CHARACTERIZATION AND MOLECULAR DOCKING OF CINNAMIC ACID DERIVATIVES: POTENTIAL INHIBITORS OF CYCLOOXYGENASE ENZYMES (original) (raw)
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Al Mustansiriyah Journal of Pharmaceutical Sciences, 2019
The synthesis of new selective COX-2 enzyme is an approach for obtaining potent, anti-inflammatory drugs that have fewer side effects. Ketoprofen has a very low selectivity toward COX-2 enzyme and has a serious GIT side effects because it induces gastric ulcer. A new series of 4-thiazolidinones bearing ketoprofen moiety was designed, synthesized, and then evaluated as a new inhibitor of cyclooxygenase-2 (COX-2). Characterization and identification of the synthesized compounds were established by determination of 1H-NMR spectra,13C-NMR spectra, FT-IR spectroscopy, and physical properties. These newly synthesized compounds have been evaluated in vivo for their anti-inflammatory efficiency and in silico selectivity toward COX-2 throughout molecular docking by using GOLD.suite.v.5.6.2. All the tested. compounds via molecular. docking showed significant. activities when compared. With ketoprofen and diclofenac as references drugs, the results were consistent with the study of in in vivo ...
International Journal of Applied Pharmaceutics, 2024
Objective: Finding novel anti-inflammatory compounds is a crucial sector of research despite the significant advances this field has made. Inefficiency and unfavorable side effects are indeed potential drawbacks of conventional therapy utilizing steroidal or nonsteroidal drugs. This study aims to screen the designed quinoline-linked pyrimidine derivatives as Cyclooxygenase (COX) inhibitors. Methods: In the present study, we assessed the binding interactions of designed quinoline-linked pyrimidine derivatives with COX enzymes using a molecular docking approach. Using Molecular Dynamics (MD) simulations, the compound’s behavior was further investigated and its stability and conformational dynamics were demonstrated. Schrödinger's QikProp program was utilized to analyze the Absorption, Distribution, Metabolism, and Excretion (ADME) properties and toxicity properties were further investigated using Osiris Property Explorer. Additionally, the protein-ligand complexes' binding free energy has been ascertained using the Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) approach, which offered crucial information regarding the strength of their interactions. Results: The designed quinoline-linked pyrimidine derivatives fulfilled the Lipinski Rule of Five and had physicochemical characteristics within acceptable ranges, better ADME properties, and were non-toxic. Among the designed compounds, QPDU1 and QPDT6 showed correspondingly good docking scores for COX-1 and COX-2. QPDT6 was additionally analyzed by MD simulation studies to thoroughly examine the interaction between protein and ligand and their stability. Conclusion: The proposed compounds exhibit strong binding affinities to COX enzymes, stable interactions in MD simulations, and favorable drug-like features. These results support the need for more research and development of these substances as possible anti-inflammatory drugs.
To explore and identify cyclooxygenase (COX) inhibitors with optimal potency and efficacy using an arylpropionic acid class of drugs as lead molecules. Methods: The selected lead molecules were dimerised through chemical processes (reflux condensation) and characterised in terms of structural properties using infrared, proton nuclear magnetic resonance, electron impact mass spectrometry, and elemental analysis techniques. The molecules were evaluated pharmacologically for acute toxicity and anti-inflammatory (carrageenaninduced paw oedema test), analgesic (acetic acid-induced writhing test in mice), and antipyretic (Brewer's yeast-induced pyrexia test in mice) activities against control (normal saline) and relevant reference standard drugs. Docking analyses were also performed to assess possible protein-ligand interactions. Results: The test compounds were non-toxic at doses of 50, 100 and 150 mg/kg body weight, ip. Pharmacological evaluation revealed that the test compounds, TC-I through TC-IV, had significant antiinflammatory and peripheral analgesic activities (p < 0.001). An antipyretic test showed that TC-I, -II, and -III showed highly significant antipyretic activities at all doses tested. TC-IV at 20 and 30 mg/kg body weight exhibited significant antipyretic activities (p < 0.05), while at 50 mg/kg body weight, the activity was highly significant (p < 0.001). Molecular modelling revealed strong inhibitory interactions with docking scores of 116.2, 128.8, 144.2, and 136.0 kcal/mol, respectively, in comparison with the reference ligand, flurbiprofen (94.9 kcal/mol). Conclusion: The dimerised lead drug molecules showed significant anti-inflammatory, analgesic, and antipyretic activities in animals and may further be explored as potential new drug candidates for inflammatory conditions.
Bioorganic & Medicinal Chemistry, 2010
A novel series of 3-(substituted)-aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines (5a-o) has been synthesized and the structures of newly synthesized compounds were characterized by IR, 1 H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their in vitro and in vivo anti-inflammatory activity, and also for their antioxidant activity. Compounds 5b, 5c, 5d and 5n were found to be selective COX-2 inhibitors. Compound 5c was found to potent inhibitor of the carrageenin induced paw edema in rats. Most of the compounds exhibited good DPPH and superoxide radical scavenging activity, while compounds 5c, 5d, 5i and 5k exhibited good hydroxyl radical scavenging activity. Molecular docking result, along with the biological assay data, suggested that compound 5c was a potential anti-inflammatory agent.
Tanzania Journal of Science, 2018
Recent phytochemical analysis of Toussaintia orientalis leaves yielded series of novel bioactive N-cinnamoyltetraketide derivatives namely toussaintines A-G (t_1 - t_8) some portraying cytotoxicity against the triple negative aggressive human breast cancer cell line (MDA-MB-231) among other potencies. Despite having broad bioactivity spectrum, their general drug-likeness profiles and mode of action (simulated or actual) targeting any enzyme remains uninvestigated. In silico pharmacokinetic, drug-likeness descriptors and molecular docking of the compounds t_1-t_8 targeting inhibition of cyclooxygenase-2 (COX-2) enzyme were evaluated. The Lipinski Rule of Five heralded the pharmacokinetic properties of the studied metabolites. The studied compounds were docked with COX-2 following already established protocol. ADMET descriptors fell within the recommended range, except for compound t_3 that was predicted to potentially have positive blood brain barrier (BBB+) penetration. Docking stud...
Molecular Docking Compounds of Cinnamaldehyde Derivatives as Anticancer Agents
Asian Pacific Journal of Cancer Prevention
Objective: Cinnamaldehyde (CM) has a molecular structure with the main reaction center of an aromatic ring which the bioactivity can be modified as an anticancer agent by substituting the groups in the ortho (o), meta (m), and para (p) position. The present study aimed to investigate the correlation of the cluster region that was substituted in CM on its activity for various anticancer receptors. Methods: The receptor types used in the test were 5FL6, 1HOV, 4GY7, 5EAM, 4XCU, 4EL9, and 4PQW. The suitability of the hydroxy (OH) and methoxy (OMe) groups, which were substituted, was studied based on the value of Ki, their interactions with metal cofactors, and the type of amino acid residues that function as cancer receptor inhibitors. The docking was conducted using AutoDock 4. Results: The study results showed that all derivative compounds (o, m, and p)-OH and-OMe CM commonly had better anticancer activities than CM. o-OH CM has the best activity against receptors 5FL6, 1HOV, 4GY7, 5EAM, and 4XCU, and m-OMe CM has better activity against the 4EL9 receptors when compared with other CM derivatives. Conclusion: Based on this study, the compound derived from CM, i.e. OHC, tends to show the best anticancer activity.
Multifunctional Cinnamic Acid Derivatives
Molecules, 2017
Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino) ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX) inhibition (IC 50 = 6 µM) and antiproteolytic activity (IC 50 = 0.425 µM). The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC 50 = 0.315 µM) and good LOX inhibitory activity (IC 50 = 66 µM). Compounds 3a and 3b, derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro. Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study.
Tropical Journal of Pharmaceutical Research
Purpose: To develop effective cancer chemopreventive and anti-inflammatory agents, a series of chalcones were prepared by reacting suitable aromatic aldehyde with appropriate acetophenones. Methods: Twenty-four synthesized chalcones (namely, 1 - 24) were assessed for their in vitro anti-cyclooxygenase-1 (COX-1) and anti-cyclooxygenase-2 (COX-2) activity in a COX catalyzed prostaglandin synthesis bioassay. Molecular docking was done to investigate the ligand-protein interactions, and selectivity on both enzymes. ADMET (absorption, distribution, metabolism, excretion, toxicity) modeling and software were also used. Results: The compounds inhibited both COX-1 and COX-2. Two compounds (3 and 19) demonstrated more marked COX-2 inhibition than compound 1. Indomethacin as a standard anti-cyclooxygenase shows unselective inhibition of 81.44 ± 6.5 and 91 ± 9.5, respectively. The in silico data revealed that a chalcone skeleton with C=O at 4-position, C2–C3 double bond and OH at 5-position ar...
Indole based cyclooxygenase inhibitors: Synthesis, biological evaluation, docking and NMR screening
European Journal of Medicinal Chemistry, 2012
The close structural similarity between the two cyclooxygenase (COXs) isoforms and the absence of selective inhibitors without side effects continues to stimulate the development of novel approaches towards selective anti-inflammatory drugs. In the present study a small library of new indolic compounds involving two different substitutions patterns at the indole scaffold was synthesized. In order to establish a relation between the spatial distribution of known functional groups related with inhibitory activity, two substitution patterns were explored: one with substituents at N-1, C-3, C-5 positions and another at C-2, C-3 and C5 positions. Accordingly, indole positions C-5, C-3 and N-1 were substituted with: sulfonamide or methylsulfone at C-5, p-halo-benzyl group at C-3, and an alkyl chain with a trifluoromethyl group at N-1. Alternatively, a p-halo-benzyl group was introduced at C-2, leaving the indolic nitrogen free. Inhibitory studies were performed and the activity results obtained against both COXs isoforms were rationalized based on docking and NMR studies. Docking studies show that dialkyation at C-2 and C-3 favors a binding with an orientation similar to that of the known selective inhibitor SC-558. From the tested compounds, this substitution pattern is correlated with the highest inhibitory activity and selectivity: 70% COX-2 inhibition at 50 mM, and low COX-1 inhibition (18 AE 9%).