Site Of COX-2 Research Articles

Novel Synthesized Benzophenone Thiazole Hybrids Exhibited ExVivo and In Silico Anti-Inflammatory Activity.

Novel benzophenone-thiazole hybrids with different substituents were synthesized and evaluated for anti-inflammatory activity using an exvivo human whole-blood assay. All hybrids (3c and 5a-h) showed significant anti-inflammatory activity via prostaglandin E2 (PGE2) release inhibition. Moreover, 5c (82.8% of PGE2 inhibition), 5e (83.1% of PGE2 inhibition), and 5h (82.1% of PGE2 inhibition) were comparable to the reference drugs. Molecular docking revealed potential preferable binding to the active sites of cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) enzymes. This study provides the first evidence that benzophenone-thiazole hybrids may also dock in mPGES-1, a new attractive anti-inflammatory drug target, besides providing promising exvivo anti-inflammatory activity. Thus, the novel hybrids are promising anti-inflammatory lead compounds and highlight the significance of optimal substituent selection in the design of potent PGE2 inhibitors.

Aspirin-aromatic amino acid conjugates as selective Cox-2 inhibitors: A docking study


 
 
 
 Purpose: To examine eight compounds in which aspirin was conjugated with aromatic amino acids virtually using docking studies for their ability to inhibit cyclooxygenase 2 (Cox-2) enzyme.
 Methods: The compounds were drawn, energy minimised and then docked into the active site of Cox-2 along with celecoxib for comparison using GOLD docking program.
 Results: Five of the designed compounds docked into the active site with a bent conformation producing a pose similar to that of celecoxib, with the aromatic amino acid moiety facing the outside of the active site. The interactions were mainly hydrophobic with some hydrogen bonds formed between the compounds and the key residues in the active site. Although the obtained scores were less than that of celecoxib, they were the top ranked poses in the solutions generated for each compound.
 Conclusion: The conjugation of aspirin with amino acids may offer a potential for the development of selective, but safe, Cox-2 inhibitors.
 
 
 

Synthesis of New Tricyclic 1,2-Thiazine Derivatives with Anti-Inflammatory Activity

New, tricyclic compounds containing a sulfonyl moiety in their structure, as potential safer COX inhibitors, were designed and synthesized. New derivatives have three conjugated rings and a sulfonyl group. A third ring, i.e., an oxazine, oxazepine or oxazocin, has been added to the 1,2-benzothiazine skeleton. Their anti-COX-1/COX-2 and cytotoxic effects in vitro on NHDF cells, together with the ability to interact with model membranes and the influence on reactive oxygen species and nitric oxide, were studied. Additionally, a molecular docking study was performed to understand the binding interaction of the compounds with the active site of cyclooxygenases. For the abovementioned biological evaluation of new tricyclic 1,2-benzothiazine derivatives, the following techniques and procedures were employed: the differential scanning calorimetry, the COX colorimetric inhibitor screening assay, the MTT, DCF-DA and Griess assays. All of the compounds studied demonstrated preferential inhibition of COX-2 compared to COX-1. Moreover, all the examined tricyclic 1,2-thiazine derivatives interacted with the phospholipid model membranes. Finally, they neither have cytotoxic potency, nor demonstrate significant influence on the level of reactive oxygen species or nitric oxide. Overall, the tricyclic 1,2-thiazine derivatives are good starting points for future pharmacological tests as a group of new anti-inflammatory agents.

A New N-Substituted 1H-Isoindole-1,3(2H)-Dione Derivative-Synthesis, Structure and Affinity for Cyclooxygenase Based on In Vitro Studies and Molecular Docking.

Isoindoline-1,3-dione derivatives constitute an important group of medicinal substances. In this study, nine new 1H-isoindole-1,3(2H)-dione derivatives and five potential pharmacophores were obtained in good yield (47.24–92.91%). The structure of the new imides was confirmed by the methods of elemental and spectral analysis: FT–IR, H NMR, and MS. Based on the obtained results of ESI–MS the probable path of the molecules decay and the hypothetical structure of the resulting pseudo-molecular ions have been proposed. The physicochemical properties of the new phthalimides were determined on the basis of Lipiński’s rule. The biological properties were determined in terms of their cyclooxygenase (COX) inhibitory activity. Three compounds showed greater inhibition of COX-2, three compounds inhibited COX-1 more strongly than the reference compound meloxicam. From the obtained results, the affinity ratio COX-2/COX-1 was calculated. Two compounds had a value greater than that of meloxicam. All tested compounds showed oxidative or nitrosan stress (ROS and RNS) scavenging activity. The degree of chromatin relaxation outside the cell nucleus was lower than the control after incubation with all test compounds. The newly synthesized phthalimide derivatives showed no cytotoxic activity in the concentration range studied (10–90 µM). A molecular docking study was used to determined interactions inside the active site of cyclooxygenases.

Protective effect of Ellipticine in ovalbumin (OVA)-induced murine model of allergic rhinitis via dual inhibition of COX-2 and NF-κB

Abstract Allergic rhinitis (AR) is a serious health concern across the globe. Despite its non-fatal character, it accounts for affecting millions of people across the world and is deemed responsible to affect their quality of life and put a significant economic burden. In the current study, we aimed to assess the anti-allergic and anti-inflammatory effects and the underlying molecular mechanisms of ellipticine (ETC) against AR using ovalbumin (OVA)-induced murine model of allergic rhinitis. The ETC was administered to mice via intra-peritoneal route after suspending in 5% CMC after sensitization by OVA. Results of the study suggested that ETC causes a significant reduction the nose rubs as compared to disease control. A significant reduction in the serum level of histamine, IgG1, TNF-α, IL-1β, MIP-2, and IL-6 was found in ETC treated group in a dose-dependent manner as compared to OVA challenged mice. It also reduces eosinophils in BALF of AR mice. In western blot analysis, the expression of aberrantly activated COX-2 and NF-ĸB found significantly reduced in ETC treated group due to inhibition of TLR-4 and caspase-1 as compared to disease-control mice. ETC showed significant interaction with residues of the active site of COX-2 and NF-ĸB. Collectively, our results indicated that ETC can be used to improve present therapeutic strategies against AR.

Synthesis, Molecular Docking, Biological Potentials and Structure Activity Relationship of New Quinazoline and Quinazoline-4-one Derivatives

In this work, a new derivative of ethyl 5-chloro-2-(3-(4-hydroxyphenyl)propanamido)benzoate (1) was synthesized by reacting the amino group of 3-(4-hydroxyphenyl)propanoic acid (0.01 mol) and methyl 2-amino-5-chlorobenzoate in presence of PCl3. Cyclcondensation of 1 with hydrazine hydrate afforded the corresponding 2-(4-hydroxyphenethyl)-3-amino-6-chloroquinazolin-4(3H)-one (2). Also, new Schiff base 3 was prepared via reaction of 2-(4-hydroxyphenethyl)-3-amino-6-chloroquinazolin- 4(3H)-one (2) with 4-hydroxy-3-methoxybenzaldehyde. The synthesized compounds were characterized by elemental analysis, IR, 1H NMR and mass spectral data. Also, the median lethal doses (LD50s) of compounds 1-3 in rats were 1125, 835 and 1785 mg/kg b.w., respectively. IC50 values of compounds (1, 3) as measured by DPPH• method was 136.47 and 73.54 μg/mL, respectively. IC50 values of compounds (1-3) as measured by ABTS•+ radical method was 0.8, 0.92 and 0.08 mg/mL, respectively. Antiulcerogenic activity at dose 1/20 LD50 in albino rats was 47.94, 24.60 and 56.45%, respectively. However, the anti-inflammatory effect at dose 1/20 LD50 of compounds (1-3) induced edema model after 120 min were 74.19, 69.93 and 59.03%, respectively. The synthesized compounds also possess hepatocytes and gastric mucosa protective activity against ibuprofen induced ulceration and LPS-induced liver toxicity, respectively in rats via normalization of oxidative stress biomarkers and inflammatory mediators (Na+/K+-ATPase, ALT, AST, LDH, TNF-α, NO, TBARS, GPx, CAT and SOD). Also, TNF-α, NO, PGE2 and COX-2 were inhibited in peritoneal macrophage cells at a concentration of 100 μg/L. Molecular docking suggested that the most active compounds 1 and 2 can be positioned within the active sites of COX-2 at Arg121 & Tyr356 similarly to ibuprofen (Arg-120, Glu-524 and Tyr-355). The compound 3–COX-2 complex generated by docking, revealed intricate interactions with a COX-2 channel, including hydrogen bonds with key residues Arg121 and phe519. These findings suggest that compounds 1-3 exhibited good antioxidant, antiulcer, anti-inflammatory activity and safe on liver enzymes in rats.

New 1,3,4-Oxadiazole Derivatives of Pyridothiazine-1,1-Dioxide with Anti-Inflammatory Activity.

Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases.

Design, Synthesis and Pharmacological Evaluation of Gastro- Protective Anti-inflammatory Analgesic Agents based on Dual Oxidative Stress / Cyclooxygenase Inhibition.

Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration. Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for the treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects. In an effort to develop gastroprotective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test compounds was also studied. To gain insight into the plausible mode of interaction of compounds within the active sites of COX-1 and COX-2, molecular docking simulations were performed. Among the various synthesized molecules, most of the compounds showed good cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory and analgesic activity with better gastric tolerability during their in vivo evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2- disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70. Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol- 1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic activities that can be used for future research. From the above results, it can be concluded that designing of multifunctional molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great promise for further development of GI-safer NSAIDs.

Synthesis, Cyclooxygenases Inhibition Activities and Interactions with BSA of N-substituted 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones Derivatives.

Inhibition of cyclooxygenase is the way of therapeutic activities for anti-inflammatory pharmaceuticals. Serum albumins are the major soluble protein able to bind and transport a variety of exogenous and endogenous ligands, including hydrophobic pharmaceuticals. In this study, a novel N-substituted 1H-pyrrolo[3–c]pyridine-1,3(2H)-diones derivatives were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases and interactions with BSA. In vitro, COX-1 and COX-2 inhibition assays were performed. Interaction with BSA was studied by fluorescence spectroscopy and circular dichroism measurement. The molecular docking study was conducted to understand the binding interaction of compounds in the active site of cyclooxygenases and BSA. The result of the COX-1 and COX-2 inhibitory studies revealed that all the compounds potentially inhibited COX-1 and COX-2. The IC50 value was found similar to meloxicam. The intrinsic fluorescence of BSA was quenched by tested compounds due to the formation of A/E–BSA complex. The results of the experiment and molecular docking confirmed the main interaction forces between studied compounds and BSA were hydrogen bonding and van der Waals force.

Design, synthesis, biological evaluation and in silico studies of novel pyrrolo[3,4-d]pyridazinone derivatives with promising anti-inflammatory and antioxidant activity

Novel Mannich base analogues of pyrrolo[3,4-d]pyridazinone 7a,b-13a,b are designed and synthesized as potential anti-inflammatory agents. The title compounds are obtained via convenient one-pot synthesis with good yields. Their structures and properties are described by spectroscopic techniques and elemental analyses. The aim of this study is to evaluate the inhibitory activity of the new derivatives against both cyclooxygenase isoforms COX1 and COX2 as well as their cytotoxicity. The results clearly indicate that the tested compounds 7a,b-13a,b are not toxic, all show better affinity towards isoform COX-2, and some of them act as selective COX-2 inhibitors. Moreover, every examined derivative of pyrrolo[3,4-d]pyridazinone demonstrates better inhibitory activity towards COX-2 and a superior COX-2/COX-1 selectivity ratio compared to the reference drug meloxicam. Molecular docking studies confirm that compounds 7a,b-13a,b preferably bind COX-2 and all of them bind to the active site of cyclooxygenase in a way very similar to meloxicam. Subsequently, taking into account that inflammation is strongly correlated with oxidative stress and both of these processes can potentiate each other, synthesized Mannich bases are evaluated for potential antioxidant activity. Most of the investigated derivatives reduce induced oxidative and nitrosative stress. Moreover, compounds 7a,b, 8a, 10a,b, 11b, 12a,b-13a,b protect chromatin from oxidative stress and decrease the number of DNA strand breaks caused by intracellular growth of free radicals. Finally, a study of the binding mechanism between compounds 7a,b-13a,b and bovine serum albumin (BSA) was carried out. According to spectroscopic and molecular docking studies, all examined derivatives interact with BSA, which suggests their potential long half-life in vivo.

In silico study of anthocyanin and ternatin flavonoids for the treatment of inflammation-related diseases using molecular docking analysis

Inflammatory markers such as cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), and prostaglandin (PEG) are widely known as major targets in discovering natural anti-inflammatory drugs for the treatment of inflammationrelated diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin are mostly used at present, however, some NSAIDS have been reported to cause gastrointestinal side effect due to ligand-protein interaction. Molecular docking is a promising tool to study such modes of interaction. In this study, we evaluated the potential use of anthocyanin and ternatin flavonoids as natural anti-inflammatory agents for treatment of inflammatory-related diseases using in silico molecular docking assay. Automated docking study using Protein-Ligand ANT System (PLANTS) and AutoDock Vina was performed with various ligand molecules, including ibuprofen, anthocyanin, and ternatin against the protein crystal structures of COX-1, COX-2, iNOS, and MPO. The in silico data demonstrated that ibuprofen bound effectively to the active site of COX-1 and MPO with minimum binding energy, yet the compound required more energy to bind the active site of COX-2. Ternatin flavonoid was bound to COX-2 and iNOS with minimum binding energy. In terms of binding energy, anthocyanin flavonoid was found to be effective for inhibiting COX-1, COX-2, and iNOS. These results suggested that anthocyanin and ternatin flavonoids may potentially be developed as anti-inflammatory drug candidate for the treatment of inflammatory-related diseases.

Flavanones from Sorghum bicolor selectively inhibit COX-2: in-silico and in-vivo validation

BackgroundCOX-2-specific inhibitors offer improved advantages over traditional NSAIDs. Plants are known to play critical roles in the discovery and developments of new pharmaceuticals. To the best of our knowledge, nothing has been reported so far on the selective inhibition of the cyclooxygenase by flavanones. The present study aims at evaluating the selective inhibition of COX-1 and/or COX-2 by flavanones from Sorghum bicolor.ResultsFlavanones demonstrate selective inhibition of COX-2 through the formation of hydrogen bonds. Eriodictyol forms two hydrogen bonds interactions (Tyr-371 and Ser-516) within the active site of COX-2, while it forms only one hydrogen bond (Met-521) with COX-1. Sorghum bicolor flavanone extract (SBFE) demonstrate hepatoprotective potentials by augmenting the antioxidant defense system of the liver and downregulate the expression of COX-2 while ineffective against COX-1. Histopathological analyses show that SBFE is effective in the prevention of HCl/ethanol-induced gastric injury in Wistar rats.ConclusionsThe side effects associated with current NSAIDs are as a result of selective inhibition of COX-1. Flavanones are potential selective inhibitors of COX-2. Sorghum bicolor flavanone extract (SBFE) demonstrates its anti-inflammatory potential through selective inhibition of COX-2. The virtual high throughput screening techniques adopted herein could help eradicate the corresponding rigors of identifying lead bioactive(s) components of plants.Graphical abstract

Antiplatelet activity of deferiprone through cyclooxygenase-1 inhibition

Thalassemia patients are susceptible to both iron overload and thromboembolism. Deferiprone is an iron chelator that shows an antiplatelet activity and thus may alleviate platelet hyperactivation in thalassemia. Therefore, this study aimed to characterize the inhibitory effects and mechanisms of deferiprone on normal human platelets. The results illustrated that deferiprone inhibited platelet aggregation at the iron chelating concentrations (0.08–0.25 mmol/l). Deferiprone inhibited human platelet aggregation stimulated by arachidonic acid and ADP more potently than epinephrine and collagen, with the IC50 of 0.24 mmol/l and 0.25 mmol/l vs. 3.36 mmol/l and 3.73 mmol/l, respectively. Interestingly, deferiprone significantly inhibited COX-1 activity, with the IC50 of 0.33 mmol/l, and slightly increased cAMP level at the high concentration of 4 mmol/l. Moreover, the results from molecular docking showed that deferiprone interacted closely with key residues in the peroxidase active site of COX-1. These results suggested that deferiprone possessed antiplatelet activity mainly through the inhibition of COX-1 activity.

Biological Evaluation and Molecular Docking Studies of Dimethylpyridine Derivatives.

Cyclooxygenase inhibitors as anti-inflammatory agents can be used in chemoprevention. Many in vitro and in vivo studies on human and animal models have explained the mechanisms of the chemopreventive effect of COX inhibitors such as: induction of apoptosis, inhibition of neoplasia, angiogenesis suppression, induction of cell cycle inhibition and inhibition of the expression of peroxisome proliferator-activated receptors. Here, biological evaluation of twelve different Schiff base derivatives of N-(2-hydrazine-2-oxoethyl)-4,6-dimethyl-2-sulfanylpyridine- 3-carboxamide are presented. Their in vitro anti-COX-1/COX-2, antioxidant and anticancer activities were studied. The molecular docking study was performed in order to understand the binding interaction of compounds in the active site of cyclooxygenases. Compounds PS18 and PS33 showed a significant inhibitory activity on COX-1 at lower concentrations compared to meloxicam and piroxicam. The IC50 of COX-1 of these compounds was 57.3 µM for PS18 and 51.8 µM for PS33. Out of the tested compounds, the highest therapeutic index was demonstrated by PS18, PS19, PS33, PS40 and PS41. Lower molar concentrations of these compounds inhibit the growth of cancer cells while not inhibiting the healthy cells. Compounds PS18, PS19 and PS33 simultaneously demonstrated a statistically-significant inhibition of COX-1 or COX-2. This opens up the possibility of applying these compounds in the chemoprevention of cancer.

Organotin(IV) compounds derived from ibuprofen and cinnamic acids, an alternative into design of anti-inflammatory by the cyclooxygenases (COX-1 and COX-2) pathway

New tributyl-, dibutyl- and diphenyl-tin(IV) complexes derived from ibuprofen and cinnamic acids were synthesized. All compounds were structurally characterized by FT-IR, multinuclear 1H, 13C, 19F and 119Sn NMR and corroborated by 2D spectra. The NMR data in CDCl3 revealed several hexacoordinated compounds with octahedral geometry. Moreover, in DMSO-d6 some of these complexes switched to heptacoordination with a pentagonal-bipyramidal geometry due to the inclusion of a solvent's molecule; their 119Sn signals moved up field by around 58 ppm compared to their chemical shifts in non-coordinated solvent CDCl3. The structural results were supported by Density Functional Theory (DFT) computational calculations. In addition, a docking study was performed to evaluate the ability of ligands to interact within the active site of cyclooxygenases (COX-1 and COX-2). Docking results showed a possible binding of stannoxanes theoretically more selective towards COX-2 than ibuprofen.

Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8 b selectively inhibited the COX-2 enzyme (IC50 = ∼0.20–0.69 μM), with SI values of (>72.5–250) compared with celecoxib (IC50 = 0.16 μM, COX-2 SI: > 312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC50 > 50 μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10 μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition = ∼0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds.

Structural Probing, Screening and Structure-Based Drug Repositioning Insights into the Identification of Potential Cox-2 Inhibitors from Selective Coxibs.

The rate-limiting enzyme cyclooxygenase-2 (COX-2) is considered as an insightful prognostic target for non-small cell lung cancer (NSCLC) therapy. Now, administration and prolonged utilization of selective COX-2 inhibitors (COXIBs) towards moderating the NSCLC has been associated with different side effects. In the present study, we focused on the structure-based drug repositioning approaches for predicting therapeutic potential de novo candidates for human COX-2. Due to discrepancies in the eminence of x-ray diffraction structures, creates a big barrier in drug discovery approach. Hence, the adaptable COX-2 structure was investigated using multi-template modeling method. Next, a dataset of twenty-six celebrex-associated optimized scaffolds were screened from ZINC database. Comparative docking approaches were then utilized to identify five compounds as best binders to the active site of COX-2 structures and strongly agree with enormous experimental consequences. MD simulations of regarded protein-ligand complexes reveals that lead molecules were stabilized dynamically in inside the cyclooxygenase site by forming potential salt bridges with Tyr348, Tyr385 and Ser530 residues. These significant results revealed that, identified druggables could prevent the tyrosyl radicals and prostaglandin production that reduces NSCLC progression. Furthermore, pharmacokinetics assets of respected ligands were analyzed, which incorporates similarity ensemble approach, druglikeness and ADMET properties. Finally, the identified novel candidates could serve as COX-2 inhibitors for NSCLC therapy, and coxibs are the best choices for designing new scaffolds to treat cyclooxygenases regard disorders.

Modelación molecular de la interacción del paracetamol y el 4-aminofenol con las enzimas Ciclooxigenasa 1 y 2

En este estudio, se presenta la modelación computacional de la interacción del paracetamol y su metabolito activo, el 4-aminofenol, con las enzimas Ciclooxigenasa 1 y Ciclooxigenasa 2. El objetivo fue utilizar métodos computacionales para explicar, a nivel molecular, la baja actividad antinflamatoria del paracetamol mediante su interacción con las enzimas Ciclooxigenasa 1 y 2. Se utilizaron métodos mecánico cuánticos para la optimización de los ligandos y acoplamiento molecular para modelar la interacción de estos ligandos con las enzimas y sus sitios activos. Los resultados obtenidos muestran que las conformaciones con más afinidad para paracetamol y 4-aminofenol no se encuentran en el sitio activo de la Ciclooxigenasa 1. Comparaciones con el ácido araquidónico muestran que las energías de enlace son alrededor de 1 kcal/mol mayores, lo cual indica una inhibición leve. Para el caso de la Ciclooxigenasa 2, los resultados obtenidos son similares, lo cual sugiere que el mecanismo de acción principal del paracetamol o su metabolito primario no se da por inhibición de las Ciclooxigenasas. Este resultado concuerda con las diferencias en la acción farmacológica y efectos secundarios que tiene el paracetamol con respecto a moléculas del mismo grupo como el ibuprofeno.

Luminescent characterization of interaction efficiency between (−)-cytisine and amino acids an indicator of anti-inflammatory of some 12-N-substituted (−)-cytisine derivatives

Abstract In the present work, the spectral fluorescent properties of N-R-12-N-methylcytisine-3-amines (R = 2-furylmethyl, 2-hydroxybenzyl, 2-thienylmethyl and 2-phenylprop-2-en-1-yl) have been studied and their relative quantum yields and lifetimes in the electronically excited states have been defined. These compounds have bioactivity as potential inhibitors of cyclooxygenase-2 (COX-2). We have studied the quenching of fluorescence (FL) of L-tyrosine (Tyr) and L-tryptophan (Trp) by amino-derivatives of 12-N-methylcytisine as well as the FL quenching of cytisines themselves by L-serine (Ser) and L-arginine (Arg). The found Stern–Volmer constants and lifetimes of the excited states reveal static mechanism of the quenching of aromatic amino acids and dynamic mechanism for the FL quenching of cytisines by Arg (Ser does not quench FL) due to the reversible photo-induced electron transfer (PET). The thermodynamic assessment of the PET probability according to the Weller equation agrees with the observed regularities and series of bioactivity of the cytisines. Using molecular docking, we have found the most probable positions of the 12-N-methylcytisine derivatives in the active site of COX-2 where their stacking interactions with Trp387 and Tyr385 and hydrogen bonding with Arg120 and Ser530 occur. As the mentioned amino acids play a key role in the complexion of the studied compounds by COX-2, we have proposed that bioactivity mechanism of the lead compounds implies the COX-2 inhibition by the withdrawal of electron from electron-transfer processes in the chain HEM–His388–Trp387–His386–Tyr385 resulted from their stacking interactions with Trp and/or Tyr.

Design, Synthesis, and Biological Evaluation of New 2-Phenyl-4H-chromen-4-one Derivatives as Selective Cyclooxygenase-2 Inhibitors.

In order to develop new selective COX-2 inhibitors, a new series of 2-phenyl-4H-chromen-4-one derivatives possessing a methylsulfonyl pharmacophore group at the para position of the C-4 phenyl ring were designed, synthesized, and evaluated for cyclooxygenase-2 inhibitory activity. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 3-(benzyloxy)-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one (5d) as a potent COX-2 inhibitor (IC50 = 0.07 μM) with a high COX-2 selectivity index (SI = 287.1) comparable to the reference drug celecoxib (COX-2 IC50 = 0.06 μM; COX-2 SI = 405). A molecular modeling study where 3-(benzyloxy)-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one (5d) was docked into the active site of COX-2 showed that the p-MeSO2 substituent on the C-4 phenyl ring was well-oriented in the vicinity of the COX-2 secondary pocket (Arg513, Val523, and His90) and the carbonyl group of the chromene ring could interact with Ser530. The structure-activity data acquired indicated that the nature and size of the substituent on the C-3 chromene scaffold are important for COX-2 inhibitory activity. Our results also indicated that the chromene moiety constitutes a suitable template to design new COX-2 inhibitors.