Formation of morpholine-acetamide derivatives as potent anti-tumor drug candidates: Pharmacological evaluation and molecular docking studies
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ABSTRACT:
SUBMITTER: Sheikh A
PROVIDER: S-EPMC10694180 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe present study is aimed to investigate the anti-inflammatory activities of thirteen substituted-isoxazole derivatives (5a-5m). Isoxazole is a key pharmacophore in medicinal chemistry, known for its broad range of pharmacological activities.This study explores the synthesis and anti-inflammatory potential of thirteen substituted-isoxazole derivatives (5a-5m), with 5c, 5d, 5e, and 5g being novel compounds.ObjectivesThe primary objectives were to synthesize some novel substituted isoxazole derivatives, evaluate their interaction with cyclooxygenase (COX-1/2) enzymes through computational methods, and assess their anti-inflammatory effectiveness in laboratory animals.MethodsSubstituted chalcones (0.01 mol) (2a-2m), sodium ethoxide (0.01 mol), and hydroxylamine hydrochloride (0.01 mol) were dissolved in absolute ethanol (15 ml), and then the mixture was refluxed for 6 h in an oil bath and monitored by TLC (ethyl acetate:hexane 7:3 v/v as eluent; a UV lamp was used to visualize the plates). After the completion of the reaction, as per TLC, the contents of the reaction mixture were poured into ice-cold water (50 ml). The obtained precipitates were filtered, washed two times, dried for 2 h at room temperature, and then recrystallized with ethenol. The structures of these compounds were confirmed via Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H NMR) spectroscopy, carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy, and mass spectrometry. Anti-inflammatory activity was evaluated using the carrageenan-induced rat paw edema method.ResultsThe results indicated that three compounds (5b, 5c, and 5d) demonstrated significant in vivo anti-inflammatory potential (% edema inhibition 75.68, 74.48, & 71.86 in 2 h and 76.71, 75.56, & 72.32 in 3 h) with modest effectiveness (0.83, 0.81 & 0.71), low toxicity, and minimal adverse effects. The molecular docking analyses further elucidated the interaction with the active site COX-2 enzyme (PDB ID: 4COX) using Autodock Vina. The compounds 5b, 5c, and 5d -8.7, -8.5, and -8.4 indicate good binding affinity (kcal/mol) and H-bond interaction with residues such as Cys41, Ala151, and Arg120 for COX-2, which also carried out RMSD values of 2.174, 41.13, and 22.25, which are decisive for the reported anti-inflammatory activity of diverse compounds.ConclusionsThe findings indicate that isoxazole derivatives have modest antiinflammatory potential, with compounds (5b, 5c, and 5d) acting as lead molecules to be studied further for pain relief with fewer adverse effects.
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Project description:2-Mercaptobenzothiazole and its derivatives are widely known for their diverse biological activities, particularly antimicrobial and anticancer potential. In the present study, a series of new hybrid compounds consisting of 2-mercaptobenzothiazole and different aryl amines 2(a-j) were synthesized and characterized by Fourier transform infrared (FTIR), 1H NMR, and 13C NMR spectral data. The synthesized compounds were screened for in vitro antibacterial activities through agar well diffusion assay. Among the series, 2b, 2c, and 2i exhibited significant antibacterial activity comparable to the standard drug levofloxacin. Based on their antibacterial potential, these compounds were further tested for their antibiofilm activity. All of the three compounds showed promising antibiofilm potential, even better than the standard drug cefadroxil at 100 μg/100 μL concentration. Molecular docking studies were performed to explore the antibacterial mechanism of these compounds. Strikingly, the molecule 2i shared the same hydrophobic pockets as those of levofloxacin in case of bacterial kinases and DNA gyrases. In addition, 2i exhibited satisfactory antibiofilm activity in comparison to the standard. Our study therefore suggested that the synthetic compound 2i possesses remarkable antibacterial activity and may serve as a lead molecule for the discovery of potent antibacterial agents.
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Project description:Flavonoids exhibit essential but limited biological properties which can be enhanced through chemical modifications. In this study, we designed, synthesized, and characterized two novel flavonoid derivatives, quercetin penta-acetamide (1S3) and apigenin tri-acetamide (2S3). These compounds were confirmed using (1H, 13C) NMR, UV-Vis, and FT-IR characterizations. Their interaction with fish sperm DNA (FS-DNA) at physiological pH was investigated by UV-Vis and fluorescence spectrophotometry. The binding constant (K b) for the UV-Vis experiment was found to be 1.43 ± 0.3 × 104 M-1 for 1S3 and 2.08 ± 0.2 × 104 M-1 for 2S3. The binding constants (K SV) for the fluorescence quenching experiment were 1.83 × 104 M-1 and 1.96 × 104 M-1 for 1S3 and 2S3, respectively. Based on molecular modeling and docking studies, the binding affinities were found to be -7.9 and -9.1 kcal mol-1, for 1S3 and 2S3, respectively. The compound-DNA docked model correlated with our experimental results, and they are groove binders. Furthermore, mutagenicity potential was examined. 1S3 and its metabolites showed no mutagenic activity for both TA98 and TA100 strains. 2S3 did not show any mutagenic activity for the strain TA 98, while its metabolites were only active at high doses. Both 2S3 and its metabolites showed mutagenic activity in the TA100 strain.
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Project description:Among the causal risk factors directly promoting the development of coronary and peripheral atherosclerosis are reactive oxygen species and elevated low-density lipoprotein plasma levels. We hereby designed new potent squalene synthase (SQS) inhibitors that may simultaneously tackle the oxidative stress induced by lipid peroxidation. Using previously developed morpholine derivatives as a starting point, we conducted extensive structural changes by either substituting or modifying the morpholine ring, aiming at an optimal SQS-antioxidant pharmacological profile. Compounds 2, 3, and 7 emerged as the most potent bifunctional analogues, displaying IC50 values for SQS inhibition of 0.014, 0.16, and 0.51 μΜ, respectively, and further significantly decreasing lipid peroxidation of hepatic microsomal membranes. The aforementioned activities were also confirmed in vivo since the most promising derivative 2 exhibited a remarkable antihyperlipidemic and antioxidant effect. In conclusion, rational drug design accompanied by structure-activity relationship studies led to compounds combining improved antioxidant and antihyperlipidemic activity that may serve as multifunctional agents against atherosclerosis.
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Project description: Not available
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Project description:(+)-Negamycin (1), a natural dipeptidic antibiotic bearing a hydrazide structure, exhibits a readthrough activity toward the nonsense mutation of the dystrophin gene and restores dystrophin expression in muscles of Duchenne muscular dystrophy model mdx mice. Herein to develop more potent readthrough compounds, we performed a structure-activity relationship (SAR) study of 3-epi-deoxynegamycin (2), which is also another natural readthrough compound with little antimicrobial activity, focusing on the main carbon chain length. We found that one carbon atom shorter derivative 9b shows a higher readthrough activity than 1 and 2. Further derivatization at the carboxylic acid part of 9b demonstrates that its meta-chlorobenzyl ester derivative 17e, which has a higher ClogP value, exhibits a more potent readthrough activity than 9b. Interestingly, in the cell-free protein expression system, the readthrough activity of 17e drastically decreases compared to that in the cell-based assay. These results suggest that benzyl ester-type derivatives enhance the hydrophobicity and function as prodrugs to produce active compound 9b in living cell systems.
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Project description:The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds (n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, ¹H-NMR, 13C-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds (2b and 2j) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b, 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases.
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Project description:Actinorhizal plants contain numerous antioxidants that may play a crucial role in preventing the formation of tumors. H-Ras p21, a member of the Ras-GTPase family, is a promising target to treat various kinds of cancers. An in silico docking study was carried out to identify the inhibitory potential of compounds of these plants against H-Ras by using Discovery Studio 3.5 and by using Autodock 4.2. Docking studies revealed that four compounds, isorhamnetin-7-rhamnoside, quercetin-3-glucoside-7-rhamnoside (present in H. rhamnoides), zeaxanthin, and translutein (present in H. salicifolia) significantly bind with binding energies -17.1534, -14.7936, -10.2105 and -17.2217 Kcal/mol, respectively, even though they slightly deviate from Lipinski's rule. Absorption, distribution, metabolism, excretion and toxicity (ADME/tox) analyses of these compounds and their stereoisomers showed that they were less toxic and non-mutagenic. Amongst them, isorhamntein-7-rhamnoside showed hepatotoxicity. Hence, these compounds can be further investigated in vivo to optimize their formulation and concentration and to develop potential chemical entities for the prevention and treatment of cancers.
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Project description:Barbatic acid, a compound isolated from lichen, has demonstrated a variety of biological activities. In this study, a series of esters based on barbatic acid (6a-q') were designed, synthesized, and evaluated for their diuretic and litholytic activity at a concentration of 100 μmol/L in vitro. All target compounds were characterized using 1H NMR, 13C NMR, and HRMS, and the spatial structure of compound 6w was confirmed using X-ray crystallography. The biological results showed that some derivatives, including 6c, 6b', and 6f', exhibited potent diuretic activity, and 6j and 6m displayed promising litholytic activity. Molecular docking studies further suggested that 6b' had an optimal binding affinity to WNK1 kinases related to diuresis, while 6j could bind to the bicarbonate transporter CaSR through a variety of forces. These findings indicate that some barbatic acid derivatives could be further developed into novel diuretic agents.
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Project description:This study reports the synthesis and characterization of a novel class of flavonoid acetamide derivatives (FA) of quercetin, apigenin, fisetin, kaempferol, and luteolin. Flavonoids display numerous biological properties but are limited by aqueous insolubility, enzymatic degradation, instability, and low bioavailability. FAs were synthesized, with 80-82% yields, through the sequential modification of the flavonoid hydroxyl groups into the acetamide moieties. Bioavailability, antioxidant, and ADMET are structure-activity-dependent properties that vary across different classes of flavonoids and dictate the prevalent biological applications of the flavonoids. Thus, the FAs were evaluated for their bioavailability, antioxidant, and ADMET toxicity properties versus the unmodified flavonoids (UFs). In vitro bioavailability analysis shows that the UFs have bio-availabilities in the range of 10.78-19.29% against that of the FAs in the range of 20.70-34.87%. The antioxidant capacity was measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH·) assay with recorded IC50 values of 2.19-13.03 μM for the UFs. Conversely, the FAs had high DPPH IC50 values ranging from 33.83 to 67.10 μM and corresponding to lower antioxidant activity. The FAs showed favorable ADMET properties. The modification of flavonoids into FAs significantly improves the bioavailability and the ADMET toxicity properties, albeit with decreased antioxidant activity. This work highlights the effect of the global modification of the flavonoids with the acetamide groups on the bioavailability, antioxidant, and ADMET toxicity properties which are critical determinants in the biological applications of the flavonoids.
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