1-(4-Methane(amino)sulfonylphenyl)-3-(4-substituted-phenyl)-5-(4-trifluoromethylphenyl)-1H-2-pyrazolines/pyrazoles as potential anti-inflammatory agents

2-Pyrazolins 14a–l and pyrazoles 15a–l were designed as celecoxib analogs for the evaluation of their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. Compounds 14i, 15a, 15d and 15f were the most COX-2 selective derivatives (S.I. = 5.93, 6.08, 5.03 and 5.27 respectively) while the pyrazoline derivatives 14g and 14i exhibited the highest AI activity (ED₅₀ = 190.5 and 160.1 μmol/kg po, respectively).     

Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-carboxymethylphenyl)-1-(4-methanesulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its aminosulfonyl analog: Synthesis,biological evaluation and nitric oxide release studies

A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs) wherein an O²-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (13a–b), or O²-acetoxymethyl-1-(2-methylpyrrolidin-1-yl)diazen-1-ium-1,2-diolate (16a–b), NO-donor moiety was covalently coupled to the COOH group of 5-(4-carboxymethylphenyl)-1-(4-methane(amino)sulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (11a–b) was synthesized. The percentage of NO released from these diazen-1-ium-1,2-diolates was significantly higher (59.6–74.6% of the theoretical maximal release of 2 molecules of NO/molecule of the parent hybrid ester prodrug) upon incubation in the presence of rat serum, relative to incubation with phosphate buffer (PBS) at pH 7.4 (5.0–7.2% range). These incubation studies suggest that both NO and the AI compound would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. All compounds were weak inhibitors of the COX-1 isozyme (IC₅₀ = 8.1–65.2 μM range) and modest inhibitors of the COX-2 isozyme (IC₅₀ = 0.9–4.6 μM range). The most potent parent aminosulfonyl compound 11b exhibited AI activity that was about sixfold greater than that for aspirin and threefold greater than that for ibuprofen. The ester prodrugs 13b, 16b exhibited similar AI activity to that exhibited by the more potent parent acid 11b when the same oral μmol/kg dose was administered. These studies indicate hybrid ester AI/NO donor prodrugs of this type (NONO-coxibs) constitute a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects.     

Synthesis of 1-(methanesulfonyl- and aminosulfonylphenyl)acetylenes that possess a 2-(N-difluoromethyl-1,2-dihydropyridin-2-one) pharmacophore: Evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

A hitherto unknown class of linear acetylene regioisomers were designed such that a SO₂Me or SO₂NH₂ group was located at the ortho-, meta- or para-position of the acetylene C-1 phenyl ring, and a N-difluoromethyl-1,2-dihydropyridin-2-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three SO₂Me regioisomers, and the 4-SO₂NH₂ analog, were potent inhibitors of 5-lipoxygenase (5-LOX IC₅₀ = 3.2–3.5 μM range) relative to the reference drug caffeic acid (IC₅₀ = 4.0 μM). The SO₂Me regioisomers exhibited weak cyclooxygenease-1 (COX-1) and -2 (COX-2) inhibitory activity with a modest COX-2 selectivity index. The most potent 3-SO₂Me, 4-SO₂Me and 4-SO₂NH₂ compounds, with respective ED₅₀ values of 66.1, 68.5 and 86.5 mg/kg po, exhibited comparable oral anti-inflammatory (AI) activity to that of the reference drug ibuprofen (ED₅₀ = 67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of inhibiting 5-LOX for exploitation in the development of 5-LOX inhibitory AI drugs.     

Design,synthesis of 2,3-disubstitued 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents: COX-1/2 inhibitory activities and molecular docking studies

A new series, 2-substituted mercapto-3-[2-(pyridin-2-yl)ethyl]-4(3H)-quinazolinone 1–21, was synthesized and evaluated for in vivo anti-inflammatory and analgesic activities and in vitro COX-1/COX-2 inhibition. Compounds 1, 4, 5, 6, 8, 10, 13, 14, 15, 16, and 17 exhibited potent anti-inflammatory and analgesic properties, with ED₅₀ values of 50.3–112.1 mg/kg and 12.3–111.3 mg/kg, respectively. These values may be compared with those of diclofenac sodium (ED₅₀ = 112.2 and 100.4 mg/kg) and celecoxib (ED₅₀ = 84.3 and 71.6 mg/kg). Compounds 4 and 6 possessed strong COX-2 inhibitory activity with IC₅₀ (0.33 μM and 0.40 μM, respectively) and selectivity index (SI > 303.0 and >250.0, respectively) values that are similar to those of the reference drug celecoxib (IC₅₀ 0.30 μM and COX-2 SI > 333). Compounds 5, 8, and 13 demonstrated effective COX-2 inhibitory activity with IC₅₀ values of 0.70–0.80 μM and COX-2 SI > 125–142. Potent COX-2 inhibitors, such as compounds 4, 6, and 13, were docked into the active site pockets of COX-1 and COX-2, with the greatest recognition occurring at the COX-2 binding site and insignificant interactions at the binding site of the COX-1 pocket.     

New 1,2-diaryl-4-substituted-benzylidene-5-4H-imidazolone derivatives: Design,synthesis and biological evaluation as potential anti-inflammatory and analgesic agents

A new series of 1,2-diaryl-4-substituted-benzylidene-5-4H-imidazolone derivatives 10a-h was designed and synthesized for evaluation as selective COX-2 inhibitors, anti-inflammatory agents and as analgesic agents. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compounds 10a, 10b, 10e and 10f were the most COX-2 selective compounds (S.I. = 10.76, 10.87, 8.69 and 9.14 respectively), the most potent anti-inflammatory derivatives (ED₅₀ = 65.7, 60.2, 76.3 and 107.4 μmol/kg respectively) in comparison with Celecoxib (COX-2 S.I. = 8.61, ED₅₀ = 82.2 μmol/kg) and were less ulcerogenic (ulcer indexes = 1.22–3.02) than Ibuprofen (ulcer index = 20.25) and comparable to Celecoxib (ulcer index = 2.93). The four derivatives (10a, 10b, 10e and 10f) showed considerable analgesic activities which are clearly parallel to their anti-inflammatory activities.     

Design,synthesis and anticonvulsant activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides

The focused library of 21 new N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules were obtained as close analogs of previously described N-benzyl derivatives and fuse the chemical fragments of clinically relevant antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, as well as in the six-Hertz (6 Hz) model of pharmacoresistant limbic seizures. Applying the rotarod test, the acute neurological toxicity was determined. The broad spectra of activity across the preclinical seizure models in mice (ip) displayed compounds 4, 5, 11, and 19. The most favorable anticonvulsant properties demonstrated 4 (ED₅₀ MES = 96.9 mg/kg, ED₅₀ scPTZ = 75.4 mg/kg, ED₅₀ 6 Hz = 44.3 mg/kg) which showed TD₅₀ = 335.8 mg/kg in the rotarod test that yielded satisfying protective indexes (PI MES = 3.5, PI scPTZ = 4.4, PI 6 Hz = 7.6). Consequently, compound 4 revealed comparable or better safety profile than model antiepileptic drugs (AEDs): ethosuximide, lacosamide, and valproic acid. In the in vitro assays, compound 4 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and diltiazem site of L-type calcium channels.     

Synthesis and biological evaluation of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: Dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

A novel class of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore attached to its C-4 or C-5 position was designed for evaluation as anti-inflammatory (AI) agents. Replacement of the 2,4-difluorophenyl ring in diflunisal by the N-difluoromethyl-1,2-dihydropyrid-2-one moiety provided compounds showing dual selective cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activities. AI structure–activity studies showed that the C-4 (14a) and C-5 (14b) salicylate regioisomers were 1.4- and 1.6-fold more potent than aspirin, and the C-5 N-acetyl-2-carboxybenzenesulfonamide regioisomer (22b) was 1.3- and 2.8-fold more potent than ibuprofen and aspirin, respectively. In vivo ulcer index (UI) studies showed that the 4- and 5-(N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl)salicylic acids (14a and 14b) were completely non-ulcerogenic since no gastric lesions were present (UI = 0) relative to aspirin (UI = 57) at an equivalent μmol/kg oral dose. The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel 5-LOX pharmacophore for the design of cyclic hydroxamic mimetics for exploitation in the development of dual COX-2/5-LOX inhibitory AI drugs.     

Design,synthesis and biological screening of new 4-thiazolidinone derivatives with promising COX-2 selectivity,anti-inflammatory activity and gastric safety profile

Two series of new thiazolidin-4-one derivatives 4a–c and 8a–e were designed and prepared. All the synthesized compounds were evaluated for their in vitro COX-2 selectivity and anti-inflammatory activity in vivo. Compounds 8c and 8d showed the best overall in vitro COX-2 selectivity (selectivity indexes of 4.56 and 5.68 respectively) and in vivo activities (edema inhibition % = 61.8 and 67 after 3 h, respectively) in comparison with the reference drug celecoxib (S.I. = 7.29, edema inhibition % = 60 after 3 h). In addition, 8c and 8d were evaluated for their mean effective anti-inflammatory doses (ED₅₀ = 27.7 and 18.1 μmol/kg respectively, celecoxib ED₅₀ = 28.2 μmol/kg) and ulcerogenic liability (reduction in ulcerogenic potential versus celecoxib = 85%, 92% respectively. Molecular docking studies were performed and the results were in agreement with that obtained from the in vitro COX inhibition assays.     

New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2-yl]pyrrolidine-2,5-diones

The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5–38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6 Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED₅₀ MES = 74.8 mg/kg, ED₅₀ scPTZ = 51.6 mg/kg, ED₅₀ 6 Hz = 16.8 mg/kg) which showed TD₅₀ = 213.3 mg/kg in the chimney test that yielded satisfying protective indexes (PI MES = 2.85, PI scPTZ = 4.13, PI 6 Hz = 12.70) at time point of 0.5 h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.     

Synthesis,biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a–d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC₅₀’s in 1.79–4.35 μM range; COX-2 selectivity index (SI) = 6.8–16.7 range). Compound 3b emerged as most potent (COX-2 IC₅₀ = 1.79 μM; COX-1 IC₅₀ >30 μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in carrageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl ring substituted with p-CF₃ substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.     

Synthesis and CYP24A1 inhibitory activity of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides

A series of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides were prepared, using an efficient three- to five-step synthesis, and evaluated for their inhibitory activity against human cytochrome P450C24A1 (CYP24A1) hydroxylase. Inhibition ranged from IC₅₀ 0.3–72 μM compared with the standard ketoconazole IC₅₀ 0.52 μM, with the styryl derivative (11c) displaying enhanced activity (IC₅₀ = 0.3 μM) compared with the standard, providing a useful preliminary lead for drug development.     

Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: Dual Inhibitors of cyclooxygenases and 5-lipoxygenase

A new group of acetic acid (7a–c, R¹ = H), and propionic acid (7d–f, R¹ = Me), regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compounds exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isozyme. Attachment of the N-difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, that is, absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl)acetic acid (7c) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Molecular modeling (docking) studies showed that the highly electronegative CHF₂ substituent present in 7c, that showed a modest selectivity for the COX-2 isozyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO₂NH₂) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region containing the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs.     

Celecoxib prodrugs possessing a diazen-1-ium-1,2-diolate nitric oxide donor moiety: Synthesis,biological evaluation and nitric oxide release studies

A new class of anti-inflammatory (AI) cupferron prodrugs was synthesized wherein a diazen-1-ium-1,2-diolato ammonium salt, and its O²-methyl and O²-acetoxyethyl derivatives, nitric oxide (NO) donor moieties were attached directly to an aryl carbon on a celecoxib template. The percentage of NO released from the O²-methyl and O²-acetoxyethyl compounds was higher (18.0–37.8% of the theoretical maximal release of one molecule of NO/molecule of the parent compound) upon incubation in the presence of rat serum, relative to incubation with phosphate buffer saline (PBS) at pH 7.4 (3.8–11.6% range). All compounds exhibited weak inhibition of the COX-1 isozyme (IC₅₀ = 5.8–17.0 μM range) in conjunction with weak or modest inhibition of the COX-2 isozyme (IC₅₀ = 1.6–14.4 μM range). The most potent AI agent 5-[4-(O²-ammonium diazen-1-ium-1,2-diolato)phenyl]-1-(4-sulfamoylphenyl)-3-trifluoromethyl-1H-pyrazole exhibited a potency that was about fourfold and twofold greater than that observed for the respective reference drugs aspirin and ibuprofen. These studies indicate that use of a cupferron template constitutes a plausible drug design approach targeted toward the development of AI drugs that do not cause gastric irritation, or elevate blood pressure and induce platelet aggregation that have been associated with the use of some selective COX-2 inhibitors.     

The discovery of potent glycine transporter type-2 inhibitors: Design and synthesis of phenoxymethylbenzamide derivatives

We describe the discovery of phenoxymethylbenzamide derivatives as a novel class of glycine transporter type-2 (GlyT-2) inhibitors. We found hit compound 1 (human GlyT-2, IC₅₀ = 4040 nM) in our library and converted its 1-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)pyrrolidin-3-yl group to an 1-(N,N-dimethylaminopropyl)piperidyl group and its tert-butyl group to a trifluoromethyl group to obtain N-(1-(3-(dimethylamino)propyl)piperidin-4-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (20). Compound 20 showed good inhibitory activity against human GlyT-2 (IC₅₀ = 15.3 nM) and exhibited anti-allodynia effects in a mouse neuropathic pain model.     

A diazen-1-ium-1,2-diolated nitric oxide donor ester prodrug of 3-(4-hydroxymethylphenyl)-4-(4-methanesulfonylphenyl)-5H-furan-2-one: synthesis, biological evaluation and nitric oxide release studies

A novel hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrug (NONO-coxib 14) wherein an O²-acetoxymethyl 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate (O²-acetoxymethyl PROLI/NO) NO-donor moiety was covalently coupled to the CH₂OH group of 3-(4-hydroxymethylphenyl)-4-(4-methylsulfonylphenyl)-5H-furan-2-one (12), was synthesized. The prodrug 14 released a low amount of NO (4.2%) upon incubation with phosphate buffer (PBS) at pH 7.4 which was significantly higher (34.8% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) upon incubation in the presence of rat serum. These incubation studies suggest that both NO and the parent compound 12 would be released from the prodrug 14 upon in vivo cleavage by non-specific serum esterases. The prodrug ester 14 is a selective COX-2 inhibitor that exhibited AI activity (ED₅₀ = 72.2 mmol/kg po) between that of the reference drugs celecoxib (ED₅₀ = 30.9 μmol/kg po) and ibuprofen (ED₅₀ = 327 μmol/kg po). The NO donor compound 14 exhibited enhanced inhibition of phenylephrine-induced vasoconstriction of isolated mesenteric arteries compared with that observed under control conditions. These studies indicate hybrid ester AI/NO donor prodrugs (NONO-coxibs) constitutes a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects.     

Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives

A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu(I)-catalyzed or Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene 9 and a panel of various para-substituted phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-NMe₂, 4-Cl, 4-F). All compounds were used in in vitro cyclooxygenase (COX) assays to determine the combined electronic and steric effects upon COX-1 and COX-2 inhibitory potency and selectivity. Structure-activity relationship studies showed that compounds having a vicinal diaryl substitution pattern showed more potent COX-2 inhibition (IC₅₀ = 0.03–0.36 μM) compared to their corresponding 1,3-diaryl-substituted counterparts (IC₅₀ = 0.15 to >10.0 μM). In both series, compounds possessing an electron-withdrawing group (Cl and F) at the para-position of one of the aryl rings displayed higher COX-2 inhibition potency and selectivity as determined for compounds containing electron-donating groups (Me, OMe, NMe₂). The obtained data show, that the central carbocyclic or heterocyclic ring system as found in many COX-2 inhibitors can be replaced by a central 1,2,3-triazole unit without losing COX-2 inhibition potency and selectivity. The high COX-2 inhibition potency of some 1,2,3-triazoles having a vicinal diaryl substitution pattern along with their ease in synthesis through versatile Ru(II)-catalyzed click chemistry make this class of compounds interesting candidates for further design and synthesis of highly selective and potent COX-2 inhibitors.     

5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties

A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a–z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI₅₀ = 850 nM), against leukemia SR cancer cells (GI₅₀ = 1.45 μM), and OVCAR-3 (GI₅₀ = 1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI₅₀ value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI₅₀ values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI₅₀ values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.     

Molecular design,synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

A group of cyclic imides (1–10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC₅₀ range of 0.1–4.0 μM. In vitro COX-1/COX-2 inhibition structure–activity studies identified compound 8a as a highly potent (IC₅₀ = 0.1 μM), and an extremely selective [COX-2 (SI) > 1000] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED₅₀ = 72.4 mg/kg) relative to diclofenac (ED₅₀ = 114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO₂NH₂ group underwent H-bonding interaction with Gln¹⁹²(2.95 Å), Phe⁵¹⁸(2.82 Å) and Arg⁵¹³(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.     

Synthesis and antinociceptive properties of N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide in the mouse tail-flick and hot-plate tests

The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception and the involvement of opioid, α₂-adrenergic, and I₂ imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ET_A receptor antagonist on 1c antinociception. Synthesis of 1c was accomplished in two steps using modifications of previously reported methods. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with 1c; antagonists + 1c; clonidine + 1c; or antagonists + clonidine + 1c. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α₂-adrenoceptor antagonist), idazoxan (α₂-adrenoceptor/I₂-imidazoline antagonist), BU224 (I₂-imidazoline antagonist) or BQ123 (endothelin ET_A receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED₅₀ values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither clonidine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The α₂-adrenergic, I₂-imidazoline and endothelin ET_A receptors are not involved in 1c antinociception.     

Design and synthesis of new 1,3-benzthiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors

A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one (7b) as a potent (IC₅₀ = 0.05 μM) and selective (selectivity index = 259) COX-2 inhibitor.