Molecular docking, synthesis, characteristics and preliminary cytotoxic study of new coumarin-sulfonamide derivatives as histone deacetylase inhibitors.

OBJECTIVE: Aim: To evaluate the cytotoxic activity of newly synthesized a series of novel HDAC inhibitors comprising sulfonamide as zinc binding group and Coumarin as cap groups. PATIENTS AND METHODS: Materials and Methods: The utilization of sulfonamide as zinc binding group and Coumarin as cap groups known to possess antitumor activity in the designed of new histone deacetylase inhibitors and using the docking and MTT assay to evaluate the compounds. RESULTS: Results: Four compounds have been synthesized and characterized successfully by ART-FTIR, NMR and ESI-Ms. The synthesized compound assessed for their cytotoxic activity against hepatoblastoma HepG2 (IC50, I=0.094, II=0.040, III=0.032, IV=0.046, SAHA=0.141) and human colon adenocarcinoma MCF-7 (IC50, I=0.135, II=0.050, III= 0.065, IV=0.059, SAHA=0.107). The binding mode to the active site of [HDAC6] were determined by docking study which give results that they might be good inhibitors for [HDAC6]. CONCLUSION: Conclusions: The synthesized compounds (I, II, III and IV) showed a comparable cytotoxic result with FDA approved drug (SAHA) toward HepG2 and MCF-7 cancer cell lines and their docking analysis provided a preliminary indication that they are viable [HDAC6] candidates.

Novel natural osthole-inspired amphiphiles as membrane targeting antibacterials against methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Herein, we designed and prepared a series of novel osthole amphiphiles 6a-6ad by mimicking the structures and function of antimicrobial peptides (AMPs). Antibacterial assays showed that osthole amphiphile 6aa strongly inhibited S. aureus and 10 clinical MRSA isolates with MIC values of 1-2 µg/mL, comparable to that of the commercial antibiotic vancomycin. Additionally, 6aa had the advantages of rapid bacteria killing without readily developing drug resistance, low toxicity, good membrane selectivity, and good plasma stability. Mechanistic studies indicated that 6aa possesses good membrane-targeting ability to bind to phosphatidylglycerol (PG) on the bacterial cell membranes, thereby disrupting the cell membranes and causing an increase in intracellular ROS as well as leakage of proteins and DNA, and accelerating bacterial death. Notably, in vivo activity results revealed that 6aa exhibits strong anti-MRSA efficacy than vancomycin as well as a substantial reduction in MRSA-induced proinflammatory cytokines, including TNF-α and IL-6. Given the impressive in vitro and in vivo anti-MRSA efficacy of 6aa, which makes it a potential candidate against MRSA infections.

Bioassay-Guided and DeepSAT-Driven Precise Mining of Monoterpenoid Coumarin Derivatives with Antifeedant Effects from the Leaves of Ailanthus altissima.

Demand for the exploration of botanical pesticides continues to increase due to the detrimental effects of synthetic chemicals on human health and the environment and the development of resistance by pests. Under the guidance of a bioactivity-guided approach and HSQC-based DeepSAT, 16 coumarin derivatives were discovered from the leaves of Ailanthus altissima (Mill.) Swingle, including seven undescribed monoterpenoid coumarins, three undescribed monoterpenoid phenylpropanoids, and two new coumarin derivatives. The structure and configurations of these compounds were established and validated via extensive spectroscopic analysis, acetonide analysis, and quantum chemical calculations. Biologically, 5 exhibited significant antifeedant activity toward the Plutella xylostella. Moreover, tyrosinase being closely related to the growth and development of larva, the inhibitory potentials of 5 against tyrosinase was evaluated in vitro and in silico. The bioactivity evaluation results highlight the prospect of 5 as a novel category of botanical insecticide.

Antibacterial Activity and Mechanism of Action of Osthole against Listeria monocytogenes.

The purpose of this study was to investigate the antibacterial activity and mechanism of action of osthole against Listeria monocytogenes. The antibacterial activity of osthole was evaluated by determining the minimum inhibitory concentration (MIC) and growth curve. Cell morphology, membrane permeability, membrane integrity, bacterial physiology, and metabolism were explored using different methods to elucidate the mechanism of action of osthole. It was shown that the MIC of osthole against L. monocytogenes was 62.5 µg/mL and it inhibited the growth of L. monocytogenes effectively in a concentration-dependent manner. Scanning electron microscopy (SEM) images demonstrated morphology changes of L. monocytogenes, including rough surface, cell shrinkage, and rupture. It was found that extracellular conductivity and macromolecule content were increased significantly in the presence of osthole, indicating the disruption of cell membrane integrity and permeability. Laser confocal microscopy results supported the conclusion that osthole caused severe damage to the cell membrane. It was also noticed that osthole depleted intracellular adenosine triphosphate (ATP), inhibited Na+-K+-ATPase and Ca2+-Mg2+-ATPase activity, and promoted the accumulation of intracellular reactive oxygen species (ROS), leading to cell death. This study suggests that osthole is a promising antibacterial agent candidate against L. monocytogenes, and it shows potential in the prevention and control of foodborne pathogens.

Synthesis, biofilm formation inhibitory, and inflammation inhibitory activities of new coumarin derivatives.

Coumarins are heterocycles of great interest in the development of valuable active structures in chemistry and biological domains. The ability of coumarins to inhibit biofilm formation of Gram positive bacterium (Staphylococcus aureus), Gram negative bacterium (Escherichia coli) as well as the methicillin-resistant S. aureus (MRSA) has been previously described. In the present work, new hybrid coumarin-heterocycles have been synthesized via the reaction of coumarin-6-sulfonyl chloride and 6-aminocoumarin with different small heterocycle moieties. The biological efficacy of the new compounds was evaluated towards their ability to inhibit biofilm formation and their anti-inflammatory properties. The antimicrobial activities of the newly synthesized compounds were tested against Gram positive bacterium (S. aureus ATCC 6538), Gram negative bacterium (E. coli ATCC 25922), yeast (Candida albicans ATCC 10231) and the fungus (Aspergillus niger NRRL-A326). Compounds 4d, 4e, 4f, 6a and 9 showed significant MIC and MBC values against S. aureus, E. coli, C. albicans, and methicillin-resistant S. aureus (MRSA) with especial incidence on compound 9 which surpasses all the other compounds giving MIC and MBC values of (4.88 and 9.76 µg/mL for S. aureus), (78.13 and 312.5 µg/mL for E. coli), (9.77 and 78.13 µg/mL for C. albicans), and (39.06 and 76.7 µg/mL for MRSA), respectively. With reference to the antibiofilm activity, compound 9 exhibited potent antibiofilm activity with IC50 of 60, 133.32, and 19.67 µg/mL against S. aureus, E. coli, and MRSA, (respectively) considering the reference drug (neomycin). Out of all studied compounds, the anti-inflammatory results indicated that compound 4d effectively inhibited nitric oxide production in lipopolysaccharide-(LPS-) stimulated RAW264.7 macrophage cells, giving NO% inhibition of 70% compared to Sulindac (55.2%).

Vasorelaxant and Blood Pressure-Lowering Effects of Cnidium monnieri Fruit Ethanol Extract in Sprague Dawley and Spontaneously Hypertensive Rats.

Cnidium monnieri (L.) Cusson, a member of the Apiaceae family, is rich in coumarins, such as imperatorin and osthole. Cnidium monnieri fruit (CM) has a broad range of therapeutic potential that can be used in anti-bacterial, anti-cancer, and sexual dysfunction treatments. However, its efficacy in lowering blood pressure through vasodilation remains unknown. This study aimed to assess the potential therapeutic effect of CM 50% ethanol extract (CME) on hypertension and the mechanism of its vasorelaxant effect. CME (1-30 µg/mL) showed a concentration-dependent vasorelaxation on constricted aortic rings in Sprague Dawley rats induced by phenylephrine via an endothelium-independent mechanism. The vasorelaxant effect of CME was inhibited by blockers of voltage-dependent and Ca2+-activated K+ channels. Additionally, CME inhibited the vascular contraction induced by angiotensin II and CaCl2. The main active compounds of CM, i.e., imperatorin (3-300 µM) and osthole (1-100 µM), showed a concentration-dependent vasorelaxation effect, with half-maximal effective concentration values of 9.14 ± 0.06 and 5.98 ± 0.06 µM, respectively. Orally administered CME significantly reduced the blood pressure of spontaneously hypertensive rats. Our research shows that CME is a promising treatment option for hypertension. However, further studies are required to fully elucidate its therapeutic potential.

Evaluation of expression level of BANCR, MALAT1 and FER1L4 and their target genes in coumarin-treated AGS cell line.

Because long non-coding RNAs (lncRNAs) can affect several interconnected processes, its value as a predictive marker for gastric cancer has been demonstrated. Coumarin - a natural compound known to contain some beneficial antitumor qualities - was tested for its effects on AGS gastric cancer cells. In this study, we investigated the expression level of selected cellular lncRNAs (BANCR, MALAT1 and FER1L4) and their target genes (PTEN, p-PI3K and p-AKT) in coumarin-treated AGS cell line. The expressions of the three lncRNAs: BANCR, MALAT1 and FER1L4, as well as their specified targets, PTEN, PI3K and AKT, were measured by qRT-PCR. To gauge the impact of coumarin on the AGS cells, a MTT assay was utilized. A Western blot has been employed to assess variations in PTEN, p-PI3K, and p-AKT expression. The experiment's results showed that AGS viability diminished with increasing doses of coumarin. Compared to the control cells, the cells exposed to coumarin had showed reduced levels of mRNAs which are known targets of the lncRNA BANCR. At the same time, levels of lncRNAs MALAT1 and FER1L4 within coumarin group have been higher comparing to those within control group. Additionally, the Western blot analysis revealed that the coumarin-treated cells expressed lower levels of p-PI3K, PTEN as well as p-AKT compared to control group. This information points to coumarin being a possible option in a treatment regimen for gastric cancer due to its ability to affect lncRNAs and the molecules they target.

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles.

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

Coumarin-azasugar-benzyl conjugates as non-neurotoxic dual inhibitors of butyrylcholinesterase and cancer cell growth.

We have applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to prepare a library of ten coumarin-azasugar-benzyl conjugates and two phthalimide-azasugar-benzyl conjugates with potential anti-Alzheimer and anti-cancer properties. The compounds were evaluated as cholinesterase inhibitors, demonstrating a general preference, of up to 676-fold, for the inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC50 = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI50 = 5.6 ± 1.1 µM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity.

Multifunctional fluorescent probe for simultaneous revealing Cys and ONOO- dynamic correlation in the ferroptosis.

Ferroptosis is a type of lipid peroxidation-induced apoptosis brought on by imbalances in iron metabolism and redox. It involves both the thiol-associated anti-ferroptosis pathway and the excessive buildup of reactive oxygen species (ROS), which stimulates the ferroptosis pathway. Determining the precise control mechanism of ferroptosis requires examining the dynamic connection between reactive sulfur species (RSS) and ROS. Cysteine (Cys) and peroxynitrite (ONOO-) are highly active redox species in organisms and play dynamic roles in the ferroptosis process. In this study, a coumarin dye was conjugated with specific response sites for Cys and ONOO-, enabling the simultaneous detection of Cys and ONOO- through the green and red fluorescence channels, respectively (λem = 498 nm for Cys and λem = 565 nm for ONOO-). Using the probe LXB, we monitored the changes in Cys and ONOO- levels in the ferroptosis pathway induced by erastin. The results demonstrate a significant generation of ONOO- and a noticeable decrease in intracellular Cys levels at the beginning upon erastin treatment and finally maintains a relatively low level. This study presents the first probe to investigate the intracellular redox modulation and control between Cys and ONOO- during ferroptosis, providing valuable insights into the potential mutual correlation between Cys and ONOO- in this process.

Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice.

Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases.

Design, synthesis and in vitro evaluation of novel thiazole-coumarin hybrids as selective and potent human carbonic anhydrase IX and XII inhibitors.

The coumarin is one of the most promising classes of non-classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. In continuation of our ongoing work on search of coumarin based selective carbonic anhydrase inhibitors, a new series of 6-aminocoumarin based 16 novel analogues of coumarin incorporating thiazole (4a-p) have been synthesized and studied for their hCA inhibitory activity against a panel of human carbonic anhydrases (hCAs). Most of these newly synthesized compounds exhibited interesting inhibition constants in the nanomolar range. Among the tested compounds, the compounds 4f having 4-methoxy substitution exhibited activity at 90.9 nM against hCA XII isoform. It is noteworthy to see that all compounds were specifically and selectively active against isoforms hCA IX and hCA XII, with Ki under 1000 nM range. It is anticipated that these newly synthesized coumarin-thiazole hybrids (4a-p) may emerge as potential leads candidates against hCA IX and hCA XII as selective inhibitors compared to hCA I and hCA II.

Osthole ameliorates early diabetic kidney damage by suppressing oxidative stress, inflammation and inhibiting TGF-ß1/Smads signaling pathway.

BACKGROUND: Osthole is a natural active ingredient extracted from the traditional Chinese medicine Cnidium monnieri. It has been demonstrated to have anti-inflammatory, anti-fibrotic, and anti-hyperglycemic properties. However, its effect on diabetic kidney disease (DKD) remains uncertain. This study aims to assess the preventive and therapeutic effects of osthole on DKD and investigate its underlying mechanisms. METHODS: A streptozotocin/high-fat and high-sucrose diet induced Type 2 diabetic rat model was established. Metformin served as the positive drug control. Diabetic rats were treated with metformin or three different doses of osthole for 8 weeks. Throughout the treatment period, the progression of DKD was assessed by monitoring increases in urinary protein, serum creatinine, urea nitrogen, and uric acid, along with scrutinizing kidney pathology. Enzyme-linked immunosorbent assay (ELISA) was employed to detect inflammatory factors and oxidative stress levels. At the same time, immunohistochemical staining was utilized to evaluate changes in alpha-smooth muscle actin, fibronectin, E-cadherin, and apoptosis. The alterations in TGF-ß1/Smads signaling pathway were ascertained through western blot and immunofluorescence. Furthermore, we constructed a high glucose-stimulated HBZY-1 cells model to uncover its molecular protective mechanism. RESULTS: Osthole significantly reduced fasting blood glucose, insulin resistance, serum creatinine, uric acid, blood urea nitrogen, urinary protein excretion, and glomerular mesangial matrix deposition in diabetic rats. Additionally, significant improvements were observed in inflammation, oxidative stress, apoptosis, and fibrosis levels. The increase of ROS, apoptosis and hypertrophy in HBZY-1 cells induced by high glucose was reduced by osthole. Immunofluorescence and western blot results demonstrated that osthole down-regulated the TGF-ß1/Smads signaling pathway and related protein expression. CONCLUSION: Our findings indicate that osthole exhibits potential preventive and therapeutic effects on DKD. It deserves further investigation as a promising drug for preventing and treating DKD.

Synthesis of novel coumarin-triazole hybrids and first evaluation of the 4-phenyl substituted hybrid loaded PLGA nanoparticles delivery system to the anticancer activity.

Despite the discovery of many chemotherapeutic drugs that prevent uncontrolled cell division processes in the last century, many studies are still being carried out to develop drugs with higher anticancer efficacy and lower level of side effects. Herein, we designed, synthesized, and characterized six novel coumarin-triazole hybrids, and evaluated for anticancer activity of the one with the highest potential against the breast cancer cell line, MCF-7 and human cervical cancer cell line, human cervical adenocarcinoma (HeLa). Compound21which was the coumarin derivative including phenyl substituent with the lowest IC50 value displayed the highest cytotoxicity against the studied cancer cell line. Furthermore, the potential use of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) prepared by the emulsifying solvent evaporation method as a platform for a drug delivery system was studied on a selected coumarin derivative21. This coumarin derivative-loaded PLGA NPs were produced with an average size of 225.90 ± 2.96 nm, -16.90 ± 0.85 mV zeta potential, and 4.12 ± 0.90% drug loading capacity. The obtained21-loaded PLGA nanoparticles were analyzed spectroscopically and microscopically with FT-IR, UV-vis, and scanning electron microscopy as well as thermogravimetric analysis, Raman, and x-ray diffraction. Thein vitrorelease of21from the nanoparticles exhibited a controlled release profile just over one month following a burst release in the initial six hours and in addition to this a total release ratio of %50 and %85 were obtained at pH 7.4 and 5.5, respectively.21-loaded PLGA nanoparticles displayed remarkably effective anticancer activity than21. The IC50 values were determined as IC50(21-loaded PLGA nanoparticles): 0.42 ± 0.01 mg ml-1and IC50(free21molecule): 5.74 ± 3.82 mg ml-1against MCF-7 cells, and as IC50(21-loaded PLGA nanoparticles): 0.77 ± 0.12 mg ml-1and IC50(free21molecule): 1.32 ± 0.31 mg ml-1against HeLa cells after the incubation period of 24 h. Our findings indicated that triazole-substituted coumarins may be used as an anticancer agent by integrating them into a polymeric drug delivery system providing improved drug loading and effective controlled drug release.

Urolithin-A Promotes CD8+ T Cell-mediated Cancer Immunosurveillance via FOXO1 Activation.

Naïve T cells are key players in cancer immunosurveillance, even though their function declines during tumor progression. Thus, interventions capable of sustaining the quality and function of naïve T cells are needed to improve cancer immunoprevention.In this context, we studied the capacity of Urolithin-A (UroA), a potent mitophagy inducer, to enhance T cell-mediated cancer immunosurveillance.We discovered that UroA improved the cancer immune response by activating the transcription factor FOXO1 in CD8+ T cell. Sustained FOXO1 activation promoted the expression of the adhesion molecule L-selectin (CD62L) resulting in the expansion of the naïve T cells population. We found that UroA reduces FOXO1 phosphorylation favoring its nuclear localization and transcriptional activity. Overall, our findings determine FOXO1 as a novel molecular target of UroA in CD8+ T cells and indicate UroA as promising immunomodulator to improve cancer immunosurveillance. SIGNIFICANCE: Urolithin-A, a potent mitophagy inducer, emerges as a promising tool to enhance cancer immunosurveillance by activating the FOXO1 transcription factor in CD8+ T cells. This activation promotes the expansion of naïve T cells, offering a novel avenue for improving cancer immune response and highlighting UroA as a potential immunomodulator for bolstering our body's defenses against cancer.

Identification and potential application of key insecticidal metabolites in Tilia amurensis, a low-preference host of Hyphantria cunea.

Developing effective insecticidal strategies is an important means of reducing the spread and host plant damage by Hyphantria cunea. In this study, key metabolites with insecticidal activity against H. cunea were screened by targeted metabolomics in Tilia amurensis, a low-preference host plant. Subsequently, the potential of key metabolites that could be used as botanical pesticides was evaluated. The results showed that coumarin was the key insecticidal metabolite of T. amurensis and had a significant insecticidal effect and weight inhibition effect on H. cunea larvae. Coumarin treatment significantly decreased the larval nutrient content and the gene expression of rate-limiting enzymes in the glycolytic pathway and tricarboxylic acid cycle. A significantly enhanced detoxification enzyme activity (CarE and GST), antioxidant oxidase activity (SOD and CAT), non-enzymatic antioxidant levels (GSH), and total antioxidant capacity were observed in coumarin-treated larvae. Coumarin treatment resulted in a significant increase in the expression levels of detoxification enzyme genes (CarE1, CarE2, CarE3, GST2, and GST3) and antioxidant oxidase genes (SOD1, CAT1, and CAT2) in H. cunea larvae. Coumarin treatment significantly increased the levels of MDA and H2O2 in larvae but did not cause pathological changes in the ultrastructure of the larval midgut. Coumarin solution sprayed directly or as a microcapsule suspension formulation with coumarin as the active ingredient had significant insecticidal activity against the H. cunea larvae. Overall, coumarin, a key anti-insect metabolite identified from T. amurensis, can significantly inhibit the growth and survival of H. cunea larvae and has the potential to be developed as a botanical pesticide.

Synthesis and evaluation of coumarin derivatives on antioxidative, tyrosinase inhibitory activities, melanogenesis, and in silico investigations.

New coumarin derivatives were designed using a 2-(2-oxo-2H-chromen-4-yl)acetic acid scaffold conjugated with amino acid esters or tyramine. The anti-tyrosinase and anti-lipid peroxidation activities of the synthesized compounds were investigated. Coumarin derivatives 7,9, 11-13, 15-18 showed strong anti-lipid peroxidation activity. Compound 13 exhibited uncompetitive tyrosinase inhibitory activity with an IC50 value of 68.86 µM. Compound 14 (% activity = 123.41) showed stronger tyrosinase activating activity than 8-methoxypsolaren (8-MOP, % activity = 109.46). In silico studies revealed different poses between the inhibitors and activators near the tyrosinase catalytic site. Compounds 13 (25-50 µM) and 14 (25-100 µM) did not show cytotoxicity against B16F10 cells. In contrast to the tyrosinase inhibition assay, compound 13 (50 µM) suppressed melanogenesis in B16F10 cells with two times higher potency than KA (100 µM). Compound 14 at 100 µM showed melanogenesis enhancement in B16F10 cells in a dose-dependent manner, however, inferior to the 8-MOP. Based on the findings, compound 13 and 14 offer potential for development as skin-lightening agents and vitiligo therapy agents, respectively.

Cocrystals of a coumarin derivative: an efficient approach towards anti-leishmanial cocrystals against MIL-resistant Leishmania tropica.

Leishmaniasis is a neglected parasitic tropical disease with numerous clinical manifestations. One of the causative agents of cutaneous leishmaniasis (CL) is Leishmania tropica (L. tropica) known for causing ulcerative lesions on the skin. The adverse effects of the recommended available drugs, such as amphotericin B and pentavalent antimonial, and the emergence of drug resistance in parasites, mean the search for new safe and effective anti-leishmanial agents is crucial. Miltefosine (MIL) was the first recommended oral medication, but its use is now limited because of the rapid emergence of resistance. Pharmaceutical cocrystallization is an effective method to improve the physicochemical and biological properties of active pharmaceutical ingredients (APIs). Herein, we describe the cocrystallization of coumarin-3-carboxylic acid (CU, 1a; 2-oxobenzopyrane-3-carboxylic acid, C10H6O4) with five coformers [2-amino-3-bromopyridine (1b), 2-amino-5-(trifluoromethyl)-pyridine (1c), 2-amino-6-methylpyridine (1d), p-aminobenzoic acid (1e) and amitrole (1f)] in a 1:1 stoichiometric ratio via the neat grinding method. The cocrystals 2-6 obtained were characterized via single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis, as well as Fourier transform infrared spectroscopy. Non-covalent interactions, such as van der Waals, hydrogen bonding, C-H...π and π...π interactions contribute significantly towards the packing of a crystal structure and alter the physicochemical and biological activity of CU. In this research, newly synthesized cocrystals were evaluated for their anti-leishmanial activity against the MIL-resistant L. tropica and cytotoxicity against the 3T3 (normal fibroblast) cell line. Among the non-cytotoxic cocrystals synthesized (2-6), CU:1b (2, IC50 = 61.83 ± 0.59 µM), CU:1c (3, 125.7 ± 1.15 µM) and CU:1d (4, 48.71 ± 0.75 µM) appeared to be potent anti-leishmanial agents and showed several-fold more anti-leishmanial potential than the tested standard drug (MIL, IC50 = 169.55 ± 0.078 µM). The results indicate that cocrystals 2-4 are promising anti-leishmanial agents which require further exploration.

Design, synthesis and mechanism study of coumarin-sulfonamide derivatives as carbonic anhydrase IX inhibitors with anticancer activity.

In this study, twenty-nine coumarin-3-sulfonamide derivatives, twenty-seven of which are original were designed and synthesized. Cytotoxicity assay indicated that most of these derivatives exhibited moderated to good potency against A549 cells. Among them, compound 8q showed potent inhibition against the four tested cancer cell lines, especially A549 cells with IC50 value of 6.01 ± 0.81 µM, and much lower cytotoxicity on the normal cells was observed compared to the reference compounds. Bioinformatics analysis revealed human carbonic anhydrase IX (CAIX) was highly expressed in lung adenocarcinoma (LUAD) and associated with poor prognosis. The inhibitory activity of compound 8q against CAIX was assessed by using molecular docking and molecular dynamics simulations, which revealed prominent interactions of both compound 8q and CAIX at the active site and their high affinity. The results of ELISA assays verified that compound 8q possessed strong inhibitory activity against CAIX and high subtype selectivity, and could also down-regulate the expression of CAIX in A549 cells. Furthermore, the significant inhibitory effects of compound 8q on the migration and invasion of A549 cells were also found. After treatment with compound 8q, intracellular reactive oxygen species (ROS) levels increased and mitochondrial membrane potential (MMP) decreased. Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.

3-Acetyl coumarin alleviate neuroinflammatory responses and oxidative stress in aluminum chloride-induced Alzheimer's disease rat model.

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability and interrupts cognitive function. Heavy metal exposure like aluminum chloride is associated with neurotoxicity linked to neuro-inflammation, oxidative stress, accumulation of amyloid plaques, phosphorylation of tau proteins associated with AD like symptoms. The objective of the present investigation was to assess the effect 3-acetyl coumarin (3AC) in a rat model of AD. Preliminary screening was performed with SWISS ADME to check for the bioavailability of 3-AC and likeness score which proved favorable. 3-AC docked against Caspase 3, NF-κß and tau protein kinase I exhibited good binding energies. Male rats were divided into six groups (n = 5). AlCl3 (100 mg/kg BW) was administered for 28 days before starting treatment to induce AD. Normal control rats received vehicle. Treatment groups received 10, 20 and 30 mg/kg 3-AC for 28 days. Rivastigmine (2 mg/kg) was the standard. Behavioral tests (EPM, MWM) were performed at 7-day intervals throughout study period. Rats showed improved spatial memory and learning in treatment groups during behavioral tests. Rats were euthanized on day 28. Inflammatory markers (IL-1ß, IL-16 and TNFα) exhibited significant improvement (p < 0.001) in treated rats. Oxidative stress enzymes (SOD, CAT, GSH, MDA) were restored. Caspase3 and NF-κß quantified through qRT-PCR also decreased significantly (p < 0.001) when compared to disease control group. Levels of acetyl cholinesterase, dopamine and noradrenaline were also restored in treated rats significantly (p < 0.001). 3-AC treatment restored neuroprotection probably because of anti-inflammatory, anti-oxidant and anti-cholinesterase potential; hence, this can be considered a promising therapeutic potential alternative.