Inhibitory Activity Research Articles

1,3-Diaryl Triazenes Incorporating Disulfonamides Show Both Antiproliferative Activity and Effective Inhibition of Tumor-associated Carbonic Anhydrases IX and XII.

The aim of this study was to synthesize a library of novel di-sulfa drugs containing 1,3- diaryltriazene derivatives TS (1-13) by conjugation of diazonium salts of primary sulfonamides with sulfa drugs to investigate the cytotoxic effect of these new compounds in different cancer types and to determine their inhibitory activity against tumor-associated carbonic anhydrases IX and XII. A carbonic anhydrase inhibitory activity of the obtained compounds was evaluated against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII) by a stoppedflow CO2 hydrase assay. In addition, in vitro, cytotoxicity studies were applied by using A549 (lung cancer), BEAS-2B (normal lung), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), CRL-4010 (normal breast epithelium), HT-29 (colon cancer), and HCT -116 (colon cancer) cell lines. As a result of the inhibition data, the 4-aminobenzenesulfonamide derivatives were more active than their 3-aminobenzenesulfonamide counterparts. More specifically, compounds TS-1 and TS-2, both of which have primary sulfonamides on both sides of the triazene linker, showed the best inhibitory activity against hCA IX with Ki values of 19.5 and 13.7 nM and also against hCA XII with Ki values of 6.6 and 8.3 nM, respectively. In addition, in vitro cytotoxic activity on the human breast cancer cell line MCF-7 showed that some derivatives of di-sulfa triazenes, such as TS-5 and TS-13, were more active than SLC-0111. With the aim of developing more potent and isoform-selective CA inhibitors, these novel hybrid molecules containing sulfa drugs, triazene linkers, and the classical primary sulfonamide chemotype may be considered an interesting example of effective enzyme inhibitors and important anticancer agents.

A computational discovery of hexokinase 2 inhibitors from Newbouldia laevis for Hepatocellular carcinoma (HCC) treatment

Newbouldia laevis, also known as the African Border Tree or Fever Tree, is a deciduous tree native to West Africa. The plant is valued for its medicinal properties and is used in traditional medicine for its antimicrobial and anti-inflammatory effects. N. laevis, is a storage tank of phytochemicals with huge health benefits and performances globally for the treatment and management of numerous disease conditions. Limited research exists on the usage of N. laevis for hepatocellular carcinoma (HCC) treatment. This study aims to explore the inhibitory activities of phytochemicals from N. laevis against the hexokinase 2 protein, a target in hepatocarcinoma (HCC) treatment. This study presents a unique in silico approach that includes ligand binding site prediction, molecular docking, molecular dynamics simulation, and Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) methods. A total of 35 phytochemicals with available 3D structures were identified through literature mining. The literature review highlighted the significance of hexokinase 2 protein as a target inhibitor in the treatment of hepatocellular carcinoma (HCC). Molecular docking experiment with the all the identified phytochemicals and hexokinase 2 revealed that all the identified phytochemicals had potential inhibitory activities against the target protein. Moreover, chrysarobin, apigenin and ursolic acid were the best inhibitors with lowest binding energy of −8.9 kcal/mol, −8.7 kcal/mol, and −8.5 kcal/mol, respectively. The docking experiment was validated by comparing the binding affinities with known reference drug Cabozantinib-S-malate (−8.3 kcal/mol). Further, molecular dynamics studies of complexes with the best docking scores and reference drug complexes were described in detail here. The results of 100 ns modeling (RMSD, RMSF, Rg and SASA) show extraordinary stability during the establishment of complexes with apigenin and ursolic acid, as well as favorable binding energy, which was determined theoretically by means of the MM/PBSA method, thereby increase the probability of their acting as promising and likely hexokinase 2 inhibitors. Therefore, the study predicted that apigenin and ursolic acid could be used as a potential inhibitor/antagonist for the hexokinase 2 enzyme.

Emodin Alcohols: Design, Synthesis, Biological Evaluation and Multitargeting Studies with DNA, RNA, and HSA.

A series of novel emodin alcohols were designed and prepared in an effort to overcome the increasing microorganism resistance. Novel emodin alcohols were prepared from commercial emodin and different nitrogen-containing heterocycles via different synthetic strategies, such as O-alkylation and N-alkylation. The antimicrobial activity of synthesized emodin compounds was evaluated in vitro by a two-fold serial dilution technique. The interaction of emodin compound 3d with biomolecule was researched using UV-vis spectroscopic method and fluorescence spectroscopy. Emodin compound 3d containing 2-methyl-5-nitro imidazole ring showed relatively good antimicrobial activity. Notably, it exhibited equivalent activity against S. aureus in comparison to the reference drug norfloxacin (MIC = 4 g/mL). The combination of strong active compound 3d with reference drugs showed better antimicrobial activity with less dosage and a broader antimicrobial spectrum than their separate use. Further research displayed that emodin compound 3d could intercalate into S. aureus DNA to form the 3d-DNA complex, which might correlate with the inhibitory activity. The hydrogen bonds were found between S. aureus DNA gyrase and strong active compound 3d during the docking research, which were in accordance with the spectral experiment results. The interaction with yeast RNA of compound 3d could also form a complex via hydrogen bonds. The hydrogen bonds were found to play a major role in the transportation of emodin compound 3d by human serum albumin (HSA), as confirmed by molecular simulation. This work provides a promising starting point to optimize the structures of emodin derivatives as potent antimicrobial agents.

A New Bioactive Thiazolidinone-based Azo Dye for Naked-eye Colorimetric Detection of Cyanide Ions

Abstract: A new bioactive azo dye embedding a thiazolidinone heterocyclic core was designed and synthesized for antibacterial application and colorimetric sensing of cyanide ion (CNˉ) in organic solutions. The structure of the prepared dye was elucidated from its 1H NMR, FT-IR and UV-Vis spectral data. It proved to be a fast and sensitive colorogenic sensor for detection of CNˉ. Spectroscopic studies were carried out to investigate the effect of different CNˉ concentrations on the detection efficiency. Moreover, the studies revealed no significant competition or influence of other anions on the sensitivity of CNˉ detection by the synthesized dye. A Job's plot indicated a 1:1 stoichiometry of the dye and CNˉ in their colorful complex. Further development of the method for naked-eye detection of CNˉ in low-concentration aqueous solutions was achieved by using the cellulose papers painted with the dye. The as-prepared testing paper allowed CNˉ sensing in concentrations as low as 2 μM. Evaluation of the dye for antibacterial activities using the well diffusion technique displayed that its inhibitory activity is at least as good as and in some cases superior to ampicillin against the bacterial strains employed in the zone assay. In response to CN¯, the dye changes color from yellow to reddish brown which accounts for its significant interactions with CNˉ and affords a naked-eye sensing method without resorting to any spectroscopic instrumentation.

Characterization and evaluation of the in vitro and in vivo anti-diabetic activities of camel milk protein hydrolysates derived with different protease digestions

The study aimed to determine the potential anti-diabetic activities of the hydrolysates of camel milk proteins (CMPH). Camel milk proteins were hydrolyzed independently by using 11 proteases, and their anti-diabetic activities were analyzed by in vitro, and in vivo. The results showed that CMPH-Flavourzyme exhibited the best α-glucosidase and dipeptidyl peptidase-IV inhibitory activity, while CMPH-Papain exhibited the highest α-amylase inhibitory activity, and best proliferative effect on streptozotocin-induced NIT-1 cells in vitro. Furthermore, CMPH-Papain exhibited the most effect in decreasing the serum levels of fasting blood glucose, oral glucose tolerance test, pro-inflammatory factors (IL-1β, IL-6) and triglyceride, as well as increasing insulin levels on in vivo streptozotocin-induced diabetic mice. Peptides identification followed with molecular docking and network pharmacology analysis also found the potential anti-diabetic peptides from CMPH-Flavourzyme and CMPH-Papain. Our results indicated the type of protease used for the treatment significantly influences the anti-diabetic activities of the resulting CMPH.

Synthesis of New Glucose-containing 5-Arylisoxazoles and their Enzyme Inhibitory Activity

Abstract: Carbohydrates are an important group of biomolecules that have received special attention due to their significant role in the design and synthesis of new bioactive compounds. In this study, a new class of 5-arylisoxazole-glucose hybrids was designed and synthesized for evaluation of their inhibitory effects on α-glucosidase, α-amylase, and tyrosinase. The target compounds depicted selective α-glucosidase inhibitory activity over α-amylase, which is an important factor in reducing probable gastrointestinal problems in the treatment of type 2 diabetes. In this respect, compound 9a, possessing the phenylisoxazole group, was found to be the most potent α-glucosidase inhibitor (IC50 = 292.2 ± 0.1 μM) compared to acarbose (IC50 = 750.2 ± 0.1 μM) as the positive control. All compounds were also evaluated for their anti-tyrosinase effect, and among them, compound 9j, containing a fluoroaryl moiety, showed potent activity (IC50 = 50.1 ± 6.3 μM) in comparison to kojic acid (IC50 = 23.6 ± 2.6 μM). Also, docking studies were performed to investigate the probable mode of action, which indicated the construction of important H-bonding interactions between the sugar moiety and the enzyme’s active sites. According to the results, hybrids containing heterocycles attached to glucose can be used to inhibit α-glucosidase.

Activity of the Ethanolic Extract Obtained from Citrus microcarpa Pericarps against Meloidogyne enterolobii, and Chemical Composition Analysis

Citrus microcarpa is a popular nutritious fruit that is widely cultivated in China. In recent years, many compounds with significant pharmacological activities have been isolated successfully from the pericarp of C. microcarpa. However, to date, there are no reports on the activity of C. microcarpa pericarp against root-knot nematodes. This study used the ethanolic extract from the pericarp of Hainan C. microcarpa and the impregnation method to determine its activity on J2 Meloidogyne enterolobii specimens and on single-egg hatching. The results showed that when J2 individuals were treated with 50 mg⋅mL–1 of the extract, the lethal concentration 50 values after 24 and 48 hours were 17.124 and 8.858 mg⋅mL–1, respectively. The mortality rate of nematodes after 48 hours of treatment was 100%, and the inhibition rate of single-egg hatching after 24 hours was 89.29%. The ethanolic extract of C. microcarpa peels showed high inhibitory and lethal activity against the M. enterolobii. The analysis of the chemical composition of the extract revealed 28 substances with insecticidal and antibacterial effects, including lignans, flavonoids, fatty acids, organic acids, terpenoids, and imidazole. The formulas of the chemical structures and pharmacological effects of these potential insecticidal and antibacterial substances were elucidated to provide a scientific basis and a theoretical reference for the use of C. microcarpa pericarps as a raw material for the development of new, natural plant nematicides.

Screening and Activity Evaluation of Novel BCR-ABL/T315I Tyrosine Kinase Inhibitors.

Chronic myeloid leukemia (CML) is a kind of malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. BCR-ABL fusion protein, found in more than 90% of patients, is a vital target for discovering anti-CML drugs. Up to date, imatinib is the first BCR-ABL tyrosine kinase inhibitor (TKI) approved by the FDA for treating CML. However, the drug resistance problems appeared for many reasons, especially the T135I mutation, a "gatekeeper" of BCR-ABL. Currently, there is no long-term effective and low side effect drug in clinical. This study intends to find novel TKIs targeting BCR-ABL with high inhibitory activity against T315I mutant protein by combining artificial intelligence technology and cell growth curve, cytotoxicity, flow cytometry and western blot experiments. The obtained compound was found to kill leukemia cells, which had good inhibitory efficacy in BaF3/T315I cells. Compound No 4 could induce cell cycle arrest, cause autophagy and apoptosis, and inhibit the phosphorylation of BCR-ABL tyrosine kinase, STAT5 and Crkl proteins. The results indicated that the screened compound could be used as a lead compound for further research to discover ideal chronic myeloid leukemia therapeutic drugs.

Potentials of TPC and TFC as Free Radical Scavengers and Microbial Growth Inhibitors in Himalayan Endemic Artemisia sieversiana Ehrhl Ex Willd. (Asteraceae) Plant from Northeastern, Pakistan

Background: In various microorganisms, various defense mechanisms have evolved against the commercially available antimicrobial agents with increased resistance. Natural antimi-crobial agents of plant origin are better alternatives when an infectious disease arises due to resistant microbial strains. Here, we have evaluated the efficacy of total phenolics and total flavonoids with antioxidant and antimicrobial potential of Artemisia sieversiana Ehrhl Ex Willd. plant extracted with methanol, ethyl acetate, ethanol, n-hexane, and chloroform using soxhlet procedures Methods: The evaluation of TPC was achieved with Folin-Ciocalteu’s reagent method and quanti-tative estimation of TFC was done with the aluminum chloride colorimetric method. The antioxi-dant activities were estimated using FRSA-DPPH and TAC methods. The inhibitory activities of five solvent extracts of A. sieversiana against 2 gram-positive and 2 gram-negative pathogenic bac-terial strains (B. subtilis, P. aerogenosa, S. aureus, and E. coli) were evaluated using the well dif-fusion technique. Results: The highest percentage yields of A. sieversiana extracts were obtained in ethanol (4.8 g, 12.1%) and methanol (4.01 g, 10%), while minimum extract yield was obtained in n-hexane (0.53 g, 1.34%). Both phenolics and flavonoids were higher in ethanol, methanol, and ethyl acetate ex-tracts while minimal in n-hexane extracts. Ethanol extract has shown maximum (69%) DPPH ac-tivity with a lower IC50 value (181 μg/ml), while the highest IC50 values of 330 and 325μg/ml were recorded for n-hexane and ethyl acetate extracts. The ethyl acetate and chloroform extracts dis-played overall highest TAC values. All the tested extracts of A. sieversiana exhibited variable in-hibitory effects in a dose-dependent manner against the tested bacterial strains with minimum 9.08 ± 0.23 to maximum 21.23 ± 7.04 mm inhibition zones. Methanol and ethyl acetate extracts at 2 to 4 mg/ml showed greater MIC results against P. aeruginosa in comparison to the B. subtilis strain. Conclusion: The extracts of A. sieversiana have been found to be rich in TPC and TFC with re-markable antibacterial and antioxidant efficacies, and the plant extracts could be employed as pos-sible alternatives to synthetic drugs in various nutraceutical and pharmaceutical industries.

Design, synthesis, and antibacterial activity of pleuromutilin derivatives.

This paper reports the design, synthesis, and antibacterial activity study of pleuromutilin derivatives with 2-methyl-4-nitroaniline and 2-methoxy-4-nitroaniline side chains at the C22 position. The structures of the new compounds were characterized by 1H-NMR, 13C-NMR and HRMS. The inhibitory activity of the compounds against MSSA, pyogeniccoccus, streptococcus, and MRSA strains was determined using the micro broth dilution method. The results showed that the compounds exhibited certain activity against Gram-positive bacteria, among which compounds A8a, A8b, A8c, A8d, and A7 demonstrated superior antibacterial activity against MSSA, MRSA, and pyogeniccoccus compared to tiamulin, although the derivatives showed lower antibacterial activity against streptococcus compared to the control drug. Based on the favorable invitro activity of A8c, the time-kill kinetics against MRSA were evaluated, revealing that compound A8c could inhibit bacterial proliferation in a concentration-dependent manner.

Five new meroterpenes from the seeds of Psoralea corylifolia and their diacylglycerol acyltransferase activity

Five new meroterpenes (1−5), have been isolated and elucidated from the seeds of Psoralea corylifolia together with four known bakuchiol analogues (6−9). The structures of these compounds were elucidated by extensive spectroscopic analysis (NMR, HRESIMS and CD). Among them, compounds 1–9 were found to exhibit selective inhibitory activity on DGAT1 with IC50 values ranging from 54.4 ± 1.3 to 98.2 ± 1.1 μM.

Insight into the antibacterial properties of terpinen-4-ol on planktonic growth and biofilm-formation of Vibrio parahaemolyticus

Vibrio parahaemolyticus outbreaks emphasize the urgency of highly efficient prevention strategies to control this foodborne pathogen. This study investigated the antibacterial effects of terpinen-4-ol on V. parahaemolyticus RIMD2210633 and explored the underlying mechanism via RNA-seq analysis. The results showed that terpinen-4-ol inhibited V. parahaemolyticus efficiently with minimum inhibitory concentration and minimum bactericidal concentration values at 0.8 μL/mL. Scanning electron microscopy and PI/SYTO 9 staining assay demonstrated that cell morphology and cell membrane integrity were dose-dependently destructed. Additionally, biofilm formation was significantly inhibited according to crystal violet and MTT assay analysis. Notably, terpinen-4-ol showed good inhibitory activity against V. parahaemolyticus on salmon fillets via fumigation at 4 °C. Transcriptional analysis revealed significant downregulation of genes participated in cell wall formation (oppB, oppF), cell membrane integrity, pilus assembly protein, biofilm formation and cell motility (ToxR , LuxR), capsular polysaccharide biosynthesis protein, type IV pilin MshA and mannose-sensitive haemagglutinin type-IV pili (MSHA) biogenesis protein (MshJ, MshJ, MshK, MshL, MshN). The results demonstrated that terpinen-4-ol can efficiently inhibit the growth and pathogenicity of V. parahaemolyticus. With its safety and pleasant odor, terpinen-4-ol can be developed as a natural antibacterial substance to tackle V. parahaemolyticus contamination in food preservation and prevent associated diseases.

Tabersonine Induces the Apoptosis of Human Hepatocellular Carcinoma In vitro and In vivo.

Tabersonine, a natural indole alkaloid derived from Apocynaceae plants, exhibits antiinflammatory and acetylcholinesterase inhibitory activities, among other pharmacological effects. However, its anti-tumor properties and the underlying molecular mechanisms remain underexplored. The present study aims to investigate the anti-tumor effects of tabersonine and its mechanisms in inducing apoptosis in hepatocellular carcinoma. The inhibitory effects of tabersonine on the viability and proliferation of liver cancer cells were evaluated using MTT assay and colony formation assay. AO/EB, Hoechst, and Annexin V-FITC/ PI staining techniques were employed to observe cell damage and apoptosis. JC-1 staining was used to detect changes in mitochondrial membrane potential. Western blot analysis was conducted to study the anti-tumor mechanism of tabersonine on liver cancer cells. Additionally, a xenograft model using mice hepatoma HepG2 cells was established to assess the anti-tumor potency of tabersonine in vivo. Our findings revealed that tabersonine significantly inhibited cell viability and proliferation, inducing apoptosis in liver cancer cells. Treatment with tabersonine inhibited Akt phosphorylation, reduced mitochondrial membrane potential, promoted cytochrome c release from mitochondria to the cytoplasm, and increased the ratio of Bax to Bcl-2. These findings suggested that tabersonine induces apoptosis in liver cancer cells through the mitochondrial pathway. Furthermore, tabersonine treatment activated the death receptor pathway of apoptosis. In vivo studies demonstrated that tabersonine significantly inhibited xenograft tumor growth. Our study is the first to demonstrate that tabersonine induces apoptosis in HepG2 cells through both mitochondrial and death receptor apoptotic pathways, suggesting its potential as a therapeutic agent candidate for hepatic cancer.

CHEMICAL COMPOSITION AND INSECTICIDAL EFFICACY OF VITEX NEGUNDO L. ESSENTIAL OIL AGAINST FALL ARMYWORM, SPODOPTERA FRUGIPERDA (J. E. SMITH)

The fall armyworm, Spodoptera frugiperda, is a key pest ofmaize crops in tropical and subtropical regions and has developed resistanceagainst synthetic pesticides and Bacillus thuringiensis toxins. Thus,the experiments were designed to evaluate the chemical analysis andinsecticidal efficacy of Vitex negundo against S. frugiperda.Chemical analysis of V. negundo essential oil revealed a total of 36compounds, and the oil contained more monoterpenes (68.16%) than sesquiterpenes(22.21%) and diterpenes (13.56%). For the ovicidal and insecticidal activities,the essential oil was found to be most effective, with a median lethalconcentration (LC50) value of 51.31 µL/mL and 0.29 L/larvae, respectively.Larval antifeedant and growth inhibitory activity of essential oil werepositively correlated (R2 = 0.9645) and (R2 = 0.9727) with oil concentrations,respectively. Therefore, the V. negundo essential oil can be used forthe development of bioinsecticides to control S. frugiperda, a highlyinvasive and polyphagous pest, which will replace chemical pesticides.

Characterization, antioxidant and α-amylase inhibition of polysaccharides and phosphorylated derivatives from finger citron (Citrus medica L. var. sarcodactylis Swingle)

In this study, the structure-activity relationship of finger citron polysaccharides (FCPs) and their phosphorylated derivatives (P-FCPs) was investigated. Three FCPs (FCP20, FCP40 and FCP60) were successively fractionated by ethanol, and were phosphorylated modification to obtain P-FCPs (P-FCP20, P-FCP40 and P-FCP60). FCPs and P-FCPs are acidic heteropolysaccharides composed of mannose, rhamnose, glucose, galactose, arabinose and galacturonic acid, and exhibited different content of neutral sugar, uronic acid, proteins, polyphenols and sulfates. FTIR and NMR analyses determined the structures of FCPs and P-FCPs, indicating that the phosphorylation modification was successful. P-FCPs possessed the smaller molecular weight distribution and particle size, with significant changes in microstructure than FCPs. Additionally, P-FCPs showed significantly increased antioxidant and α-amylase inhibitory activities compared to FCPs. The inhibitory mechanisms of FCP40 and P-FCP40 on α-amylase was a mixed-type manner and dynamic fluorescence quenching. The results demonstrate that phosphorylation modification can alter the structural features and bioactivities of FCPs, providing an approach for the further development of finger citron in the field of medicinal and functional foods.

Antiviral Compounds to Address Influenza Pandemics: An Update from 2016-2022.

In recent decades, the world has gained experience of the dangerous effects of pandemic events caused by emerging respiratory viruses. In particular, annual epidemics of influenza are responsible for severe illness and deaths. Even if conventional influenza vaccines represent the most effective tool for preventing virus infections, they are not completely effective in patients with severe chronic disease and immunocompromised and new small molecules have emerged to prevent and control the influenza viruses. Thus, the attention of chemists is continuously focused on the synthesis of new antiviral drugs able to interact with the different molecular targets involved in the virus replication cycle. To date, different classes of influenza viruses inhibitors able to target neuraminidase enzyme, hemagglutinin protein, Matrix-2 (M2) protein ion channel, nucleoprotein or RNA-dependent RNA polymerase have been synthesized using several synthetic strategies comprising the chemical modification of currently used drugs. The best results, in terms of inhibitory activity, are in the nanomolar range and have been obtained from the chemical modification of clinically used drugs such as Peramivir, Zanamivir, Oseltamir, Rimantadine, as well as sialylated molecules, and hydroxypyridinone derivatives. The aim of this review is to report, covering the period 2016-2022, the most recent routes related to the synthesis of effective influenza virus inhibitors.

Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI–H1975 cells, and NCI–H1975-TM cells (IC50 = 0.009 μM, 0.49 μM and 3.24 μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 μM and 0.63 μM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

Anacardic acid derivatives with significant α-glucosidase inhibitory activity from Syzygium samarangense

Our continuous effort to search for antidiabetic constituents from the leaves of Syzygium samarangense resulted in the isolation of one new anacardic acid derivative, 2-[(Z)-nonadec-14-enyl]-6-hydroxylbenzoic acid (1) along with four known analogues (2−5). The new structure was elucidated by means of extensive spectroscopic data including 1D and 2D NMR along with HRESIMS. The anacardic acid derivatives were isolated from this species for the first time. All compounds exhibited significant inhibitory effect with IC50 value of 0.75−3.60μM against α-glucosidase.

A comprehensive review of the docking studies of chalcone for the development of selective MAO-B inhibitors.

Monoamine oxidase B is a crucial therapeutic target for neurodegenerative disorders like Alzheimer's and Parkinson's since they assist in disintegrating neurotransmitters such as dopamine in the brain. Pursuing efficacious monoamine oxidase B inhibitors is a hot topic, as contemporary therapeutic interventions have many shortcomings. Currently available FDA-approved monoamine oxidase inhibitors like safinamide, selegiline and rasagiline also have a variety of side effects like depression and insomnia. In the quest for a potent monoamine oxidase B inhibitor, sizeable, diverse chemical entities have been uncovered, including chalcones. Chalcone is a renowned structural framework that has been intensively explored for its monoamine oxidase B inhibitory activity.The structural resemblance of chalcone (1,3-diphenyl-2-propen-1-one) based compounds and 1,4-diphenyl-2-butene, a recognized MAO-B inhibitor, accounts for their MAO-B inhibitory activity. Therefore, multiple revisions to the chalcone scaffold have been attempted by the researchers to scrutinize the implications of substitutions onthe molecule's potency. In this work, we outline the docking investigation results of various chalcone analogues with monoamine oxidase B available in the literature until now to understand the interaction modes and influence of substituents. Here we focused on the interactions between reported chalcone derivatives and the active site of monoamine oxidase B and the influence of substitutions on those interactions. Detailed images illustrating the interactions and impact of the substituents or structural modifications on these interactions were used to support the docking results.

Design, Synthesis, Evaluation and Toxicity Studies of Novel Acridine Derivatives in Zebra Fish Larvae

Background: Alzheimer’s disease (AD) is a complex neurodegenerative condition for which a single protein-targeting medication is not enough to provide a cure. All the medications now available for AD are palliative. FDA has approved five medications for the treatment of AD, i.e., tacrine, donepezil, galantamine, rivastigmine, and memantine. Due to hepatotoxicity, tacrine is no longer utilized in clinical practice. Due to the lack of therapeutic efficiency of single-target medications and the multifaceted etiology of AD, multitarget-directed ligands have been developed. Objectives: The present research focused on incorporating a flavone nucleus into the amino group of 9-amino acridine nucleus to make it an acetylcholinesterase (AChE) and butyryl cholinesterase inhibitor (BuChE) with less toxicity Methods: We designed and synthesized ten flavone-substituted acridine derivatives and evaluated them for in vitro AChE and BuChE inhibitory activity. Molecular modeling studies were conducted using AutoDock Vina with hAChE (PDB ID: 4EY7) and hBuChE (PDB ID: 4TPK). The toxicity profile of the most active novel compound tested on zebrafish larvae for determining the liver and cardiac toxicity and LD50 value of the compound were determined. Results: In vitro AChE and BuChE inhibitory study by Ellman assay showed acceptable results. The compound AF2 showed the highest activity with an IC50 value of 0.99 ± 0.1 µM for AChE and 1.78 ± 0.19 for BuChE. The in vivo acute toxicity studies conducted on zebra fish larvae did not show cardiac and hepatotoxicity, and the LD50 value was found to be 1000 µL Conclusion: The results highlighted the AChE and BuChE inhibitory effects of the novel acridine-flavone hybrids, and they can be promising multitarget-directed ligands for AD.