Inhibitory Activity Of Compounds Research Articles

Identification of lignans as selective cyclooxygenase-2 inhibitors from the extract of Acanthopanacis cortex

Acanthopanacis cortex (the dried root bark of Acanthopanax gracilistylus W. W. Smith) has been used for the treatment of rheumatic diseases in China for over 2000 years. Four previously undescribed lignans (1–4) and 12 known lignans (5–16) were isolated from Acanthopanacis cortex. In this study, the inhibitory activities of compounds 1–16 against neutrophil elastase (NE), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) are reported. The results show that compounds 1–16 exhibit weak inhibitory activities against NE and COX-1. However, compounds 2, 6–8 and 13–16 demonstrate better COX-2 inhibitory effects with IC50 values from 0.75 to 8.17 μΜ. These findings provide useful information for the search for natural selective COX-2 inhibitors.

Arylsulfonamido-alkyl-sulfamates act as inhibitors of bovine carbonic anhydrase II

A small library of arylsulfonamido-alkyl sulfamates was prepared by a two-step synthesis from readily available starting materials. The compounds were tested for their ability to inhibit bovine carbonic anhydrase II. Several of them were found as good competitive inhibitors holding Ki values as low as Ki = 0.9 μM (compound 47b). The activity was influenced by the substitution pattern of the arylsulfonamide moiety as well as the length of the spacer to the distal sulfamate group. Molecular docking studies were used to substantiate these findings. For the aryl-substituted analogues, the increase in inhibitory activity for compounds with a shorter spacer can be explained by stabilization via aromatic π-interactions. For the cyclopropyl or methylsulfonyl substituted analogues, their inhibitory activity can be attributed to their reduced steric hindrance. These results provide a basis for designing effective CA II inhibitors.

Nivalones C[sbnd]F, four new meroterpenoids from Rhododendron nivale

Four new meroterpenoids, namely nivalones CF (1–4), along with a known meroterpenoid, cannabiorcicyclolic acid (5), were isolated from the branches and leaves of Rhododendron nivale. The chemical structures of compounds 1–4 were elucidated through comprehensive spectroscopic analyses, including NMR, UV–Vis, IR, ECD spectroscopy, as well as HR-ESI-MS. The isolated compounds were evaluated for their anti-inflammatory and neuroprotective properties. The inhibitory activity of compound 5 against lipopolysaccharide (LPS)-induced nitric oxide (NO) production was initially demonstrated, showcasing an IC50 value of 21.1 μM. Additionally, both compounds 2 and 5 displayed a notable effect on the viability of H2O2-damaged SH-SY5Y cells, indicating their significant neuroprotection effects.

FRET Assays for the Identification of C. albicans HSP90-Sba1 and Human HSP90α-p23 Binding Inhibitors.

Heat shock protein 90 (HSP90) is a critical target for anticancer and anti-fungal-infection therapies due to its central role as a molecular chaperone involved in protein folding and activation. In this study, we developed in vitro Förster Resonance Energy Transfer (FRET) assays to characterize the binding of C. albicans HSP90 to its co-chaperone Sba1, as well as that of the homologous human HSP90α to p23. The assay for human HSP90α binding to p23 enables selectivity assessment for compounds aimed to inhibit the binding of C. albicans HSP90 to Sba1 without affecting the physiological activity of human HSP90α. The combination of the two assays is important for antifungal drug development, while the assay for human HSP90α can potentially be used on its own for anticancer drug discovery. Since ATP binding of HSP90 is a prerequisite for HSP90-Sba1/p23 binding, ATP-competitive inhibitors can be identified with the assays. The specificity of binding of fusion protein constructs-HSP90-mNeonGreen (donor) and Sba1-mScarlet-I (acceptor)-to each other in our assay was confirmed via competitive inhibition by both non-labeled Sba1 and known ATP-competitive inhibitors. We utilized the developed assays to characterize the stability of both HSP90-Sba1 and HSP90α-p23 affinity complexes quantitatively. Kd values were determined and assessed for their precision and accuracy using the 95.5% confidence level. For HSP90-Sba1, the precision confidence interval (PCI) was found to be 70-120 (100 ± 20) nM while the accuracy confidence interval (ACI) was 100-130 nM. For HSP90α-p23, PCI was 180-260 (220 ± 40) nM and ACI was 200-270 nM. The developed assays were used to screen a nucleoside-mimetics library of 320 compounds for inhibitory activity against both C. albicans HSP90-Sba1 and human HSP90α-p23 binding. No novel active compounds were identified. Overall, the developed assays exhibited low data variability and robust signal separation, achieving Z factors > 0.5.

Synthesis, Characterization, In‐Vitro and In‐Vivo Anti‐Cancer Evaluation of Novel Benzopyrylium Salts on Colorectal Cancer Model of Drosophila Melanogaster

AbstractA total of 10 benzopyrylium salts, 7 being novel, were synthesized by Claisen‐Schmidt condensation reaction and characterized by 1H and 13C NMR, High‐Resolution Mass Spectrometry, FT‐IR, and UV‐Vis spectroscopy. The purity of these synthesized compounds was determined by HPLC. The in‐vitro anti‐cancer evaluation of these synthesized benzopyrylium salts was done at National Cancer Institute (NCI), USA, against 60 human cancer cell lines. The compounds 4 and 8 showed promising anti‐cancer activities against various human cancer cell lines. The docking studies of the compounds were carried out against the oncogenic target JNK and their docking scores were compared to that of the known JNK inhibitor SP600125 (Pyrazolanthrone). Compound 4 exhibited an outstanding docking score of −9.0 kcal/mol, comparable to the docking score of SP600125 (−9.3 kcal/mol). The ex‐vivo studies in the hind‐gut of Drosophila were carried out and the inhibitory activity of compound 4 supported the findings of the docking studies. Furthermore, the potent compounds 4 and 8 were taken up for their in‐vivo anti‐cancer evaluation in the colorectal cancer model (CRC) of Drosophila melanogaster. The toxicity studies of these potent compounds were carried out both in wild type and mutant type Drosophila and the lethal doses were determined to be 200 μM.

Bioactive 5/5/5/6 Four-Ring System Iridoids from Plumeria alba L.

Two rare 5/5/5/6 four-ring system iridoids, allamancins A and B (1 and 2) together with one known biogenetically related iridoid derivative, 3-O-methyallamancin (3) were isolated from the flowers of Plumeria alba L. The structures of these iridoid derivatives were determined by comprehensive spectroscopic analyses. The absolute configuration of 1 was confirmed by X-ray crystallographic analysis. The inhibitory activities of compounds 1-3 against nitric oxide (NO) production induced and three cancer cell lines were evaluated in vitro. Compounds 1 and 3 showed inhibitory activities on NO production with IC50 values of 18.3±0.12 and 22.1±0.14 μM, respectively. Compounds 1-3 showed moderate inhibitory activities against cancer cell lines of A549, Hela and MCF-7.

Three new indole alkaloid derivatives from Fissistigma oldhamii Levl. and their anti-inflammatory effects

Three new indole alkaloid derivatives, fissindoalkas A-C (1–3) together with one known biogenetically related polysubstituted indole alkaloid (4) were isolated from the roots of Fissistigma oldhamii (Hemsl.) Merr. The structures of compounds 1–4 were elucidated using comprehensive spectroscopic methods. The inhibitory activities of compounds 1–4 against nitric oxide (NO) production induced by lipopolysaccharide (LPS) were evaluated in vitro using mouse macrophage RAW264.7 cells. Compounds 2 and 3 showed potent inhibitory activities on NO production with IC50 values of 2.52 ± 0.18 and 2.33 ± 0.16 μM. These results indicate that the discovery of indole alkaloid derivatives, from the roots of F. oldhamii, which show significant anti-inflammatory properties, could be of great importance to the research and for the development of novel natural anti-inflammatory agents.

Plumeriapropionics A-E, Carboxyl-Substituted Phenylpropionic Acid Derivatives with Anti-Inflammatory Activity from Plumeria rubra L.

Five rare carboxyl-substituted phenylpropionic acid derivatives, plumeriapropionics A-E (1-5), together with one known analog, cerberic acid B (6), were isolated from flowers of Plumeria rubra L. Their structures were elucidated using comprehensive spectroscopic methods. To date, only one compound of this structural type has been reported. The inhibitory activities of compounds 1-6 against nitric oxide (NO) production induced by lipopolysaccharide (LPS) were evaluated in vitro using mouse macrophage RAW264.7 cells. Compounds 1-6 showed remarkable inhibitory activities on NO production, with IC50 values in the range of 6.52 ± 0.23 to 35.68 ± 0.17 µM. These results indicate that the discovery of carboxyl-substituted phenylpropionic acid derivatives from the flowers of P. rubra, which show significant anti-inflammatory properties, could be of great importance for the research and development of novel natural anti-inflammatory agents.

Inhibitory activity of compounds in Ficus palmata Forsk (wild Himalayan fig) against oxidative stress-induced diabetes vascular complications: A computational approach

Inhibitory activity of compounds in Ficus palmata Forsk (wild Himalayan fig) against oxidative stress-induced diabetes vascular complications: A computational approach

Synthesis and Antiproliferative Activity Evaluation of B-norcholesterol-6- amide Compounds.

The structure modification of steroids is commonly used to change the biological activity of steroids in medicinal chemistry. In recent years, it has been found that some derivatives derived from the structural modification of cholesterol display good inhibitory activity against tumor cell proliferation in vitro</i>. Using cholesterol as the starting material, different types of B-norcholesterol-6-amide derivatives were synthesized by the reaction of 6-carboxyl-B-norcholesterol with different alkyl amines or 6-amino-B-norcholesterol with different acyl chlorides. The inhibitory activity of compounds on the proliferation of tumor cell lines was investigated by the MTT method. The results showed that the B-norcholesterol-6-amide compounds displayed distinct cytotoxicity against Sk-Ov-3 cells but caused no obvious damage against HEK-293T cells. Additionally, the steroidal amide derivatives formed from 6-amino-B-norcholesterol showed stronger cytotoxicity than those produced from 6-carboxyl-B-norcholesterol. Specially, compounds with chloroalkyl structure displayed significant inhibitory activity against all tumor cells tested. Among them, compounds 19-21 showed cytotoxicity like 2-methoxyestradiol as a positive control, and the IC</i>₅₀ value of compound 20 on HeLa cells was 3.9 μM. After introducing chloroalkyl acyl groups into 6-position of 6-amino-B-norcholesterol, the cytotoxicity of resulting B-norcholesterol-6-amide compounds can be greatly enhanced.

Computational Insights into Novel Inhibitor N-(3-(tert-Butylcarbamoyl)-4-methoxyphenyl)-indole and Ingliforib Specific against GP Isoenzyme Dimers Interaction Mechanism.

The high conservation of the three subtypes of glycogen phosphorylase (GP) presents significant challenges for specific inhibitor studies targeting GP. Our prior screening revealed that compound 1 exhibited unequal inhibitory activity against the three GP subtypes, with a noticeable effect against brain GP (PYGB). The commercially available ingliforib demonstrated potent inhibitory activity specifically against liver GP (PYGL). To guide the further design and screening of high-specificity inhibitors, the possible reasons for the differential inhibitory activity of two compounds against different GP subtypes were analyzed, with ingliforib as a reference, through molecular docking and molecular dynamics simulations. Initially, the study predicted the binding modes of ligands with the three GP receptor subtypes using molecular docking. Subsequently, this was validated by molecular dynamics experiments, and possible amino acid residues that had important interactions were explored. The strong correlation between the calculated interaction free energies and experimental inhibitory activity implied the reasonable binding conformations of the compounds. These findings offer insight into the different inhibitory activity of compound 1 and ingliforib against all three GP subtypes and provide guidance for the design of specific target molecules that regulate subtype selectivity.

Identification of novel antimicrobial compounds targeting Mycobacterium tuberculosis shikimate kinase using in silico hierarchical structure-based drug screening

The development of new anti-TB drugs to prevent the spread of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is imperative. Mtb shikimate kinase (MtSK) was selected as the target protein to screen for new anti-TB drugs. We performed hierarchical in silico screening using a library of 154,118 compounds to search for novel compounds that could bind to the active site of MtSK. The growth-inhibitory effects of the candidate compounds on Mycobacterium smegmatis were evaluated in vitro. Nine of the 11 candidate compounds exhibited inhibitory effects against mycobacteria in vitro. The inhibitory activity of Compound 2 (IC50 = 1.39 μM) was higher than that of isoniazid, the first-line drug for TB treatment. Moreover, Compound 2 did not exhibit toxicity against mammalian cells and Escherichia coli. Molecular dynamics simulations using the MtSK-Compound 2 complex structure in a timeframe of 100 ns suggested that Compound 2 could stably bind to MtSK. The binding free energy of Compound 2 was estimated to be −37.96 kcal/mol using the MM/PBSA method, demonstrating that Compound 2 can stably bind to MtSK. These in silico and in vitro results indicated that Compound 2 is a promising hit compound for the development of novel anti-TB drugs.

AChE inhibitory effect, anti-oxidant and anti-inflammatory properties of cyclen and L-Dopa related compounds: Targeting in neurodegenerative disease

1,4,7,10-tetraazacyclododecane (cyclen), a macrocyclic polyamine, and L-3,4-dihydroxyphenylalanine (L-DOPA), a tyrosine polyphenolic compound are compounds having various applications in medicine, biology, chemistry, etc. Derivatization of these precursor compounds aims to increase their biological activity, blood-brain barrier (BBB) permeability, solubility, binding ability, and lower toxicity. Synthesis and in vitro cytotoxicity of small new peptide-modified cyclen and L-DOPA derivatives were described previously. In the present study, in vitro biological activities such as radical scavenging capacity, anti-inflammatory, and acetylcholinesterase (AChE) inhibitory activities of compounds were evaluated. The results showed that some of them are good candidates for further detailed studies targeting neurodegenerative diseases, such as Alzheimer's and Parkinson's, and their pharmacokinetics and interaction with amyloidal aggregations characterized for neurodegenerative diseases. Dopa-DH-Dopa showed the highest anti-oxidant activity (IC50, 0.12 µM) and Dopa-HH-Dopa as AChE inhibitor (21 µM). Dopa-HH mainly inhibited nitric oxide (NO) production as an inflammatory marker.

Polyene Carboxylic Acids from a Streptomyces sp. Isolated from Tibet Soil.

Six new polyene carboxylic acids named serpentemycins E-J (1-6), together with three known analogs (7-9), were isolated from the fermentation medium of Streptomyces sp. TB060207, which was isolated from arid soil collected from Tibet, China. The structures of the new compounds were elucidated mainly on the basis of HR-ESI-MS and NMR spectroscopic analyses. The inhibitory activities of compounds 1-9 against NO production in LPS-activated RAW264.7 cells were evaluated. Compound 9 has an inhibition rate of 87.09% to 60.53% at concentrations ranging from 5.0 to 40.0 µM.

Evaluating a Specific Dual ROCK Inhibitor against Bleomycin-Induced Idiopathic Pulmonary Fibrosis in Rats.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease. Rho-associated protein kinases (ROCK) 1/2 are promising therapeutic targets for the treatment of IPF. However, a single inhibition of each of them is insufficient to prevent bleomycin-induced lung fibrosis. The current work reported that bleomycin-induced lung fibrosis can be reduced by dual inhibition of ROCK1/2 with compound 1. We evaluated the dual-selective ROCK1/2 inhibition activity of compound 1, its toxicity, and its preliminary efficacy on bleomycin-induced lung fibrosis. In vitro, compound 1 served as the ROCK1/2 inhibitor with half-maximal inhibitory concentration (IC50) values of 165 ±10.4 nM for ROCK1 and 16.1 ± 2.82 nM for ROCK2. In NIH/3T3 cells, compound 1 inhibited the mRNA expression of COL 1A1 and α-SMA. At therapeutic levels, compound 1 exhibited neither hepatic nor cardiac toxicity, also no CYP450 enzyme inhibition. In vivo, compound 1 had good pharmacokinetic properties, and its oral administration reduced bleomycin-induced pulmonary fibrosis in rats. All the outcomes prove the drug-like characteristics of compound 1 for the treatment of IPF.

Identification of Dual-Targeted Mycobacterium Tuberculosis Aminoacyl-tRNA Synthetase Inhibitors Using Machine Learning

Background: The most serious challenge in the treatment of tuberculosis is themultidrug resistance of Mycobacterium tuberculosis to existing antibiotics. As a strategy to overcome resistance we used a multitarget drug design approach. The purpose of the work was to discover dual-targeted inhibitors of mycobacterial LeuRSand MetRSwith machine learning. Methods: The artificial neural networks were built using module nnet from R 3.6.1. The inhibitory activity of compounds toward LeuRS and MetRS was investigated in aminoacylation assays. Results: Using a machine-learning approach, we identified dual-targeted inhibitors of LeuRS and MetRS among 2-(quinolin-2-ylsulfanyl)-acetamide derivatives. The most active compound inhibits MetRS and LeuRS with IC50 values of 33μm and 23.9μm, respectively. Conclusion: 2-(Quinolin-2-ylsulfanyl)-acetamide scaffold can be useful for further research.

Synthesis, antimicrobial activity and 3D-QSAR study of novel 5-substituted-1,3,4-thiadiazole Schiff base derivatives

In this study, 21 new thiadiazole Schiff base derivatives were synthesized based on the reactive group splicing principle, and the structures of the target compounds were confirmed and characterized by 1H NMR, FT-IR and HRMS. The inhibition activity of the compounds was tested in vitro against Escherichia coli, Staphylococcus aureus, Aspergillus niger, Rhizopus, Penicillium, Botrytis cinerea and Alternaria using mycelial growth rate method. The results showed that most of the compounds exhibited good biological activity at a dose of 50 µg/mL. Among them, compounds 2b, 2r, and 2a exhibited inhibition rates against the tested microbe comparable to that of the control drug Chlorothalonil. A preliminary three-dimensional quantitative conformational relationship (3D-QSAR) study of the inhibitory activity of the target compounds against Aspergillus niger was carried out using CoMFA and CoMSIA, and the model results showed that increasing the volume of the 2- and 6-positions of benzene ring A and the 3-position substituent of benzene ring B, decreasing the volume of the 5-position substituent benzene ring A; increasing hydrophobic groups at the 6-position of benzene ring A and the 2′-position of benzene ring B; increasing the 3′-position hydrogen bond donor group and decreasing the 3′-position hydrogen bond acceptor group of benzene ring B can improve the biological activity of the compounds. The inhibitory activity of the compounds can be improved.

Pandatonkinosides A and B: two new phenolic glycosides from the roots of Pandanus tonkinensis and their nitric oxide production inhibitory activities

Two new phenolic glycosides, 4-(3-hydroxypropyl)-2,6-dimethoxyphenol β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (1), trans-cinnamyl alcohol 9-O-(6′-O-β-D-apiofuranosyl)-β-D-glucopyranoside (2), together with nine known phenolic glycosides (3-11) were isolated from the roots of Pandanus tonkinensis. Their structures were determined by extensive analysis of HRESIMS and NMR spectral data, as well as by comparison of their spectral data (including CD spectra) with those reported in the literature. Compounds 1-4 and 6-11 inhibited NO production in LPS-activated RAW264.7 cells with IC50 values in the range from 0.80 ± 0.06 µM to 43.38 ± 3.92 µM, whereas compound 5 was inactive. The NO production inhibitory activities of compounds 1, 4, 8, and 10 with IC50 values of 10.16 ± 1.05, 0.80 ± 0.06, 1.10 ± 0.13, and 2.79 ± 0.21 µM, respectively, are as potent as that of the positive control of N G-monomethyl-L-arginine acetate (L-NMMA) with an IC50 value of 9.80 ± 0.78 µM.

Identification of potential antivirals against 3CLpro enzyme for the treatment of SARS-CoV-2: A multi-step virtual screening study

ABSTRACT The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak is posing a serious public health threat worldwide in the form of COVD-19. Herein, we have performed two-dimensional quantitative structure–activity relationship (2D-QSAR) and three-dimensional pharmacophore modelling analysis employing inhibitors of 3-chymotrypsin-like protease (3CLpro), the leading protease that is crucial for the replication of SARS-CoV-2. The investigation aims to identify the important structural features responsible for the enzyme inhibition and the search for novel 3CLpro enzyme inhibitors as effective therapeutics for treating SARS-CoV-2. Furthermore, we carried out molecular docking studies using the most and least active compounds in the dataset, aiming to validate the contributions of various features as appeared in the QSAR models. Later, the stringently validated 2D-QSAR model was used to estimate the 3CLpro inhibitory activity of compounds from five chemical databases. Compounds with the significant predicted activity were then subjected to pharmacophore-based virtual screening to screen the top-rated compounds, which were then further subjected to molecular docking analysis, absorption, distribution, metabolism, excretion – toxicity (ADMET) profiling, and molecular dynamics (MD) simulation. The multi-step virtual screening analyses suggested that compounds CASAntiV-865453-58-3, CASAntiV-865453-40-3, and CASAntiV-2043031-84-9 could be used as effective therapeutic agents for the treatment of SARS-CoV-2.

Synthesis, antibacterial, antibiofilm evaluation and molecular docking studies of 3-methyl- 2-propyl-2H-[1,2,4]triazolo[4,3b] [1,2,4,6]thiatriazine-1,1-dioxide

ABSTRACT. In the current study, a simple method for the synthesis of 3-methyl-2-propyl-2H-[1,2,4]triazolo[4,3b][1,2,4,6]thiatriazine-1,1-dioxide (2) was carried out. In the presence of pyridine, a reaction between amidine (1) and sulfuryl chloride occurs. FTIR spectroscopy, 1H and 13C NMR, mass spectra, and elemental analysis were utilized in order to verify the structure of a novel synthetic molecule. The antibacterial activities of compound (2) were tested against eight pathogenic bacteria and the minimum inhibitory concentration as well as minimum bactericidal concentration were determined. Moreover, the possible antibiofilm effect of compound (2) was evaluated. Molecular docking was investigated to determine the interaction between compound (2) and eight crystal structures of bacterial and yeast proteins associated with virulence activity and antimicrobial resistance. Our results showed that the new 3-methyl-2-propyl-2H-[1,2,4]triazolo[4,3b][1,2,4,6]thiatriazine-1,1-dioxide (2) compound has a moderate antibacterial activity toward the selected pathogenic bacteria. The obtained MICs varied from 32 to 512 µg/mL being the lowest values attributed to Staphylococcus epidermidis ATCC 14990 and Streptococcus mutans ATCC 25175 (MIC = 32 µg/mL).We noted also that heterocyclic compound (2) may inhibit bacterial biofilm formation at concentration depend manner with a lowest value obtained against S.mutans ATCC 25175 (BIC50 = 490 µg/mL). Molecular docking showed a promising inhibitory activity of compound (2) on TetM-mediated tetracycline resistance (3J25) and Staphylococcus aureus gyrase (3G7B) with lower binding energy compared to the other target proteins.&#x0D; &#x0D; KEY WORDS: Synthesis, Thiatriazine-1,1-dioxide, Antibacterial, Antibiofilm, Molecular docking&#x0D; Bull. Chem. Soc. Ethiop. 2022, 36(1), 109-117. &#x0D; DOI: https://dx.doi.org/10.4314/bcse.v36i1.10