One-pot three-component azide-alkyne cycloaddition: Synthesis of new pyrazole, 1,2,3-triazole,and oxadiazole tethered and their anti-inflammatory,quantitative structure-activity relationship,and docking studies

A simple and efficient one-pot three-component azide-alkyne cycloaddition of 5-chloro-1-phenyl-pyrazole-4-carbaldehyde with 2-(prop-2-yn-1-ylthio)-5-(substituted phenoxy)methyl-1,3,4-oxadiazole and sodium azide is reported. The newly synthesized compounds were characterized by spectral and analytical data. They were screened for in vitro anti-inflammatory activity by bovine serum albumin denaturation assay. All the tested compounds showed moderate anti-inflammatory activity, whereas three compounds ( 4d , 4i , and 4k ) showed excellent activity comparable with that of the standard drug diclofenac sodium. The quantitative structure-activity relationship (QSAR) study was carried out for anti-inflammatory activities of the synthesized compounds and developed a QSAR model. Inspired by their in vitro anti-inflammatory activities, they were docked to the active site of COX-2 to know the anti-inflammatory potency in silico.     

3-(羟基-p-甲磺酰苯甲撑基)-5-氯-2-吲哚酮-1-羧酰胺类化合物的合成及生物活性研究

为了寻找高效低毒的非甾体抗炎药物, 将5-氯-2-吲哚酮与氯甲酸苯酯经酯化及水解制得1-苯氧羰基-5-氯-2-吲哚酮, 在4-N,N-二甲氨基吡啶作用下与对甲磺酰基苯甲酰氯反应, 经酸化得1-苯氧羰基-3-[羟基-(p-甲磺酰基)苯甲撑基]-5-氯-2-吲哚酮(II₁), 最后与相应的胺(氨)反应, 经盐酸中和制得未见文献报道的目标化合物II₂～II₁₅, 其结构经IR, ¹H NMR, MS和元素分析确证. 二甲苯致小鼠耳肿胀模型测试显示II₁₀, II₁₁, II₁₅具有明显的抗炎活性; 角叉菜胶致大鼠足跖肿胀模型试验结果表明, II₁₀, II₁₁抗炎活性与双氯芬酸钠和替尼达普钠相当(P＞0.05); 其中II₁₁的胃肠道副作用显著小于双氯芬酸钠(P＜0.05)和替尼达普钠(P＜0.01).     

Synthesis,evaluation and docking studies of some 4-thiazolone derivatives as effective lipoxygenase inhibitors

Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model, whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38, and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC₅₀?=?12.98 µM and IC₅₀?=?12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC₅₀?>?50 µM and, COX-2; IC₅₀?>?50 µM). The enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are promising pharmacophore for anti-inflammatory activity.     

Synthesis and anti-inflammatory activity of some benzofuran and benzopyran-4-one derivatives

New series of furosalicylic acids 3a-c, furosalicylanilides 6a-n, furobenzoxazines 8a-f, 1-benzofuran-3-arylprop-2-en-1-ones 12a,b, 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4-ones 16a-c and 6-[6-aryl-2-thioxo-2,5-dihydropyrimidin-4-yl]-4H-chromen-4-ones 17a-c were synthesized. Anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema model in rats and prostaglandin E(2) (PGE(2)) synthesis inhibition activity. Some of the tested compounds revealed comparable activity with less ulcerogenic effect than Diclofenac at a dose 100 mg/kg. All the synthesized compounds were docked on the active site of cyclooxygenase-2 (COX-2) enzyme and most of them showed good interactions with the amino acids of the active site comparable to the interactions exhibited by Diclofenac.     

Synthesis and biological activity evaluation of new thiazolidinone-diclofenac hybrid molecules

Abstract

A novel series of [2-(2,6-dichlorophenylamino)-phenyl]-acetic acid N`-3-(substituted)-4-thiazolidin-5-ylidenemethyl-hydrazide derivatives has been designed and synthesized. The structures of synthesized compounds were confirmed by their <sup>1</sup>H NMR, <sup>13</sup>C NMR and LCMS spectroscopic data. Target compounds were screened for their in vitro anticancer activity according to US NCI protocols, in vitro trypanocidal activity toward Trypanosoma brucei brucei (Tbb) and evaluated for anti-inflammatory activity on the carrageenan edema model in rats. Biological screening data led to identification of compounds 3.3 ([2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid N`-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-hydrazide) and 3.7 ([2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid N`-(4-oxo-2-thioxo-3-(3-trifluoromethylphenyl)thiazolidin-5-ylidenemethyl)-hydrazide) which demonstrated moderate antitumor activity on the non-small-cell lung cancer NCI-H522 and colon cancer HCT-116 cell lines. Several hit compounds (3.2, 3.4) exhibited the promising and significant inhibition growth of the parasites at micromolar concentrations (IC₅₀ values of 4.8 and 7.06?μM, respectively). The synthesized compounds also demonstrated considerable anti-inflammatory effect comparable to the reference non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac sodium or ketorolac tromethamine.     

Synthesis of 4,5-diaryl-1H-pyrazole-3-ol derivatives as potential COX-2 inhibitors

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its analogues 11a-c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representative compound from each class was confirmed by X-ray crystallography. Selected compounds tested for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus COX-1 enzyme.     

2-hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation

Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog and the 4-NHMe-phenyl analog with a CF3, and the 4-OEt-phenyl analog with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.     

Synthesis,antibacterial and anti-inflammatory activity of bis(indolyl)methanes

A series of bioactive bis(indolyl)methanes are synthesized by one-pot green reaction of indole with various substituted aldehydes by microwave irradiation under solvent free conditions. The antibacterial activity against Staphylococcus aureus and anti-inflammatory activity of the synthesized bis(indolyl)-methanes are evaluated in vitro and compared to standard drugs tetracycline and diclofenac, respectively. The majority of the compounds showed good antibacterial and anti-inflammatory activity. Interestingly, compounds 3j, 3i, 3k and 3g exhibited much higher anti-inflammatory activity than the standard diclofenac drug and thus qualify for clinical trials to be used as an anti-inflammatory compound.     

Optimization of pyrazolo[1,5-a]pyrimidine based compounds with pyridine scaffold: Synthesis,biological evaluation and molecular modeling study

BackgroundPyrazolopyrimidine heterocycle and its isosteres represent the main scaffold for many pharmacologically active drugs including anti-inflammatory agents. The COX-2 inhibitors are the principal gate for the design of new safe and potent anti-inflammatory agents.MethodsNovel derivatives of pyrazolo[1,5-a] pyrimidines were synthesized and screened in vivo and in vitro for their anti-inflammatory potential.ResultsWithin the constructed compounds, compound 11 was the most active compound on IL-6 and TNF-α (percentage inhibition = 80 and 89%, respectively). In addition, compound 12 displayed the most inhibitory effect towards COX-2 (IC₅₀ = 1.11 µM), whereas compound 11 recorded the highest COX-2 selectivity (S.I = 8.97). The target derivatives 11–14 displayed good edema inhibitory potential (46–68%) and compound 11 was the most potent candidate (ED₅₀ = 35 mg/kg). Additionally, the most potent sPLA2-V inhibitors were compounds 11 and 13 (IC₅₀ = 1 and 1.7 µM respectively). Regarding activity towards 15-LOX, derivative 12 was the most active compound with IC₅₀ = 5.6 µM revealing higher inhibitory activity than nor-dihydroguaiaretic acid (IC₅₀ = 8.5 µM). To confirm the anti-inflammatory potential of the target derivatives, molecular modeling was performed inside COX-2 and 15-LOX active sites.ConclusionDisplay discoveries increment the plausibility that these pyrazolo[1,5-a]pyrimidines might act as a beginning point for the improvement of anti-inflammatory agents.     

Synthesis,anti-inflammatory activities and docking studies of amide derivatives of meclofenamic acid

NSAIDs constitute a heterogeneous class of pharmacological agents widely prescribed for the treatment of inflammation, pain and edema, as well as osteoarthritis, rheumatoid arthritis and musculoskeletal disorders. This class of drugs has proved efficacious on account of their analgesic, anti-pyretic and anti-inflammatory activities, but gastrointestinal toxicity exists as the biggest problem associated with their chronic use. Many attempts have been made to structurally modify conventional NSAIDs as selective COX-2 inhibitors based on the old and still prevalent common belief that selective inhibition of COX-2 would provide safer NSAIDs. The present work thus focused on the synthesis of amide derivatives of one of the conventional non-selective NSAID, meclofenamic acid utilizing the one pot procedure involving a selective agent, bis (2-oxo-3-oxazolidinyl) phosphonic chloride. The synthesized compounds were tested for their in vivo inflammatory activity using carrageenan rat paw edema assay, and were subsequently docked on COX-2 PDB code 4COX to have better insights into their mechanism of action. The amide derivative with N-4-methoxybenzyl moiety (TSN4) proved to have anti-inflammatory potential (72.8%) better than meclofenamic acid (56.75%). This compound also docked with the highest dock score among the synthesized compounds and was found to have both hydrogen bonding with Arg120 and Tyr355 and hydrophobic interactions with Val349, Leu352, Ser353, Tyr385, Trp387, Met522, Val523, Ala527 and Ser530. N-4-methoxybenzyl amide derivative (TSN4) followed by benzyl amide derivative (TSN1) of meclofenamic acid were identified as potential anti-inflammatory compounds in both in vivo and in silico studies.     

Synthesis and pharmacological evaluation of some 3-(4-methoxyphenyl)-2-substitutedamino-quinazolin-4(3H)-ones as analgesic and anti-inflammatory agents

A variety of novel 3-(4-methoxyphenyl)-2-substitutedamino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one with a variety of alkyl and aryl ketones. The starting material 2-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one was synthesized from 4-methoxyaniline. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. While the test compounds exhibited significant activity, compounds 2-(1-methylpropylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A1), 2-(1-ethylpropylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A2) and 2-(1-methylbutylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A3) showed moderately more potent analgesic activity and the compound 2-(1-methylbutylidene)-hydrazino-3-(4-methoxyphenyl)-quinazolin-4(3H)-one (A3) showed moderately more potent anti-inflammatory activity when compared to the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that cyclooxygenase-1 (COX-1) plays an important role in inflammation and carcinogenesis. In order to find more selective COX-1 inhibitors a series of novel curcumin derivatives was synthesized and evaluated for their ability to inhibit this enzyme using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. All curcumin analogues showed a higher rate of COX-1 inhibition. The most potent curcumin compounds were (1E,6E)-1,7-di-(2,3,4-trimethoxyphenyl)-1,6-heptadien-3,5-dione (4) (COX-1: IC(50) = 0.06 microM, COX-2: IC(50) > 100 microM, selectivity index>1666) and (1E,6E)-methyl 4-[7-(4-methoxycarbonyl)phenyl]-3,5-dioxo-1,6-heptadienyl]benzoate (6) (COX-1: IC(50) = 0.05 microM, COX-2: IC(50) > 100 microM, selectivity index > 2000). Curcumin analogues therefore represent a novel class of highly selective COX-1 inhibitors and promising candidates for in vivo studies.     

Antiinflammation Derived Suzuki-Coupled Fenbufens as COX-2 Inhibitors: Minilibrary Construction and Bioassay

A small fenbufen library comprising 18 compounds was prepared via Suzuki Miyara coupling. The five-step preparations deliver 9–17% biphenyl compounds in total yield. These fenbufen analogs exert insignificant activity against the IL-1 release as well as inhibiting cyclooxygenase 2 considerably. Both the para-amino and para-hydroxy mono substituents display the most substantial COX-2 inhibition, particularly the latter one showing a comparable activity as celecoxib. The most COX-2 selective and bioactive disubstituted compound encompasses one electron-withdrawing methyl and one electron-donating fluoro groups in one arene. COX-2 is selective but not COX-2 to bioactive compounds that contain both two electron-withdrawing groups; disubstituted analogs with both resonance-formable electron-donating dihydroxy groups display high COX-2 activity but inferior COX-2 selectivity. In silico simulation and modeling for three COX-2 active—p-fluoro, p-hydroxy and p-amino—fenbufens show a preferable docking to COX-2 than COX-1. The most stabilization by the p-hydroxy fenbufen with COX-2 predicted by theoretical simulation is consistent with its prominent COX-2 inhibition resulting from experiments.     

Previously undescribed antioxidative azocinyl morpholinone alkaloid from red seaweed Gracilaria opuntia with anti-cyclooxygenase and lipoxygenase properties

In vitro antioxidative and anti-inflammatory bioassay-guided fractionation of the methanol: ethyl acetate crude extract of the thalli of red seaweed Gracilaria opuntia collected from the Gulf of Mannar led to the isolation of a new morpholine alkaloid 3-(2-ethyl-6-((3Z,7Z)-1,2,5,6-tetrahydroazocin-5-yl)hexyl) morpholin-6-one. The substituted azocinyl morpholinone recorded significant 1,1-diphenyl-2-picryl-hydrazil free radical scavenging activities (IC₅₀ ~ 0.086 mg/mL) compared to the commercially available antioxidants, butylated hydroxyanisole, butylated hydroxytoluene, and α-tocopherol (IC₅₀ > 0.20 mg/mL). The title compound showed greater cyclooxygenase-2 (COX-2) inhibitory activity (IC₅₀ 0.84 mg/mL) in conjunction with in vitro 5-lipoxidase inhibitory activity (IC₅₀ 0.85 mg/mL) than non-steroidal anti-inflammatory drugs (NSAIDs). The test compound had better selectivity index (COX-1/COX-2 ratio) (1.17 mg/mL) compared to aspirin (0.02 mg/mL), Na salicylate (0.73 mg/mL) and ibuprofen (0.44 mg/mL). The animals challenged with the substituted azocinyl morpholinone significantly mitigated the carrageenan-induced paw edema in time-dependent manner till the end of 6 h.     

Antiedematogenic activity of two thiazolidine derivatives: N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28)

The search for new anti-inflammatory drugs has been constant in several research centers. The use of the Bioisostery concept allows the elaboration of new bioactive compounds with different properties through the introduction of substitute groups in one or more positions of a main molecule with known biological activity. Preliminary works accomplished at our laboratory with 2,4-thiazolidinedione isosters demonstrated inhibitory activity on edema formation for N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26). We verified the antiedematogenic and ulcerogenic activity of these two compounds in Wistar rats. The carrageenan induced paw edema suffered significant (p<0.05) inhibition (28.36% on average) for GS28 (100 mg/kg; v.o.) during the entire time of the experiment. GS26 (50 and 100 mg/kg; v.o.) significantly inhibited (p<0.05) the paw edema dextran induced (22.1 and 27.8%, for the respective doses) after 180 min. The compounds GS26 and GS28 did not show ulcerogenic activity on gastric mucous. The results suggest antiedematogenic action for both compounds without the appearance of gastric lesions.     

Molecular modeling and structural analysis of some tetrahydroindazole and cyclopentanepyrazole derivatives as COX-2 inhibitors

In an attempt to rationalize the search for new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines the prediction of physicochemical and pharmacokinetic properties, molecular docking, molecular dynamic simulation, and free energy calculation. Starting from a small library of compounds synthesized previously, it was found that 70% of the compounds analyzed satisfy with the associated values to physicochemical principles as key evaluation parameters for the drug-likeness; all the compounds presented good gastrointestinal absorption and cerebral permeability and they showed an interaction with the Arg 106 residue of the COX-2 isoenzyme. Finally, it was obtained that compound 3ab has a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug celecoxib, suggesting that this compound could become a powerful candidate in the inhibition of the COX-2 enzyme. In addition, we realized the crystallographic analysis of compounds 3j, 3r, and 3t defining the crystal parameters and the Packing interactions.     

Synthesis of Sugar and Nucleoside Analogs and Evaluation of Their Anticancer and Analgesic Potentials

Chemical modification of sugars and nucleosides has a long history of producing compounds with improved selectivity and efficacy. In this study, several modified sugars (2–3) and ribonucleoside analogs (4–8) have been synthesized from α-d-glucose in a total of 21 steps. The compounds were tested for peripheral anti-nociceptive characteristics in the acetic acid-induced writhing assay in mice, where compounds 2, 7, and 8 showed a significant reduction in the number of writhes by 56%, 62%, and 63%, respectively. The compounds were also tested for their cytotoxic potential against human HeLa cell line via trypan blue dye exclusion test followed by cell counting kit-8 (CCK-8) assay. Compound 6 demonstrated significant cytotoxic activity with an IC₅₀ value of 54 µg/mL. Molecular docking simulations revealed that compounds 2, 7, and 8 had a comparable binding affinity to cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. Additionally, the bridged nucleoside analogs 7 and 8 potently inhibited adenosine kinase enzyme as well, which indicates an alternate mechanistic pathway behind their anti-nociceptive action. Cytotoxic compound 6 demonstrated strong docking with cancer drug targets human cytidine deaminase, proto-oncogene tyrosine-protein kinase Src, human thymidine kinase 1, human thymidylate synthase, and human adenosine deaminase 2. This is the first ever reporting of the synthesis and analgesic property of compound 8 and the cytotoxic potential of compound 6.     

NO-NSAIDs. Part 3: nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs

In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially "Safe NSAIDs," we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33). Among these NO-NSAIDs, the ester-containing NO-aspirin (9), NO-diclofenac (10), NO-naproxen (11), and the imide-containing NO-aspirin (25), NO-flurbiprofen (27) and NO-ketoprofen (28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E(2) (PGE(2)) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially "Safe NSAIDs" for the treatment of arthritic pain and inflammation.     

Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol

The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs.     

Docking studies and anti-inflammatory activity of beta-hydroxy-beta-arylpropanoic acids

The article describes a two-step synthesis of diastereomeric 3-hydroxy-2-methyl-3-(4-biphenylyl)butanoic acids. In the first step an intermediate alpha-bromo propanoic acid 1-ethoxyethyl ester was synthesized. The second step is a new modified Reformatsky reaction in presence of Zn in tetrahydrofuran (THF) at -5 to 10 degrees C between the previously synthesized intermediate and 4-acetylbiphenyl. Synthesis of the other studied beta-hydroxy-beta-arylpropanoic acids has already been reported. These beta-hydroxy-beta-arylpropanoic acids belong to the arylpropanoic acid class of compounds, structurally similar to the NSAIDs such as ibuprofen. The anti-inflammatory activity and gastric tolerability of the synthesized compounds were evaluated. Molecular docking experiments were carried out to identify potential COX-2 inhibitors among the beta-hydroxy-beta-aryl-alkanoic acids class. The results indicate that all compounds possess significant anti-inflammatory activity after oral administration and that the compounds 2-(9-(9-hydroxy-fluorenyl))-2-methylpropanoic acid (5) and 3-hydroxy-3,3-diphenyl-propanoic acid (3) possess the strongest anti-inflammatory activity, comparable to that of ibuprofen, a standard NSAID,and that none of tested substances or ibuprofen produced any significant gastric lesions.