New benzimidazothiazole derivatives as anti-inflammatory,antitumor active agents: Synthesis,in-vitro and in-vivo screening and molecular modeling studies

A new series of benzimidazothiazole derivatives has been synthesized. The structure of the products was confirmed by spectroscopic techniques such as IR, NMR and mass spectroscopy. The tested compounds were evaluated for their anti-inflammatory activity either in vitro through the COX enzyme inhibition assay, or in vivo through carrageenan paw edema technique. Results revealed that compound 25 and 29 represented the most active ones among the entire series with % inhibition 72.19, 72.07 for COX-1, and 87.46, 87.38 for COX-2, respectively. Interestingly, all synthesized compounds exhibited IC₅₀ values less than both reference drugs celecoxib and naproxen, indicating their superior potency. For compound 25, it showed about 340 and 198 times more potent than celecoxib and naproxen respectively as COX-1 inhibitor (IC₅₀ value 0.044 vs. 15.000 and 8.700 µM), and 10 and 115 times more potent than the same drugs as COX-2 inhibitor (IC₅₀ value 4.52 vs. 40.00 and 520.00 nM). The antitumor activity of the products was also evaluated and the results obtained are consistent with those obtained by the anti-inflammatory screening where compounds 25 and 29 proved to be the most active ones among the other compounds with %GI ranging from 31.5 to 62.5% and they exhibited the lowest IC₅₀ values as well. The ADMET analysis of the tested compounds was also performed in addition to the molecular modeling studies that included flexible alignment, surface and electrostatic maps in addition to the Lipinisk's rule of five.     

New phenolic cinnamic acid derivatives as selective COX-2 inhibitors. Design,synthesis, biological activity and structure-activity relationships

Selective inhibition of cyclooxygenase (COX)-2 enzyme is an important achievement when looking for potent anti-inflammatory agents, with fewer gastrointestinal side effects. In this work, a new series of cinnamic acid derivatives, namely hexylamides, have been designed, synthesized and evaluated in human blood for their inhibitory activity of COX-1 and COX-2 enzymes. From this, new structure-activity relationships were built, showing that phenolic hydroxyl groups are essential for both COX-1 and COX-2 inhibition. Furthermore, the presence of bulky hydrophobic di-tert-butyl groups in the phenyl ring strongly contributes for selective COX-2 inhibition. In addition, a correlation with the theoretical log P has been carried out, showing that lipophilicity is particularly important for COX-2 inhibition. Further, a plasma protein binding (PPB) prediction has been performed revealing that PPB seems to have no influence in the activity of the studied compounds. From the whole study, effective selective inhibitors of COX-2 were found, namely compound 9 (IC₅₀ = 3.0 ± 0.3 μM), 10 (IC₅₀ = 2.4 ± 0.6 μM) and 23 (IC₅₀ = 1.09 ± 0.09 μM). Those can be considered starting point hit compounds for further optimization as potential non-steroidal anti-inflammatory drugs.     

Synthesis,biological evaluation and docking study of N-(2-(3,4,5-trimethoxybenzyl)benzoxazole-5-yl) benzamide derivatives as selective COX-2 inhibitor and anti-inflammatory agents

A series of N-(2-(3,4,5-trimethoxybenzyl)-benzoxazole-5-yl)benzamide derivatives (3a–3n) was synthesized and evaluated for its in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC₅₀ < 1 µM), were evaluated in vivo for their anti-inflammatory and ulcerogenic potential. Out of the fourteen newly synthesized compounds; 3b, 3d, 3e, 3h, 3l and 3m were found to be most potent COX-2 inhibitors in in vitro enzymatic assay with IC₅₀ in the range of 0.14–0.69 µM. In vivo anti-inflammatory activity of these six compounds (3b, 3d, 3e, 3h, 3l and 3m) was assessed by carrageenan induced rat paw edema method. The compound 3b (79.54%), 3l (75.00%), 3m (72.72%) and 3d (68.18%) exhibited significant anti-inflammatory activity than standard drug ibuprofen (65.90%). Ulcerogenic activity with histopathological studies was performed, and the screened compounds demonstrated significant gastric tolerance than ibuprofen. Molecular Docking study was also performed with resolved crystal structure of COX-2 to understand the interacting mechanisms of newly synthesized inhibitors with the active site of COX-2 enzyme and the results were found to be in line with the biological evaluation studies of the compounds.     

1,4-Dihydroquinazolin-3(2H)-yl benzamide derivatives as anti-inflammatory and analgesic agents with an improved gastric profile: Design,synthesis, COX-1/2 inhibitory activity and molecular docking study

The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a–o) as anti-inflammatory and analgesic agents and COX-1/2 inhibitors are reported. The target compounds (4a–o) were synthesized using a two-step scheme, and their chemical structures were confirmed with ¹H NMR, ¹³C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC₅₀ 0.04–0.07 μM), which was nearly the same as that of the reference drug celecoxib (IC₅₀ 0.049 μM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates.     

Synthesis,potential anti-inflammatory and analgesic activities study of (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamides

A series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives were designed, synthesized and evaluated for their anti-inflammatory and analgesic effects in vivo. Among the synthesized compounds 2a and 2n showed the best anti-inflammatory activity (inhibition rate: 95% and 92.7%, respectively) and analgesic effect (inhibition rate: 100% and 100%, respectively), which was greater than that or nearly equivalent to that of indomethacin. Compounds 2a and 2n were selected to test their inhibitory effects against ovine COX-1 and COX-2 using the cyclooxygenase inhibition assay in vitro. Compounds 2a and 2n are weak inhibitors of COX-1 isozyme but displayed moderate COX-2 isozyme inhibitory effects (IC₅₀ = 0.47 μM and 1.63 μM, respectively) and COX-2 selectivity indexes (SI = 11.5 and 4.8). Furthermore, compound 2a was more inhibitors of COX-2 isozyme active than the reference drug celecoxib.     

1,2,3-triazole tethered Indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX,COX-2 & tubulin: Their anti-proliferative & anti-inflammatory activity

To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC₅₀ 0.12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046 respectively. Compounds 11q and 13s also demonstrated comparable 5-LOX inhibitory activity with IC₅₀ 7.73 and 7.43 µM respectively to that of standard Norhihydroguaiaretic acid (NDGA: IC₅₀ 7.31 µM). Among all the selected cell lines, prostate cancer cell line DU145 was found to be susceptible to this class of compounds. Among all the tested compounds, compounds 11g, 11i, 11k, 11q, 13r, 13s and 13u demonstrated excellent to moderate anti-proliferative activity with IC_50s ranging between 6.29 and 18.53 µM. Compounds 11q and 11g demonstrated better anti-proliferative activities against DU145 cancer cell line with IC₅₀ values 8.17 and 8.69 µM respectively when compared to the standard drug etoposide (VP16; IC₅₀ 9.80 µM). Compounds 11g, 11k, 11q, 13s and 13u showed good dual COX-2/5-LOX inhibitory potentials with excellent anti-proliferative activity. Results from carrageenan-induced hind paw edema demonstrated that compounds 11b, 11l, 11q and 13q exhibited significant anti-inflammatory activity with 69–77% inhibition at 3 h, 75–82% inhibition at 5 h when compared to the standard drug indomethacin (66.6% at 3 h and 77.94% at 5 h). Ulcerogenic study revealed that compounds 11q and 13q did not cause any gastric ulceration. In vitro tubulin assay resuted that compound 11q interfered with microtubulin dynamic and act as tubulin polymerization inhibitor. In silico molecular docking studies demonstrated that compounds 11q and 13s are occupying the colchicines binding site of tubulin polymer and 11q illustrated very good binding affinities towards COX-2 and 5-LOX.     

Chalcone derivatives bearing chromen or benzo[f]chromen moieties: Design,synthesis, and evaluations of anti-inflammatory,analgesic, selective COX-2 inhibitory activities

Thirty-eight chalcone derivatives bearing a chromen or benzo[f]chromen moiety were synthesized and evaluated for their anti-inflammatory and analgesic activities. Using an ear edema model, anti-inflammatory activities were observed for compounds 3a-3s (ear inflammation: 1.75–3.71 mg) and 4a-4s (ear inflammation: 1.71–4.94 mg). All compounds also displayed analgesic effects with inhibition values of 66.7–100% (3a-3s) and 96.2–100% (4a-4s). The 12 compounds that displayed excellent anti-inflammatory and analgesic effects were tested for their inhibitory activity against ovine COX-1 and COX-2. Six compounds bearing a chromen moiety were weak inhibitors of the COX-1 isozyme but showed moderate COX-2 isozyme inhibitory effects (IC₅₀s from 0.37 μM to 0.83 μM) and COX-2 selectivity indexes (SI: 22.49–9.34). Those bearing a benzo[f]chromen moiety were more selective toward COX-2 than those bearing a chromen moiety with IC₅₀s from 0.25 μM to 0.43 μM and COX-2 selectivity indexes from SI: 31.08 to 20.67.     

Novel pyrazoles and pyrazolo[1,2-a]pyridazines as selective COX-2 inhibitors; Ultrasound-assisted synthesis,biological evaluation,and DFT calculations

COX-2 is an inducible enzyme mediating inflammatory responses. Selective targeting of COX-2 is useful for developing anti-inflammatory agents devoid of ulcerogenic activity. Herein, we report the design and synthesis of a series of pyrazoles and pyrazolo[1,2-a]pyridazines with selective COX-2 inhibitory activity and in vivo anti-inflammatory effect. Both series were accessed through acid-catalyzed ultrasound-assisted reactions. The most active compounds in this study are two novel molecules, 11 and 16, showing promising selectivity and decent IC₅₀ of 16.2 and 20.1 nM, respectively. These compounds were also docked into the crystal structure of COX-2 enzyme (PDB ID: 3LN1) to understand their mode of binding. Finally, Mulliken charges and electrostatic surface potential were calculated for both compound 11 and celecoxib using DFT method to get insights into the molecular determinants of activity of this compound. These results could lead to the development of novel COX-2 inhibitors with improved selectivity.     

Novel N-substituted 5-aminosalicylamides as dual inhibitors of cyclooxygenase and 5-lipoxygenase enzymes: Synthesis,biological evaluation and docking study

Three new series of 5-aminosalicylic acid derivatives; series I (14, 16–18), series II (19–30) and series III (31–41) were synthesized as potential dual COX-2/5-LOX inhibitors. Their chemical structures were confirmed using spectroscopic tools including IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity for all target compounds was evaluated in vivo using carrageenan-induced paw edema. Compound 36 showed the highest anti-inflammatory activity (114.12%) relative to reference drug indomethacin at 4 h interval. Selected derivatives were evaluated in vitro to inhibit ovine COX-1, human recombinant COX-2 and 5-LOX enzymes. Compounds 34 & 35 exhibited significant COX-2 inhibition (IC₅₀ = 0.10 µM) with significant COX-2 selectivity indices (SI = 135 & 145 respectively) approximate to celecoxib (IC₅₀ = 0.049 µM, SI = 308.16) and exceeding indomethacin (IC₅₀ = 0.51 µM, SI = 0.08). Interestingly, all compounds showed superior 5-LOX inhibitory activity about 2–5 times relative to zileuton. Compound 16 was the superlative 5-LOX inhibitor that revealed (IC₅₀ = 3.41 µM) relative to zileuton (IC₅₀ = 15.6 µM). Compounds 34, 35, 36 and 41 showed significant dual COX-2/5-LOX inhibitions. The gastric ulcerogenic effect of compound 36 was examined on gastric mucosa of albino rats and they showed superior GI safety profile compared with indomethacin. Molecular docking studies of the compounds into the binding sites of COX-1, COX-2 and 5-LOX allowed us to shed light on the binding mode of these novels dual COX and 5-LOX inhibitors.     

Synthesis,biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide,sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold

A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10–12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect.Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.     

Ligand based design and synthesis of pyrazole based derivatives as selective COX-2 inhibitors

The design and synthesis of novel pyrazole based derivatives has been carried out using the ligand based approach like pharmacophore and QSAR modelling of reported pyrazoles from the available literature to investigate the chemical features that are essential for the design of selective and potent COX-2 inhibitors. Both pharmacophore and QSAR models with good statistical parameters were selected for the design of the lead molecule. Also by exploiting the chemical structures of selective and marketed COX-2 inhibitors, celecoxib and SC-558 were used in designing the molecules which are used in the treatment of inflammation and related disorders. The therapeutic action of the Non-Steroidal Anti-inflammatory Agents (NSAIDs) is based primarily on the COX-2 inhibition. With this background we have synthesized some azomethine derivatives of 3-methyl-1-substituted-4-phenyl-6-[{(1E)-phenylmethylene}amino]-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile 6(a-o) and were characterized by ¹HNMR, ¹³CNMR and Mass spectral techniques. All the synthesized pyrazole derivatives were tested for in vitro membrane stability property in both COX-1 & COX-2 inhibition studies and in vivo anti-inflammatory activity by carrageenan induced rat paw edema model. Among them, compound 6k showed very good activity by in vivo anti-inflammatory activity with 0.8575 mmol/kg as ED₅₀. Similarly compounds 6m, 6o, 6i and 6h exhibited comparable anti-inflammatory activity to standard drugs. Also the active compounds were further screened for ulcerogenic activity and were found be safer with less ulcer index compared to the marketed drugs like aspirin, ibuprofen and celecoxib.     

Synthesis,biological evaluation and docking study of a new series of di-substituted benzoxazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents

A new series of substituted-N-(3,4-dimethoxyphenyl)-benzoxazole derivatives 13a–13p was synthesized and evaluated in vitro for their COX (I and II) inhibitory activity, in vivo anti-inflammatory and ulcerogenic potential. Compounds 13d, 13h, 13k, 13l and 13n exhibited significant COX-2 inhibitory activity and selectivity towards COX-2 over COX-1. These selected compounds were screened for their in vivo anti-inflammatory activity by carrageenan induced rat paw edema method. Among these compounds, 13d was the most promising analogs of the series with percent inhibition of 84.09 and IC₅₀ value of 0.04?µM and 1.02?µM (COX-2 and COX-1) respectively. Furthermore, ulcerogenic study was performed and tested compounds (13d, 13h, 13k, 13l) demonstrated a significant gastric tolerance than ibuprofen. Molecular docking study was also performed with resolved crystal structure of COX-2 to understand the binding mechanisms of newly synthesized inhibitors in the active site of COX-2 enzyme and the results were found to be concordant with the biological evaluation studies of the compounds. These newly synthesized inhibitors also showed acceptable pharmacokinetic profile in the in silico ADME/T analyses.     

Spiroindolone analogues bearing benzofuran moiety as a selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors

To design and discover a new compound can used as a COX with TNF-α and IL-6 inhibitors is highly challenge. A series of spiroindolone-bearing benzofuran moieties were resynthesized from the chalcone-based benzo[b]furan with substituted isatin, and amino acids. The requisite spiroindolone analogues were tested for their potential inhibitory activities against lipid metabolizing enzymes such as cyclooxygenase COX-1, COX-2, and the release of pro-inflammatory cytokines interleukin IL-6, and tumor necrosis factor TNF-α. Among the tested compounds, 5a, 5c, 5h, 5i, 5l, and 5p exhibited COX-1 inhibitor selectively with percent of inhibition 40.81–83.4% and IC₅₀ values ranging from 20.42 µM to 38.24 µM. In addition, all the synthesized target compounds possessed lipopolysaccharide-induced TNF-α, and IL-6 expression with a varying degree of COX-1 inhibition. Compounds 5d, 5e, 5f, 5g, and 5k markedly inhibited TNF-α, and IL-6 release in WI-38 fibroblast cells. Molecular docking of the most effective and highly selective compounds were investigated and shown important binding mechanisms which could affect pro-inflammatory enzymes and cytokines via the inhibition of COX-1, COX-2, IL-6, and TNF-α.     

Design,synthesis of novel isoindoline hybrids as COX-2 inhibitors: Anti-inflammatory,analgesic activities and docking study

A group of novel isoindoline hybrids incorporating oxime, hydrazone, pyrazole, chalcone or aminosulfonyl pharmacophores (9–14) was designed and characterized by spectral data and elemental analyses results. All newly synthesized compounds were evaluated as COX-2 inhibitors, anti-inflammatory and analgesic agents. Six hybrid derivatives (10b, 10c, 11a, 11d, 13, 14) were moderate COX-2 inhibitors (IC₅₀ = 0.11–0.18 µM) close to standard celecoxib (IC₅₀ = 0.09 µM). The most active compounds showed outstanding in vivo anti-inflammatory activity (% edema inhibition = 41.7–50, 1 h; 40.7–67.4, 3 h; 20–46.7, 6 h) better than reference drug diclofenac (% edema inhibition = 29.2, 1 h; 22.2, 3 h; 20, 6 h). Most compounds showed significant peripheral and/or central analgesic activity. The moderate selective COX-2 inhibitor; dimethoxychalcone 11d (SI = 103) displayed excellent anti-inflammatory activity (% edema inhibition = 45.8–59.3) and increased thermal pain threshold (50–92.85%) comparable to piroxicam (75%). Molecular docking studies have been established.     

Novel class of benzimidazole-thiazole hybrids: The privileged scaffolds of potent anti-inflammatory activity with dual inhibition of cyclooxygenase and 15-lipoxygenase enzymes

The present study includes design and synthesis of new molecular hybrids of 2-methylthiobenzimidazole linked to various anti-inflammatory pharmacophores through 2-aminothiazole linker, to investigate the effect of such molecular variation on cyclooxygenase (COX) and 15-lipoxygenase (15-LOX) enzymes inhibition as well as in vivo anti-inflammatory activity. The chemical structures of new hybrids were confirmed using different spectroscopic tools and elemental analyses. Benzimidazole-thiazole hybrids linked to acetyl moiety 13, phenyl thiosemicarbazone 14, 1,3-thiazolines 15a-c and 4-thiazolidinone 16 exhibited significant COX-2 inhibition (IC₅₀ = 0.045–0.075 µM) with significant COX-2 selectivity indices (SI = 142–294). All hybrids revealed potent 15-LOX inhibitory activity (IC₅₀ = 1.67–6.56 µM). Benzimidazole-thiazole hybrid 15b was the most potent dual COX-2 (IC₅₀ = 0.045 µM, SI = 294) inhibitor approximate to celecoxib (COX-2; IC₅₀ = 0.045 µM, SI = 327), with double inhibitory activity versus 15-LOX enzyme (IC₅₀ = 1.67 µM) relative to quercetin (IC₅₀ = 3.34 µM). Three hybrids (14, 15b & 16) were selected for in vivo screening using carrageenan-induced paw edema method. Benzimidazole-thiazole hybrid linked to 4-thiazolidinone 16 showed the maximum edema inhibition at both 3 h and 4 h intervals as well (~119% and 102% relative to indomethacin, respectively). The gastric ulcerogenic effect of benzimidazole-thiazole hybrid 16 was estimated compared with indomethacin showing superior gastrointestinal safety profile. In bases of molecular modeling; all new active hybrids were subjected to docking simulation into active sites of COX-2 and 15-LOX enzymes to study the binding mode of these novel potent dual COX-2/15-LOX inhibitors.     

Pyrazoles containing thiophene,thienopyrimidine and thienotriazolopyrimidine as COX-2 selective inhibitors: Design,synthesis, in vivo anti-inflammatory activity,docking and in silico chemo-informatic studies

New thiophene and annulated thiophene pyrazole hybrids were synthesized and screened for their in vitro COX-1/COX-2 enzymatic inhibition and in vivo anti-inflammatory activities. All compounds were more COX-2 selective inhibitors than COX-1 with compound 13 exhibiting the highest COX-2 selectivity index. Compounds 3, 6a, 9 and 11 were the most promising in the acute anti-inflammatory assay while compounds 3, 5, 6a, 6c, 9, 10, 11 and 13 exerted promising anti-inflammatory activity in the sub-acute anti-inflammatory assay. Compounds 3, 6a, 6c, 9, 10 and 11 were evaluated for their ED₅₀ values and were more potent than diclofenac sodium while compounds 6a, 6c and 9 were of greater potency than celecoxib with compound 6a being the most potent showing ED₅₀ = 0.033 mmol/kg. These compounds were non-toxic and proved to be gastrointestinal safe compared to indomethacin, diclofenac sodium and celecoxib. Docking studies into COX-2 active site (PDB code 3LN1) revealed that compounds 3, 6a, 6c, 9, 10, 11 and 13 had binding modes and energies comparable to that of celecoxib. Compounds 3, 9, 10 and 11 complied with Lipinski’s RO5 while compounds 6a and 6c showed one violation whereas compound 13 deviated by 2 violations. Compounds 6a, 6c and 13 showed 100% plasma protein binding (PPB) and showed no aqueous solubility while compounds 3, 10 and 11 demonstrated the best drug likeness model scores. Therefore, the thiophene analog 3 and the thienopyrimidine derivatives 10 and 11 are promising anti-inflammatory candidates that exert moderate selective COX-2 inhibition with acceptable physicochemical properties.     

Design,synthesis, evaluation and molecular modelling studies of some novel 5,6-diphenyl-1,2,4-triazin-3(2H)-ones bearing five-member heterocyclic moieties as potential COX-2 inhibitors: A hybrid pharmacophore approach

A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2H)-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c–3e and 4c–4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c–3e and 4c–4e (IC₅₀ 0.60–1.11 μM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design.     

Synthesis of novel 3,5,6-trisubstituted 2-pyridone derivatives and evaluation for their anti-inflammatory activity

The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo anti-inflammatory activity, reducing ear edema and myeloperoxidase (MPO) activity. The most active compounds (2a and 7a) were inhibitors of COX enzymes. Compound 2a selectively inhibited the COX-2, while 7a was nonselective. Further, the compound 2a showed effective binding at the active site of COX-2 co-crystal by docking molecular study.     

Novel aryl carboximidamide and 3-aryl-1,2,4-oxadiazole analogues of naproxen as dual selective COX-2/15-LOX inhibitors: Design,synthesis and docking studies

A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC₅₀ range of 6.4 – 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC₅₀ = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC₅₀ range of 1.77–4.91 nM comparing to meclofenamate sodium (IC₅₀ = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities.     

Novel diphenylthiazole derivatives with multi-target mechanism: Synthesis,docking study,anticancer and anti-inflammatory activities

Over the last few decades, a growing body of studies addressed the anticancer activity of NSAIDs, particularly selective COX-2 inhibitors. However, their exact molecular mechanism is still unclear and is not fully investigated. In this regard, a novel series of compounds bearing a COXs privilege scaffold, diphenyl thiazole, was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines. The most active compounds 10b, 14a,b, 16a, 17a,b and 18b were evaluated in vitro for COX-1/COX-2 inhibitory activity. These compounds were suggested to exert their anticancer activity through a multi-target mechanism based on their structural features. Thus, compounds 10b and 17b with the least IC₅₀ values in MTT assay were tested against three known anticancer targets; EGFR, BRAF and tubulin. Compounds 10b and 17b showed remarkable activity against EGFR with IC₅₀ values of 0.4 and 0.2 μM, respectively and good activity against BRAF with IC₅₀ values of 1.3 and 1.7 μM, respectively. In contrast, they showed weak activity in tubulin polymerization assay. The in vivo anti-inflammatory potential was assessed and interestingly, compound 17b was the most potent compound. Together, this study offers some important insights into the correlation between COXs inhibition and cancer treatment. Additionally, the results demonstrated the promising activity of these compounds with a multi-target mechanism as good candidates for further development into potential anticancer agents.