Compounds 4k Research Articles

Design, Synthesis, and Antirheumatoid Arthritis Mechanism of TLR4 Inhibitors.

A total of 12 carbonyl compounds were synthesized, their lipopolysaccharide induced inhibition, and activity of RAW264.7 cells was evaluated. The most active compound 3k inhibited RAW264.7 cells with IC50 value of 1.02 ± 0.08 μM. Compound 3k significantly inhibited the release of TNF-α, IL-1β, and IL-6 in supernatant for RAW264.7 cells. In vivo collagen-induced arthritis model tests administered orally, compound 3k showed effects similar to those of methotrexate in the positive control group. The preliminary mechanism study showed that compound 3k had an effect on abnormal expression for TLR4, TNF-α, NF-κB protein, and genes related to inflammation signaling pathway in RAW264.7 cells. Meanwhile, compound 3k showed a good affinity for the TLR4 receptor in molecular docking simulation. Therefore, compound 3k may be a promising lead compound for the treatment of rheumatoid arthritis.

Synthesis, antioxidant, antimicrobial activities and molecular modeling analysis of some 5-Nitro-N-phenyl-3-(phenylamino)-1H-indazole-1-carboxamide derivatives: Docking, SAR, toxicity and molecular dynamics analysis

This study reports the synthesis and characterization of a novel series of 5-nitro-N-phenyl-3-(phenylamino)-1H-indazole-1-carboxamide derivatives (5a-5v) obtained through the reaction of 3-chloro-5-nitro-N-phenyl-1H-indazole-1-carboxamide (4) with diverse aniline derivatives in isopropanol. The compounds underwent thorough biological evaluation encompassing antibacterial, antifungal, and in addition to antioxidant potential assessed through DPPH (IC50 = 0.105-0.513 μmol/mL) and ABTS assays (IC50 = 0.124-0.538 μmol/mL). Remarkably, compound 5b displayed exceptional antibacterial efficacy, while compounds 5k, 5p, and 5q exhibited noteworthy antifungal potential. Compound 5k showed the most significant antioxidant activity. Molecular docking studies unveiled robust binding interactions with target enzymes (PDB ID: 3SRG), and molecular dynamics simulations indicated the stability of the most active compound at the binding site. Additionally, favourable drug-likeness and ADMET properties underscore the promising therapeutic potential of these derivatives, urging further investigations for potential clinical applications. The multifaceted activities, including antibacterial, antifungal, and antioxidant properties, make these derivatives compelling candidates for in-depth exploration in the pursuit of novel therapeutic agents.

Natural Derivatives of Selective HDAC8 Inhibitors with Potent in Vivo Antitumor Efficacy against Breast Cancer.

HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 μM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.

Novel quinolone substituted 1,3,4-oxadiazole derivatives: design, synthesis, antimicrobial and anti-inflammatory potential.

A novel series of quinolone-substituted 1,3,4-oxadiazole derivatives 4(a-l) have been designed and synthesized. The target compounds were investigated for their antibacterial activity against gram positive (Staphylococcus aureus, ATCC 25923, Enterococcus faecalis, ATCC 29212) and gram negative bacterium (Escherichia coli, ATCC 25922, Pseudomonas aeruginosa, ATCC 27853) for antifungal activity using (Candida albicans, ATCC 10231) and anti-inflammatory activity as COX-II inhibitors, respectively. The 1,3,4-oxadiazole functionality was introduced at C-6 position of pipemidic acid derivatives. IR, 1H NMR and Mass spectrometry techniques confirmed the structure of synthesized derivatives. The quinolone (pipemidic acid)-oxadiazole hybrid derivatives were effective against bacterial strains. When compared to ciprofloxacin (MIC 16µg/mL), the compounds under consideration (4f, 4h, and 4k) showed significant antibacterial activity against all bacterial strains except Enterococcus faecalis, with MICs of 8µg/mL. On the other hand, synthesized target compounds 4(a-l) did not respond wellagainst Candida albicans fungal strain. The compound (4k) represents high % inhibition against COX-II. The compounds (4f, 4h and 4k) exhibited highest hydrogen bonding interaction with ARG57, ARG72, ARG78, LEU54 and MET16 target residues with a binding energy of - 8.4, - 8.6 and - 8.5kcal/mol into the active pocket of DNA gyrase enzyme respectively even better in comparison to reference ligands. Based on the docking study, quinolone (pipemidic acid) oxadiazole hybrid structural ligands exhibited strong interaction at binding pockets of DNA gyrase enzyme.

Probing N-substituted 4-(5-mercapto-4-ethyl-4H-1,2,4-triazol-3-yl)-N-phenylpiperdine-1-carboxamides as potent 15-LOX inhibitors supported with ADME, DFT calculations and molecular docking studies

In our continuous efforts to find out leads against the enzyme 15-lipoxygenase (15-LOX), the current study deals with the synthesis of a series of new N-alkyl/aralkyl/aryl derivatives of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)methylacetamide (7a-n) with anti-LOX activities. The synthesis was started by reacting phenylisocyanate with isonipecotate that sequentially converted into N-substituted ester (1), hydrazide (2), semicarbazide (3) and N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The final compounds, 7a-n, were obtained by reacting 4 with various N-alkyl/aralkyl/aryl electrophiles. Both the intermediates and target compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX by chemiluminescence method. The eight compounds 7e, 7j, 7h, 7a, 7g, 7b, 7n, 7c showed potent inhibitory activities against 15-LOX with values ranging from IC50 0.36 ± 0.15 μM (7e) to IC50 6.75 ± 0.17 μM (7c) compared with the reference quercetin (IC50 4.86 ± 0.14 μM) and baicalein (IC50 2.24 ± 0.13 μM). Two analogues (7l, 7f) had significantly outstanding inhibitory potential with IC50 values 12.15 ± 0.23 μM and 15.54 ± 0.26 μM, whereas, the derivatives 7i, and 7d displayed IC50 values of 21.56 ± 0.27 μM, 23.59 ± 0.24 μM and the compounds 7k, 7m were found inactive. All analogues exhibited blood mononuclear cells (MNCs) viability >75 % at 0.25 mM concentration as determined by MTT method. Calculated pharmacokinetic properties projected good lipophilicity, bioavailability and drug-likeness properties and did not violate Lipinski's/Veber rule. Molecular docking studies revealed lower binding free energies of all the derivatives than the reference compounds. The binding free energies were −9.8 kcal/mol, −9.70 k/mol and −9.20 kcal/mol for 7j, 7h and 7e, respectively, compared with the standard quercetin (−8.47 kcal/mol) and baicalein (−8.98 kcal/mol). The docked ligands formed hydrogen bonds with the amino acid residues Gln598 (7e), Arg260, Val 126 (7h), Gln762, Gln574, Thr443, Arg580 (7j) while other hydrophobic interactions observed therein further stabilized the complexes. The results of density functional theory (DFT) revealed that analogues with more stabilized lower unoccupied molecular orbital (LUMO) had significant enzyme inhibitory activity. The data collectively supports these molecules as leads against 15-LOX and demand further investigations as anti-inflammatory agents.

Design, synthesis, in vitro, and in silico anti-α-glucosidase assays of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives as new anti-diabetic agents

In this work, a novel series of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives 5a–n were designed by consideration of the potent α-glucosidase inhibitors containing indole and carboxamide-1,2,3-triazole-N-phenylacetamide moieties. These compounds were synthesized by click reaction and evaluated against yeast α-glucosidase. All the newly title compounds demonstrated superior potency when compared with acarbose as a standard inhibitor. Particularly, compound 5k possessed the best inhibitory activity against α-glucosidase with around a 28-fold improvement in the inhibition effect in comparison standard inhibitor. This compound showed a competitive type of inhibition in the kinetics. The molecular docking and dynamics demonstrated that compound 5k with a favorable binding energy well occupied the active site of α-glucosidase.

Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives.

Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. The newly synthesized compounds had their structures identified using NMR HRMS and IR techniques. Some of prepared compounds, including compounds 4g and 4k, showed potent cytotoxic activity against four cancer cell lines compared to the positive control of cisplatin and tetrahydrocurcumin. Compound 4g exhibited anticancer activity with a IC50 value of 1.09 ± 0.17 μM against human colon carcinoma HCT-116 and 45.16 ± 0.92 μM against A549 cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Moreover, further biological examination in HCT-116 cells showed that compound 4g can arrest the cell cycle at the G1 phase. A docking study revealed that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhabiting the binding of APC-Asef. Compound 4g can be used as a promising lead for further exploration of potential anticancer agents.

Quantum chemical modelling, molecular docking, synthesis and experimental anti-microbial activity of 1,4-diazepan linked piperidine derivative

BackgroundIn this work, we represent synthesis, in silico analysis and biological activity of 1,4 diazepine linked piperidine derivatives (6a–6o). All the derivatives were screened for their anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. Compounds were synthesized from reaction of tert-butyl 1,4-diazepane-1-carboxylic, butyryl chloride and varied aromatic aldehyde, further characterized by 1H NMR and LCMS spectral techniques.ResultUsing ampicillin as a positive control, the synthetic compounds 6a–6o were tested for their in-silico study and experimental anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. According to in vitro assay compound 6a, compound 6c, compound 6d, compound 6m and compound 6I showed higher activity against all the tested strains. Molecule 6i, compound 6j, compound 6k, compound 6f has good to moderate antibacterial activity. DFT computations were used to optimize the molecular geometry at the B3LYP/6-31G (d, p) theoretical level. The corresponding energy values of molecular orbitals were visualized using optimized geometries. Moreover, Auto Dock Vina 1.2.0 is used to assess molecular docking against two target proteins, Bacillus subtilis (PDB ID: 6UF6) and Protease Vulgaris (PDB ID: 5HXW). The target molecule 6b displayed the best binding energies for both. Additionally, we calculated the ADME for each molecule (6a–6o).ConclusionAll fifteen synthesized compounds were screened for their in vitro and in silico analysis. In vitro analysis for anti-microbial activity was carried out against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria and compound 6a, compound 6c, compound 6d, compound 6m and compound 6I exhibits more potent activity towards all tested strains. Molecular docking is performed against target proteins, L-amino acid deaminase from Proteus Vulgaris and LcpA ligase from Bacillus subtilis, representing the Gram-negative bacterium and Gram-positive bacterium, respectively. Compound 6b showed the highest no. of interaction with protein according to molecular docking. With the advent of innovative techniques like ADME, we select their hit compounds early on and anticipate future pharmacokinetic and pharmacodynamic benefits and drawbacks of these promising therapeutic candidates.Graphical abstract

Development of chromone-thiazolidine-2,4-dione Knoevenagel conjugates as apoptosis inducing agents

Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on in vitro cancer cell lines revealed the presence of compounds 8a, 8k, 8l, and 8n, which were found to have good to moderate anti-proliferative activity (with an IC50 concentration less than 10 µM). Among them, 8l depicted the highest cytotoxicity on the A549 cell line with an IC50 of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of 8l, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound 8l reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 family) with comparable binding affinities.

Synthesis of pyrrole-heterocyclic derivatives as anti-Alzheimer and antidiabetic candidates: An in vitro-in silico study

In this study, pyrrole-based heterocyclic compounds (2a-k) were synthesized and characterized by elemental analysis, IR and NMR spectra. 11 representatives of the pyrrole derivatives were chosen as objects for the studying biological activity. Among them were the ensembles of pyrroles with other pharmacologically active heterocycles, such as pyridines, aminopyrimidines, benzo[b][1,4]diazocin-2(1H)-ones, and fused pyrrole compounds, namely pyrrolo[1′,2′:3,4]imidazo[1,2-a]pyridines. The compounds 2c, 2e, and 2k were synthesized for the first time in this study. This assessment focused on their inhibitory potential against acetylcholinesterase (AChE) and α-glycosidase (α-Gly) enzymes. Among the studied compounds, 4-[5-(4-fluorophenyl)-1-vinyl-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (2e) and 4-[5-(4-fluorophenyl)-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (2f) emerged as leading candidates, demonstrating potent inhibition against AChE and α-glycosidase enzymes with favorable pharmacokinetic profiles. AChE was most effectively inhibited by compounds of 2f and 2i (Ki: 4.50 ± 0.16 and 6.01 ± 0.15 nM). The results from biological activities, molecular docking, dynamics simulations, and ADME predictions collectively highlight the potential of these compounds to be an inhibitor candidate for AChE and α-Gly.

Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors

USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure−activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI–H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.

Compound 3K attenuates isoproterenol-induced cardiac hypertrophy by inhibiting pyruvate kinase M2 (PKM2) pathway

AimChronic sympathetic stimulation has been identified as a primary factor in the pathogenesis of cardiac hypertrophy (CH). However, there is no appropriate treatment available for the management of CH. Recently, it has been revealed that pyruvate kinase M2 (PKM2) plays a significant role in cardiac remodeling, fibrosis, and hypertrophy. However, the therapeutic potential of selective PKM2 inhibitor has not yet been explored in cardiac hypertrophy. Thus, in the current study, we have studied the cardioprotective potential of Compound 3K, a selective PKM2 inhibitor in isoproterenol-induced CH model. MethodsTo induce cardiac hypertrophy, male Wistar rats were subcutaneously administered isoproterenol (ISO, 5 mg/kg/day) for 14 days. Compound 3K at dosages of 2 and 4 mg/kg orally was administered to ISO-treated rats for 14 days to explore its effects on various parameters like ECG, ventricular functions, hypertrophic markers, histology, inflammation, and protein expression were performed. ResultsFourteen days administration of ISO resulted in the induction of CH, which was evidenced by alterations in ECG, ventricular dysfunctions, increase in hypertrophy markers, and fibrosis. The immunoblotting of hypertrophy heart revealed the significant rise in PKM2 and reduction in PKM1 protein expression. Treatment with Compound 3K led to downregulation of PKM2 and upregulation of PKM1 protein expression. Compound 3K showed cardioprotective effects by improving ECG, cardiac functions, hypertrophy markers, inflammation, and fibrosis. Further, it also reduced cardiac expression of PKM2-associated splicing protein, HIF-1α, and caspase-3. ConclusionOur findings suggest that Compound 3K has a potential cardioprotective effect via PKM2 inhibition in isoproterenol-induced CH.

Novel Pyrazole-Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer.

More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF-7 and MDA-MB-231 cells by NRU assay. Among them, 8 k, 8 d, 8 m, 8 h, and 8 f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61 μM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8 k [3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-(2-(pyrrolidin-1-yl)-ethoxy)-phenyl)-chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER-α protein in western blotting study. Docking studies of 8 k and 8 d established adequate interactions with estrogen receptor-α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug-likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8 k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.

Targeting pyruvate kinase M2 for the treatment of kidney disease.

Pyruvate kinase M2 (PKM2), a rate limiting enzyme in glycolysis, is a cellular regulator that has received extensive attention and regards as a metabolic regulator of cellular metabolism and energy. Kidney is a highly metabolically active organ, and glycolysis is the important energy resource for kidney. The accumulated evidences indicates that the enzymatic activity of PKM2 is disturbed in kidney disease progression and treatment, especially diabetic kidney disease and acute kidney injury. Modulating PKM2 post-translational modification determines its enzymatic activity and nuclear translocation that serves as an important interventional approach to regulate PKM2. Emerging evidences show that PKM2 and its post-translational modification participate in kidney disease progression and treatment through modulating metabolism regulation, podocyte injury, fibroblast activation and proliferation, macrophage polarization, and T cell regulation. Interestingly, PKM2 activators (TEPP-46, DASA-58, mitapivat, and TP-1454) and PKM2 inhibitors (shikonin, alkannin, compound 3k and compound 3h) have exhibited potential therapeutic property in kidney disease, which indicates the pleiotropic effects of PKM2 in kidney. In the future, the deep investigation of PKM2 pleiotropic effects in kidney is urgently needed to determine the therapeutic effect of PKM2 activator/inhibitor to benefit patients. The information in this review highlights that PKM2 functions as a potential biomarker and therapeutic target for kidney diseases.

Discovery of new Schiff bases of the disalicylic acid scaffold as DNA gyrase and topoisomerase IV inhibitors endowed with antibacterial properties.

DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060μg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050μg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC50 value of 11µM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.

Synthesis and biological evaluation of novel 1,2,3,4-tetrahydro-β-carboline derivatives as potential antibacterial agents

The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-β-carboline (THβC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THβC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THβC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs.

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids.

Considering early-stage drug discovery programs, the Ugi four-component reaction is a valuable, flexible, and pivotal tool, facilitating the creation of two new amide bonds in a one-pot fashion to effectively yield the desired α-aminoacylamides. Here, we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell lines, among them, non-small cell lung carcinoma, cervical adenocarcinoma, breast cancer and colon adenocarcinoma. The most potent compounds 8d, 8h and 8k showed GI50 values in the range of 1-10 μM.

Click-chemistry mediated synthesis of OTBN-1,2,3-Triazole derivatives exhibiting STK33 inhibition with diverse anti-cancer activities

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4′-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91–98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time.

Exploring chalcone-sulfonyl piperazine hybrids as anti-diabetes candidates: design, synthesis, biological evaluation, and molecular docking study.

To address the escalating rates of diabetes mellitus worldwide, there is a growing need for novel compounds. The demand for more affordable and efficient methods of managing diabetes is increasing due to the inevitable side effects associated with existing antidiabetic medications. In this present research, various chalcone-sulfonyl piperazine hybrid compounds (5a-k) were designed and synthesized to develop inhibitors against alpha-glucosidase and alpha-amylase. In addition, several spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, and HRMS, were employed to confirm the exact structures of the synthesized derivatives. All synthesized compounds were evaluated for their ability to inhibit alpha-glucosidase and alpha-amylase in vitro using acarbose as the reference standard and they showed excellent to good inhibitory potentials. Compound 5k exhibited excellent inhibitory activity against alpha-glucosidase (IC50 = 0.31 ± 0.01 µM) and alpha-amylase (IC50 = 4.51 ± 1.15 µM), which is 27-fold more active against alpha-glucosidase and 7-fold more active against alpha-amylase compared to acarbose, which had IC50 values of 8.62 ± 1.66 µM for alpha-glucosidase and 30.97 ± 2.91 µM for alpha-amylase. It was discovered from the Lineweaver-Burk plot that 5k exhibited competitive inhibition against alpha-glucosidase. Furthermore, cytotoxicity screening assay results against human fibroblast HT1080 cells showed that all compounds had a good level of safety profile. To explore the binding interactions of the most potent compound (5k) with the active site of enzymes, molecular docking research was conducted, and the results obtained supported the experimental data.

Design, synthesis and bioactivity evaluation of novel monomethyl auristatin F analogues.

Monomethyl auristatin F (MMAF), a synthetic analogue of the natural compound dolastatin 10, has garnered significant attention in cancer research due to its high potency in vitro. While previous studies have focused on modifying the N-terminal extension of the amino group and the C-terminal modification of the carboxyl group, there has been limited exploration into modifying the P1 and P5 side chains. In this study, we substituted the valine residue at the P1 position with various natural or unnatural amino acids and introduced triazole functional groups at the P5 side chain. Compounds 11k and 18d exhibited excellent inhibition on tubulin. Additionally, compound 18d demonstrated enhanced cytotoxicity against HCT116 cells compared to the parent compound MMAF, suggesting its potential as a cytotoxic payload for further antibody-drug conjugates (ADCs) development.