, specifically MCF-7, MDA-MB-231 and non-tumorigenic MCF-10A mammary cells. The study compared the impact of aliphatic and benzylic groups in the salts’ structure on their anticancer activity. Screening results revealed that compound 1c, in particular, showed promising inhibitory activity against the growth of MDA-MB-231 breast cancer cells, with an IC50 value of 12.8 ± 1.2 μM, indicating its potential as a chemotherapeutic agent. Cell apoptosis analysis demonstrated a tendency for compound 1c to induce early apoptosis in breast cancer cells. The stability/aquation of compound 1c was investigated using 1H NMR spectroscopy and its binding modes with DNA were explored via UV–Vis spectroscopy. Additionally, the study investigated the interaction residues and docking scores of compound 1c and the reference drug doxorubicin against Bax and Bcl-2 proteins using molecular docking.

Green synthesis and cytotoxic activity of functionalized naphthyridine.

A multicomponent synthesis of 1,8-naphthyridine with high yields utilizing benzaldehydes, malononitrile, phenol, and acetylenic esters in aqueous solution at room temperature in the presence of SiO2/Fe3O4 as a reusable catalyst is reported. Using the MTT test, the cytotoxic properties of all the produced compounds were assessed in vitro against cancer cell lines (MCF-7 and A549) and normal cell lines (BEAS-2B). It was discovered that the most effective cytotoxic agent, doxorubicin-like in its lack of selectivity, was the derivative 5h. On the other hand, the compound 5c might be regarded as an equipotent molecule with greater selectivity in relation to doxorubicin. Also, this study investigates the antioxidant effects of 1,8-naphthyridine carboxylates, along with other studies conducted in this study.

Peptidic Boronic Acid Plasmodium falciparum SUB1 Inhibitors with Improved Selectivity over Human Proteasome.

Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is essential for egress of invasive merozoite forms of the parasite, rendering PfSUB1 an attractive antimalarial target. Here, we report studies aimed to improve drug-like properties of peptidic boronic acid PfSUB1 inhibitors including increased lipophilicity and selectivity over human proteasome (H20S). Structure-activity relationship investigations revealed that lipophilic P3 amino acid side chains as well as N-capping groups were well tolerated in retaining PfSUB1 inhibitory potency. At the P1 position, replacing the methyl group with a carboxyethyl substituent led to boralactone PfSUB1 inhibitors with remarkably improved selectivity over H20S. Combining lipophilic end-capping groups with the boralactone reduced the selectivity over H20S. However, compound 4c still showed >60-fold selectivity versus H20S and low nanomolar PfSUB1 inhibitory potency. Importantly, this compound inhibited the growth of a genetically modified P. falciparum line expressing reduced levels of PfSUB1 13-fold more efficiently compared to a wild-type parasite line.

Virtual Screening and Molecular Docking: Discovering Novel METTL3 Inhibitors.

Methyltransferase-like 3 (METTL3) is an RNA methyltransferase that catalyzes the N6 -methyladenosine (m6A) modification of mRNA in eukaryotic cells. Past studies have shown that METTL3 is highly expressed in various cancers and is closely related to tumor development. Therefore, METTL3 inhibitors have received widespread attention as effective treatments for different types of tumors. This study proposes a hybrid high-throughput virtual screening (HTVS) protocol that combines structure-based methods with geometric deep learning-based DeepDock algorithms. We identified unique skeleton inhibitors of METTL3 from our self-built internal database. Among them, compound C3 showed significant inhibitory activity on METTL3, and further molecular dynamics simulations were performed to provide more details about the binding conformation. Overall, our research demonstrates the effectiveness of hybrid virtual algorithms, which is of great significance for understanding the biological functions of METTL3 and developing treatment methods for related diseases.

GPX4 allosteric activators inhibit ferroptosis and exert myocardial protection in doxorubicin-induced myocardial injury mouse model

Ferroptosis is a unique type of non-apoptotic form of cell death characterized by increased lipid hydroperoxide levels. It has relevance for a number of pathological conditions including multiple organ injuries and degenerative diseases. GPX4 plays an important role in ferroptosis by repairing lipid hydroperoxides. Based on the reported allosteric sites, we obtained the GPX4 allosteric activator hit compound A9 through virtual screening. A9 can bind to GPX4 and prevent RSL3-induced lipid peroxidation production in HT-1080 cells. In addition, A9 can specifically rescue erastin-induced cell death. Further chemical modification and structure-activity relationship studies afforded the optimized compound C3. C3 showed the activity of alleviating myocardial injury in the doxorubicin-induced myocardial injury mouse model. This study demonstrated that inhibiting ferroptosis by activating GPX4 is expected to be a potential solution to treat myocardial injury.