Potent Compounds Research Articles

Novel Quinoline Schiff-Bases as Mtb DNA Gyrase Inhibitors - A Combined In Vitro and In Silico Study.

A new series of quinoline Schiff-bases was designed, synthesized, and characterized using 1H NMR, 13C NMR, and HRMS analysis. Further, all the compounds were screened for their antitubercular, antibacterial, and antifungal activity, and the minimum inhibitory concentrations (MICs) were determined. Among all, compound 7f displayed a significantly potent broad-spectrum antitubercular and antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 1.95-15.62 μg/ml. A subsequent in-vitro study evaluated the most promising compounds (7a, 7d, 7f, 7p, and 7q) against Mtb DNA gyrase. Among these, compounds 7a, 7d, and 7f exhibited the highest activity, with IC50 values of 1.98 μM, 1.26 μM, and 3.96 μM, respectively. Furthermore, molecular docking and molecular dynamics analysis were conducted for the most potent compounds to investigate their binding affinity for Mtb DNA gyrase enzyme. Additionally, the ADMET profiles of the most effective derivatives were examined to assess their suitability for further development as promising drug candidates.

Quinoline and quinolone carboxamides: A review of anticancer activity with detailed structure-activity relationship analysis.

Quinoline is a highly privileged scaffold with significant pharmacological potential. Introducing a carbonyl group into the quinoline ring generates a quinolone ring, which exhibits promising biological properties. Incorporating a carboxamide linkage at different positions within the quinoline and quinolone frameworks has proven an effective strategy for enhancing pharmacological properties, particularly anticancer potency. Consequently, various scientific communities have explored quinoline and quinolone carboxamides for their anticancer activities, introducing modifications at key positions. This review article aims to compile the anticancer activity of various quinoline and quinolone carboxamide derivatives, accompanied by a detailed structure-activity relationship (SAR) analysis. It also categorizes the data into activities of isolated/fused quinoline and quinolone carboxamide derivatives, which were further subclassified based on the mechanisms of anticancer action. Among the numerous derivatives studied, compounds 8, 19, 31, 34, 40, 68, 108, 116, and 132 have emerged as the most potent anticancer agents, making them strong candidates for further drug design and development. The mechanisms underlying the anticancer activity of these potent compounds have been identified as inhibitors of topoisomerase (8, 19, 31, and 34), protein kinase (40, 108, and 116), human dihydroorotate dehydrogenase (68), and as a cannabinoid receptor 2 agonist (132). We anticipate this review will be valuable to researchers engaged in the structural design and development of quinoline and quinolone carboxamide-based anticancer drugs with high efficacy.

Environmentally Friendly Synthesis of New Mono- and Bis-Pyrazole Derivatives; In Vitro Antimicrobial, Antifungal, and Antioxidant Activity; and In Silico Studies: DFT, ADMETox, and Molecular Docking

Background/Objectives: Antimicrobial resistance and oxidative stress are major global health challenges, necessitating the development of novel therapeutic agents. Pyrazole derivatives, known for their diverse pharmacological properties, hold promise in addressing these issues. This study aimed to synthesize new mono- and bis-pyrazole derivatives using an eco-friendly, catalyst-free approach and evaluate their antioxidant, antibacterial, and antifungal activities, supported by in silico ADMET profiling, molecular docking, and Density Functional Theory (DFT) analysis. Methods: The compounds were synthesized via a green condensation reaction and characterized using NMR and mass spectrometry, which was verified by DFT analysis. Biological activities were assessed through DPPH and FRAP antioxidant assays, as well as disk diffusion and MIC methods, against bacterial strains (Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli) and fungal strains (Candida albicans and Aspergillus niger). Computational ADMET profiling evaluated pharmacokinetics and toxicity, while molecular docking assessed interactions with target proteins, including catalase, topoisomerase IV, and CYP51. Results: Theoretical calculations using DFT were in agreement with the experimental results; regarding biological activities, O4 demonstrated the most significant antioxidant activity, with 80.14% DPPH radical scavenging and an IC50 value of 40.91 µg/mL. It exhibited potent antimicrobial activity, surpassing Streptomycin with a 30 mm inhibition zone against Pseudomonas aeruginosa and showing strong efficacy against Staphylococcus aureus and Candida albicans. Computational studies confirmed favorable pharmacokinetic properties, no AMES toxicity, and strong binding affinities. DFT analysis revealed O4’s stability and reactivity, further validating its potential as a therapeutic candidate. Conclusions: This study identified and characterized novel pyrazole derivatives with promising biological and pharmacological properties. O4 emerged as the most potent compound, demonstrating strong antioxidant and antimicrobial activities alongside favorable computational profiles. These findings highlight the potential of the synthetized compounds for therapeutic development and underscore the value of integrating green synthesis with computational techniques in drug discovery.

Design, Synthesis and in Silico Molecular Docking Studies of Adamantanyl hydrazinylthiazoles as Potential Anti-diabetic Agents.

Diabetes mellitus is a widespread disease that poses a major threat to millions of people. To address this issue, we have synthesized seventeen new 4-(adamantan-1-yl)-(2-(arylidene)hydrazinyl)thiazolesvia Hantzsch synthetic approach. The molecular structures of all the compounds were confirmed using spectroscopic techniques. Protein kinase, α-amylase, glycation, and oxidation inhibition potential of all compounds were also investigated and it was found, compounds 3b, 3c, 3e-3g and 3i-3q have shown excellent α-amylase inhibition (IC50= 7.91 ± 0.07 to 28.57 ± 0.1 µM), compounds 3c, 3e, 3i, 3k and 3p (IC50= 30.6 ± 0.06 to 37.8 ± 0.005 ppm) were found to be highly potent anti-glycating agents and compounds 3c, 3g, 3h, 3k, and 3m were found more potent protein kinase inhibitors. The compounds 3b, 3c, 3d, 3e, 3f, 3g, 3i, 3k, 3l, 3m, 3n, 3p and 3q have shown good antioxidant potential (IC50= 27.5 ± 0.09 to 48.8 ± 0.09 µM). The biocompatibility of all samples was also tested by employing brine-shrimp lethality and in-vitro hemolytic assays and was found to be safe to human erythrocytes at tested concentrations. Furthermore, the Molecular docking simulation study also revealed that almost all synthesized compounds have potential interactions with target proteins at the molecular level.

Design, Synthesis, and Biological Evaluation of Thieno[3,2-d]pyrimidine Derivatives as the First Bifunctional PI3Kδ Isoform Selective/Bromodomain and Extra-Terminal Inhibitors.

The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-d]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound (10b) was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC50) = 112 ± 8 nM] and BRD4-BD1 (IC50 = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells. Notably, this compound demonstrated good PI3Kδ selectivity over other kinases with minimal cytotoxicity in normal cells. Moreover, 10b has a good oral pharmacokinetic profile in mice and achieves outstanding antitumor activity in the SU-DHL-6 xenograft model. Taken together, these results indicate that targeting PI3Kδ and BET with a bifunctional inhibitor is a promising strategy to treat DLBCL.

Cyclic Lipopeptides as Selective Anticancer Agents: In vitro Efficacy on B16F10 Mouse Melanoma Cells.

In this study, 25 synthetic cyclic lipopeptides (CLPs) were investigated for their anticancer potential against mouse melanoma (B16F10) cells, human prostate cancer (PC-3), human colorectal adenocarcinoma (HT-29) and mouse embryonic fibroblast (NIH3T3) cells. The cytotoxic activity of investigated compounds was evaluated using MTT and CV assays. In order to examine the mechanism of action of the most potent compound cell cycle analysis, apoptosis assay, caspase activity, CFSE and DHR staining, DAF-FM, autophagy and immunocytochemistry caspase-3 assays were performed. During the fast screening, compound 9, was identified as prospective active CLP against B16F10 cell line at 10 μM concentration. MTT and CV assays exhibited at least four times higher cytotoxic potential of 9 (IC50 = 8.4±1.3 μM, MTT; 10.6±1.1 μM, CV) in comparison to control drug natural occurring CLP surfactin (IC50 = 50.3±0.6 μM, MTT; 40.4±0.3 μM, CV). The use of flow cytometry analysis confirmed that apoptosis was involved in the death of B16F10 cells after treatment with 9, as demonstrated also by DAPI staining. Caspase activity could be detected during cell death (ApoStat assay, immunocytochemistry caspase-3 assay). Compound 9 provokes enhancement of nitric oxide (NO) production in B16F10 cells but does not trigger ROS/RNS generation or autophagy. The study highlights synthetic compound 9 superior tumor-specificity and potential as an anticancer agent compared to surfactin and cisplatin. These findings could guide the development of more selective and less harmful macrocyclic lipopeptides for cancer therapy.

Potent antibacterial and cytotoxic bioactive compounds from endophytic fungi Diaporthe sp. associated with Salacia intermedia.

Antibacterial screening of endophytic fungi from Salacia intermedia identified Diaporthe longicolla as a potent strain exhibiting good activity against multidrug-resistant Staphylococcus aureus and Pseudomonas aeruginosa, with an MIC of 39.1µg/mL. Scale-up fermentation and chromatographic purification of this strain yielded three known compounds, which were cytochalasin J (1), cytochalasin H (2), and dicerandrol C (3), as identified by liquid chromatography - high mass resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance (NMR) spectroscopy. Among those compounds, dicerandrol C exhibited broad-spectrum antibacterial activity against ATCC and multidrug-resistant strains of Bacillus subtilis, S. aureus, and P. aeruginosa, and multidrug-resistant strains of Klebsiella pneumoniae and Escherichia coli, with MIC values ranging from 1.04 to 33.30 µM. Furthermore, dicerandrol C outperformed tetracycline in antibacterial efficacy against S. aureus ATCC 6538 and methicillin-resistant S. aureus (MRSA) strains (MIC of 1.04 µM). Further antibacterial evaluation showed that cytochalasin J (221.43 µM), cytochalasin H (202.59 µM), and dicerandrol C (tested at its MIC values of 1.04 µM for S. aureus ATCC 6538 and 16.65 µM for P. aeruginosa ATCC 15442) significantly inhibited bacterial biofilm formation. The biofilm inhibition percentages ranged from 61.09 to 78.17% for S. aureus and 41.22-56.83% for P. aeruginosa. In cytotoxicity assays against MCF-7 cells, all three compounds reduced cell viability (48.68-74.50%), with dicerandrol C demonstrating the highest potency. These findings highlight the potential of dicerandrol C as a powerful antibacterial and cytotoxic agent, facilitating further investigations into its therapeutic applications.

Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models.

Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of S-methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C-N atropisomeric chirality utilizing structure-based drug design. The Hit compound 9 exhibited high potency in enzymatic activity (IC50 = 7 nM) and in HCT-116 MTAP(-/-) cell potency (IC50 = 17 nM). Further optimization has led to the identification of two new lead compounds: a brain-penetrant compound, 29-1, and a potent but limited brain-penetrant compound, 39. Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of S-adenosylmethionine modulation in the central nervous system.

Design, Synthesis, Anticancer Screening, and Mechanistic Study of Spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide Derivatives.

The present study aims to create spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide derivatives with anticancer activities. The in vitro anticancer evaluation showed that only the novel spiro-acenaphthylene tethered-[1,3,4]-thiadiazole (compound 1) exhibited significant anticancer efficacy as a selective inhibitor of tumor-associated isoforms of carbonic anhydrase. Compound 1 demonstrated considerable efficacy against the renal RXF393, colon HT29, and melanoma LOX IMVI cancer cell lines, with IC50 values of 7.01 ± 0.39, 24.3 ± 1.29, and 9.55 ± 0.51 µM, respectively. In comparison, doxorubicin exhibited IC50 values of 13.54 ± 0.82, 13.50 ± 0.71, and 6.08 ± 0.32 µM for the corresponding cell lines. Importantly, compound 1 exhibited lower toxicity to the normal WI 38 cell line than doxorubicin, with IC50 values of 46.20 ± 2.59 and 18.13 ± 0.93 µM, respectively, indicating greater selectivity of the target compound compared to the standard anticancer agent doxorubicin. Also, mechanistic experiments demonstrated that compound 1 exhibits inhibitory activity against human carbonic anhydrase hCA IX and XII, with IC50 values of 0.477 ± 0.03 and 1.933 ± 0.11 μM, respectively, indicating enhanced selectivity for cancer-associated isoforms over cytosolic isoforms hCA I and II, with IC50 values of 7.353 ± 0.36 and 12.560 ± 0.74 μM, respectively. Cell cycle studies revealed that compound 1 caused G1 phase arrest in RXF393 cells, and apoptosis experiments verified a substantial induction of apoptosis with significant levels of early and late apoptosis, as well as necrosis (11.69%, 19.78%, and 3.66%, respectively), comparable to those induced by the conventional cytotoxic agent doxorubicin, at 9.91%, 23.37%, and 6.16%, respectively. Molecular docking experiments confirmed the strong binding affinity of compound 1 to the active sites of hCA IX and XII, highlighting significant interactions with zinc-binding groups and hydrophobic residues. These findings underscore the target compound's potential as a viable anticancer agent via targeting CA.

Unraveling the synthetic strategy, structure activity relationship of azetidinones: Insights into their multidrug and toxin extrusion protein (MATE transporter) inhibition facilitating drug development against MDR.

Heterocyclic chemistry gathered a wide audience due to their presence in potential drug candidates and being attractive synthons initiating several retro-syntheses the organic as well as in medicinal chemistry fields. Among them, azetidinones have been a subject of discussion due to their serendipity, curiosity, versatility by Penicillin and Cephalosporins as β-lactam antibiotics. Despite possessing a large margin of biological activities, azetidinones mainly work as antimicrobial, interfering with bacterial cell-wall synthesis blocking transpeptidase. The structure and synthetic strategy of the azetidinone arouse its research interest in drug discovery pipeline. However, the extensive use of antibiotics in the modern era contributes to drug resistance that could only be counterbalanced involving hybridization approach. To explore the potency of the azetidinones, potent compounds found from literatures, have been screened through molecular docking against MATE transporter, targeting for prevailing multidrug resistance. The present review makes a sincere effort to compile the synthetic information and orientations involving hybridization of azetidinones with biologically active scaffolds emphasizing on antimicrobial and anticancer efficacies along with their MATE inhibition, keeping an eye upon the structure activity relationship in a systematic way. The study could motivate the researchers for developing a wide array of β-lactam derivatives more prominently targeting newer pathways to fight MDR.

A multicenter Phase II randomized, placebo-controlled single-blind trial with the SV2A ligand seletracetam in photosensitive epilepsy patients.

The objective of this study was to evaluate the effect of seletracetam (SEL), a potent modulator of synaptic vesicle glycoprotein 2A (SV2A), in patients with photoparoxysmal EEG response (PPR) to intermittent photic stimulation (IPS) as proof-of-principle of efficacy in patients with epilepsy. In this multicenter, single-blind Phase II study, adults with photosensitive epilepsy, with/without concomitant antiseizure medication therapy, underwent IPS under 3 eye conditions (at eye closure, eyes closed and eyes open) after a single oral dose of placebo (day-1) or SEL (day 1; 0.5, 1, 2, 4, 10, or 20mg). Complete suppression was a standardized photosensitivity range reduction to 0 over≥1 time points for all eye conditions. Partial suppression was a≥3-point reduction over≥3 testing times vs the same time points on day-1 in≥1 eye condition. In addition, pharmacokinetics and safety were assessed. Of 27 evaluable patients, 9 reentered to receive a 2nd dosing 1-6months later, providing a total of 36 individual exposures. At all doses administered - even the lowest -, several subjects reached a complete abolishment of PPR, with a rapid onset of effect. Overall, complete abolishment of PPR was obtained in 40-71% of the patients; the effect increasing with the dose. In terms of effective doses to suppress PPR, SEL was at least 1,500 times more potent than levetiracetam and 10-20 times more potent than brivaracetam. Adverse events of SEL, including dizziness and somnolence, were mild to moderate. Pharmacokinetics of SEL demonstrated rapid absorption and a linear dose:plasma level relationship. This proof-of-principle study demonstrates that - based on our own experience - SEL is the most potent compound ever tested in the photosensitivity model.

(E)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1H-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer.

Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of 29 compounds was synthesized and examined by a preliminary screening in estrogen receptor (ER) and progesterone receptor (PR)-positive MCF-7 breast cancer cells together with cell cycle analysis and tubulin polymerization inhibition. Results: (E)-5-(3-(1H-1,2,4-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-methoxyphenol 22b was identified as a potent antiproliferative compound with an IC50 value of 0.39 mM in MCF-7 breast cancer cells, 0.77 mM in triple-negative MDA-MB-231 breast cancer cells, and 0.37 mM in leukemia HL-60 cells. In addition, compound 22b demonstrated potent activity in the sub-micromolar range against the NCI 60 cancer cell line panel including prostate, melanoma, colon, leukemia, and non-small cell lung cancers. G2/M phase cell cycle arrest and the induction of apoptosis in MCF-7 cells together with inhibition of tubulin polymerization were demonstrated. Immunofluorescence studies confirmed that compound 22b targeted tubulin in MCF-7 cells, while computational docking studies predicted binding conformations for 22b in the colchicine binding site of tubulin. Compound 22b also selectively inhibited aromatase. Conclusions: Based on the results obtained, these novel compounds are suitable candidates for further investigation as antiproliferative microtubule-targeting agents for breast cancer.

Fucoidan Oligosaccharide Supplementation Relieved Kidney Injury and Modulated Intestinal Homeostasis in D-Galactose-Exposed Rats.

Background/Objectives: A fucoidan oligosaccharide (FOS), a potent compound derived from algae, is known for its diverse biological activities, including prebiotic activity, anticancer activity, and antioxidative properties, and has demonstrated supportive therapeutic effects in treating kidney ailments. This study was conducted to explore the protective influence of FOS on kidney damage due to aging induced by D-galactose in Sprague Dawley (SD) rats. Methods: The low-dose FOS group was administered FOS (100 mg/kg) by gavage, and the high-FOS group received FOS (200 mg/kg) by gavage. Results: The findings showed that FOS could effectively mitigate kidney damage and improve the pathological condition of kidney tissues caused by D-gal and enhance kidney function. Intervention with FOS significantly reduced serum creatinine, serum uric acid, and serum urea nitrogen levels, compared to the model group. The protective mechanism of FOS on D-gal-induced kidney injury may be to inhibit oxidative stress and improve impaired mitochondrial function by downregulating the AMPK/ULK1 signaling pathway. FOS could also modulate the expression of mitochondrial autophagy-related proteins (Beclin-1, P62, and LC3II/LC3I), thereby mitigate D-gal-induced excessive mitophagy in the kidney. Furthermore, FOS may protect against kidney injury by preserving intestinal homeostasis. FOS decreased serum lipopolysaccharide levels and enhanced intestinal mucosal barrier function. FOS upregulated the abundances of Bacteroidota, Muribaculaceae, and Lactobacillus, while it decreased the abundances of Firmicutes, NK4A136_group, and Lachnospiraceae_NK4A136_group. FOS supplementation modulated gut microbiota composition, increasing beneficial bacteria and reducing detrimental ones, potentially contributing to improved kidney function. Conclusions: FOS may safeguard against renal injury in D-gal-exposed rats by inhibiting kidney excessive mitophagy, preserving mitochondrial function, and regulating intestinal homeostasis.

Discovery of PPAR Alpha Lipid Pathway Modulators That Do Not Bind Directly to the Receptor as Potential Anti-Cancer Compounds.

Peroxisome proliferator-activated receptors (PPARs) are considered good drug targets for breast cancer because of their involvement in fatty acid metabolism that induces cell proliferation. In this study, we used the KAIMRC1 breast cancer cell line. We showed that the PPARE-Luciferase reporter gets highly activated without adding any exogenous ligand when PPAR alpha is co-transfected, and the antagonist GW6471 can inhibit the activity. Using this reporter system, we screened 240 compounds representing kinase inhibitors, epigenetic modulators, and stem cell differentiators and identified compounds that inhibit the PPARα-activated PPARE-Luciferase reporter in the KAIMRC1 cell. We selected 11 compounds (five epigenetic modulators, two stem cell differentiators, and four kinase inhibitors) that inhibited the reporter by at least 40% compared to the controls (DMSO-treated cells). We tested them in a dose-dependent manner and measured the KAIMRC1 cell viability after 48 h. All 11 compounds induced the cell killing at different IC50 values. We selected two compounds, PHA665752 and NSC3852, to dissect how they kill KAIMRC1 cells compared to the antagonist GW6741. First, molecular docking and a TR-FRET PPARα binding assay showed that compared to GW6471, these two compounds could not bind to PPARα. This means they inhibit the PPARα pathway independently rather than binding to the receptor. We further confirmed that PHA665752 and NSC3852 induce cell killing depending on the level of PPARα expression, and as such, their potency for killing the SW620 colon cancer cell line that expresses the lowest level of PPARα was less potent than for the KAIMRC1 and MDA-MB-231 cell lines. Further, using an apoptosis array and fatty acid gene expression panel, we found that both compounds regulate the PPARα pathway by controlling the genes involved in the fatty acid oxidation process. Our findings suggest that these two compounds have opposite effects involving fatty acid oxidation in the KAIMRC1 breast cancer cell line. Although we do not fully understand their mechanism of action, our data provide new insights into the potential role of these compounds in targeting breast cancer cells.

Uses of Cyclohexan-1,3-diones to Synthesis Xanthenes Derivatives with Anti-proliferative Activity Against Cancer Cell Lines and their Inhibitions Toward Tyrosine Kinases.

Xanthene derivatives are a notable class of heterocyclic compounds widely studied for their significant biological impact. These molecules, found in both natural and synthetic forms, have attracted substantial scientific interest due to their broad spectrum of biological activities. The xanthene nucleus, in particular, is associated with a range of potential pharmaceutical properties, including antibacterial, antiviral, antiinflammatory, anticancer, and antioxidant effects. Their structural flexibility allows for modifications that can enhance specific biological functions, making them valuable candidates in medicinal chemistry and drug development. Multi-component reactions involving two equivalents of 5,5-dimethylcyclohexane-1,3-dione with aromatic aldehydes yield xanthene derivatives that are known for their biological activity. Additionally, fused xanthene derivatives are formed through subsequent heterocyclization reactions, resulting in compounds with a broad range of biological properties. Various xanthene derivatives incorporating thiophene and thiazole moieties were synthesized. Compounds 3a-c were further subjected to heterocyclization reactions to produce fused xanthene derivatives with additional heterocyclic components, enhancing their biological activity. The cytotoxic effects of the synthesized compounds were assessed across six cancer cell lines. Inhibition studies on c-Met kinase and the PC-3 cell line were conducted. Additionally, the compounds' inhibitory activity against tyrosine kinases was evaluated, and morphological changes in the A549 cell line were observed with the two most potent compounds. The synthesized heterocyclic compounds, derived from 5,5-dimethylcyclohexane-1,3-dione and related cyclohexanone derivatives, exhibited significant inhibitory effects across various cancer cell lines. Specifically, compounds 3b, 5c, 5d, 7b, 7c, 7d, 9a, 9b, 10b, 10c, 12c, 15b, 15c, 16b, 16c, 17c, 17d, 17e, and 17f demonstrated high levels of inhibition, indicating potential for further exploration of xanthene-based heterocyclic compounds to enhance anticancer properties.

Naphtho[1,2-b][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.

The P2X4 receptor is implicated in various pathological conditions, including neuropathic pain and cancer. This study reports the development of 1,4-naphthodiazepinedione-based P2X4 receptor antagonists aimed at both therapeutic applications and potential use as PET tracers for imaging P2X4 receptor expression in cancer. Structure-activity relationship studies aided by docking studies and molecular dynamics simulations led to a series of compounds with potent P2X4 receptor antagonism, promising in vitro inhibition of interleukin-1β release in THP-1 cells and suitability for radiolabeling with fluorine-18. The most potent compounds were further evaluated for their physicochemical properties, metabolic stability, and in vivo biodistribution using PET imaging in mice. While these antagonists exhibited strong receptor binding and serum stability, rapid in vivo metabolism limited their potential as PET tracers, highlighting the need for further structural optimization. This study advances the understanding of P2X4 receptor antagonism and underscores the challenges in developing effective PET tracers for this target.

Improving Antioxidant Effect of Stemona tuberosa by Fermentation with Endophytic Fungus Penicillium expansum STRB13

Background: Stemona tuberosa Lour. is a plant belonging to the genus Stemona (Stemonaceae) that has been utilized in traditional Chinese medicine (TCM) for its antitussive and antiparasitic properties. Endophytic fungi have been shown to play an important role in the growth and metabolism of plants. Fermentation involving endophytic fungi tends to result in the production of new or more potent pharmacological compounds. Objective: The study aims to enhance the antioxidant activity of S. tuberosa by fermenting it with a symbiotic endophytic fungus. Methods: Seven symbiotic endophytic fungi were used to screen and ferment S. tuberosa to improve antioxidant activity estimated by 2,2’-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and ferric ion-reducing antioxidant power (FRAP). The chemical constituent changes were characterized by ultraviolet (UV) spectrum and high-performance liquid chromatography (HPLC) analysis. Results: Penicillium expansum STRB13, an endophytic fungus associated with S. tuberosa, was screened for its ability to enhance antioxidant capacity through fermentation. The fermentation of S. tuberosa using P. expansum STRB13 significantly improved its DPPH radical scavenging activity, achieving an IC50 value of 24.2 μg/mL. Additionally, the ferric reducing antioxidant power (FRAP) of the fermented sample was fourteen times greater, measuring 388.1 ± 32.6 μmol/L compared to 27.5 ± 1.0 μmol/L in the blank sample. Differences observed between the blank and P. expansum STRB13 fermented S. tuberosa (FST) in UV spectra and HPLC analysis indicated the production of new aromatic phenolic compounds through fermentation, which contributed to the enhanced antioxidant activity. Conclusion: This is the first time reporting on the fermentation processing of S. tuberosa with symbiotic endophytic fungus. This study revealed that P. expansum STRB13 FST will be an alternative natural antioxidant. Fermentation with symbiotic endophytic fungus is a new approach to processing TCM and discovering new compounds.

Integrating machine learning and structure-based approaches for repurposing potent tyrosine protein kinase Src inhibitors to treat inflammatory disorders

Tyrosine-protein kinase Src plays a key role in cell proliferation and growth under favorable conditions, but its overexpression and genetic mutations can lead to the progression of various inflammatory diseases. Due to the specificity and selectivity problems of previously discovered inhibitors like dasatinib and bosutinib, we employed an integrated machine learning and structure-based drug repurposing strategy to find novel, targeted, and non-toxic Src kinase inhibitors. Different machine learning models including random forest (RF), k-nearest neighbors (K-NN), decision tree, and support vector machine (SVM), were trained using already available bioactivity data of Src kinase targeting compounds. The performance evaluation of these models demonstrated SVM as the best model, which was further utilized to shortlist 51 highly potent compounds by screening an FDA-approved library of 1040 drugs. Molecular docking and molecular dynamic simulation were subsequently employed to evaluate the binding affinity and stability of the proposed compounds. Orlistat, acarbose and afatinib were identified as the potent leads, demonstrating stable conformations and stronger interactions, validated by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (RoG), and hydrogen bond analyses. Molecular Mechanics/Generalized Born Surface Area (MMGBSA) analysis validated their binding affinities by providing comparably lower binding free energies for orlistat (− 33.4743 ± 3.8908), acarbose (− 19.5455 ± 5.4702), and afatinib (− 36.4944 ± 5.4929) than the control, dasatinib (− 13.7785 ± 5.8058). Finally, toxicity analysis revealed orlistat and acarbose as the possible safer therapeutics by eliminating afatinib as it showed significant toxicity concerns. Our investigation supports the advance computational methods utilization in the field of drug discovery and suggest further experimental validation of proposed inhibitors of Src kinase for their safer use against inflammatory diseases. The ultimate aim of this study is to advance the development of effective treatments for inflammatory diseases, linked with Src overexpression.

Anti-Biofilm Agents to Overcome Pseudomonas aeruginosa Antibiotic Resistance.

Pseudomonas aeruginosa is one of world's most threatening bacteria. In addition to the emerging prevalence of multi-drug resistant (MDR) strains, the bacterium also possesses a wide variety of virulence traits that worsen the course of the infections. Particularly, its ability to form biofilms that protect colonies from antimicrobial agents is a major cause of chronic and hard-to-treat infections in immune-compromised patients. This protective barrier also ensures cell growth on abiotic surfaces and thus enables bacterial survival on medical devices. Hence, as the WHO alerted to the need to develop new treatments, the use of anti-biofilm agents (ABAs) appeared as a promising approach. Given the selection pressure imposed by conventional antibiotics, a new therapeutic strategy has emerged that aims at reducing bacterial virulence without inhibiting cell growth. So-called anti-virulence agents (AVAs) would then restore the efficacy of conventional antibiotics (ATBs) or potentiate the effectiveness of the immune system. The last decade has seen the development of ABAs as AVAs against P. aeruginosa. This review aims to highlight the design strategy and critical features of these molecules to pave the way for further discoveries of highly potent compounds.

Development of 1,2,3-triazole hybrids as multi-faced anticancer agents co-targeting EGFR/mTOR pathway and tubulin depolymerization.

Novel 1,2,3-triazole hybrids bearing various substituents have been synthesized as potential anticancer agents. Ligand-based approach has been adopted to design these compounds relying on the hybridization of 1,2,3-triazole with α,β-unsaturated carbonyl, 5- and 6-membered heterocyclic scaffolds. All synthesized members were investigated for their cytotoxic potency against nine types comprising 60 panels of human cancerous cells by the US National Cancer Institute: Development Therapeutic Program (US_NCI_DTP). Among the tested members, 4b, 4e, and 4h showed prominent cytotoxic effects (> 80% growth inhibition: GI) on a wide panel of tested cancer cell lines, mainly melanoma and colorectal cancer redeeming their selection for five dose testing. Presenting low nanomolar GI50 concentrations, two representative potent anticancer compounds 4b and 4e were subjected to cytotoxicity testing on colon normal cell (FHC) to investigate their safety window and they showed less toxicity to normal cells at the concentration required to produce anticancer effect. Furthermore, 4b and 4e were exposed to additional mechanistic studies in colorectal cancer cell HCT-116 suggesting multifaceted mechanisms of action. A study into the effects of cytotoxic chemicals 4b and 4e on cell cycle progression regulation showed triggered the arrest of cell cycles during the G1 and S phases. Moreover, 4b and 4e caused cell death mainly through apoptosis the thing that has been reinforced by the elevated Bax: Bcl2 ratio, as well as concentrations of caspases 3 and 9 within HCT-116. Further, both compounds showed prominent inhibition profiles against tubulin polymerization as well as EGFR catalytic activity reaching down to low-digit micromolar and sub-micromolar concentrations, respectively, as compared to positive reference controls. Compounds' impacts on gene expression of cancer-associated and EGFR-downstream signaling markers including TNFα, IL-6, and mTOR, were explored in HCT-116 highlighted significant downregulations versus the untreated cells. Docking studies demonstrated the specific fit of 4b and 4e into EGFR and the colchicine binding site of tubulin.