Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole and its methanesulfonyl analog: synthesis, biological evaluation and nitric oxide release studies

A new class of hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrugs (NONO-coxibs 12a-b) wherein an O(2)-acetoxymethyl 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, O(2)-acetoxymethyl PROLI/NO) NO-donor moiety was covalently coupled to the bromomethyl group of 5-(4-bromomethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (9a), and its methanesulfonyl analog (9b), were synthesized. The diazen-1-ium-1,2-diolate compounds 12a-b released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (6.1-8.2% range). In comparison, the percentage NO released was significantly higher (76-77% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs 12a-b were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 5-(4-hydroxymethylphenyl)-1-(4-aminosulfonylphenyl)-3-trifluoromethyl-1H-pyrazole (10a), and its methanesulfonyl analog (10b), would be released from the parent NONO-coxib 12a or 12b upon in vivo cleavage by non-specific serum esterases. The hydroxymethyl compounds 10a-b were weak inhibitors of the cyclooxygenase-1 (COX-1) and COX-2 isozymes (IC(50)=3.7-10.5 microM range). However, the hydroxymethyl compounds 10a-b and the parent NONO-coxibs 12a-b exhibited good AI activities (ED(50)=76.7-111.6 micromol/kg po range) that were greater than that exhibited by the reference drugs aspirin (ED(50)=710 micromol/kg po) and ibuprofen (ED(50)=327 micromol/kg po), but less than that of celecoxib (ED(50)=30.9mumol/kg po). 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.     

Diazen-1-ium-1,2-diolated and nitrooxyethyl nitric oxide donor ester prodrugs of anti-inflammatory (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic acids: synthesis, cyclooxygenase inhibition, and nitric oxide release studies

A new group of hybrid nitric oxide-releasing anti-inflammatory drugs wherein an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-d), or 2-nitrooxyethyl (12a-d), (*)NO-donor moiety is attached directly to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. The 2-nitrooxyethyl ester prodrugs (12a-d) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC(50)=0.07-2.8 microM range). All compounds released a low amount of (*)NO upon incubation with phosphate buffer (PBS) at pH 7.4 (1.0-4.8% range). In comparison, the percentage (*)NO released was significantly higher (76.2-83.0% range) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum, or moderately higher (7.6-10.1% range) when the nitrooxyethyl ester prodrugs were incubated in the presence of L-cysteine. These incubation studies suggest that both (*)NO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases in the case of the diazen-1-ium-1,2-diolate esters (11a-d), or interaction with systemic thiols in the case of the nitrate esters (12a-d). O(2)-Acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-phenylacrylate (11a) released 83% of the theoretical maximal release of 2 molecules of (*)NO/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester anti-inflammatory/(*)NO donor prodrugs offer a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects.     

Dinitroglyceryl and diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of aspirin,indomethacin and ibuprofen: Synthesis,biological evaluation and nitric oxide release studies

A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) ester prodrugs (NONO-NSAIDs) wherein a 1,3-dinitrooxy-2-propyl (12a–c), or O²-acetoxymethyl-1-[2-(methyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (14a–c), NO-donor moiety is directly attached to the carboxylic acid group of aspirin, indomethacin or ibuprofen were synthesized. NO release from the dinitrooxypropyl, or diazen-1-ium-1,2-diolate, ester prodrugs was increased substantially upon incubation in the presence of l-cysteine (12a–c) or rat serum (14a–c). The ester prodrugs (12a–c, 14a–c), which did not inhibit the COX-1 isozyme, exhibited modest inhibitory activity against the COX-2 isozyme. The NONO-NSAIDs 12a–c and 14a–c exhibited in vivo AI activity that was similar to that exhibited by the parent drug aspirin, indomethacin or ibuprofen when the same oral dose (μmol/kg) was administered. These similarities in oral potency profiles suggest these NONO-NSAIDs act as classical prodrugs that require metabolic activation by esterase-mediated hydrolysis. Hybrid NO-donor/anti-inflammatory prodrugs of this type (NONO-NSAIDs) offer a potential drug design concept targeted toward the development of anti-inflammatory drugs with reduced adverse gastrointestinal effects.     

Celecoxib analogs possessing a N-(4-nitrooxybutyl)piperidin-4-yl or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridin-4-yl nitric oxide donor moiety: Synthesis,biological evaluation and nitric oxide release studies

A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) coxib prodrugs (NO-coxibs) wherein the para-tolyl moiety present in celecoxib was replaced by a N-(4-nitrooxybutyl)piperidyl 15a–b, or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl 17a–b, NO-donor moiety was synthesized. All compounds released a low amount of NO upon incubation with phosphate buffered saline (PBS) at pH 7.4 (2.4–5.8% range). In comparison, the percentage NO released was higher (3.1–8.4% range) when these nitrate prodrugs were incubated in the presence of l-cysteine. In vitro COX-1/COX-2 isozyme inhibition studies showed this group of compounds are moderately more potent, and hence selective, inhibitors of the COX-2 relative to the COX-1 enzyme. AI structure–activity relationship data acquired showed that compounds having a MeSO₂ COX-2 pharmacophore exhibited superior AI activity compared to analogs having a H₂NSO₂ substituent. Compounds having a MeSO₂ COX-2 pharmacophore in conjunction with a N-(4-nitrooxybutyl)piperidyl (ED₅₀ = 132.4 mg/kg po), or a N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl (ED₅₀ = 118.4 mg/kg po), moiety exhibited an AI potency profile that is similar to aspirin (ED₅₀ = 128.7 mg/kg po) but lower than ibuprofen (ED₅₀ = 67.4 mg/kg po).     

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.     

Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids: synthesis, nitric oxide release studies and anti-inflammatory activities

A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs) wherein an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-c) NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids were synthesized. The diazen-1-ium-1,2-diolate compounds 11a-c all released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (7.7-9.3% range). In comparison, the percentage of NO released was significantly higher (67.5-73.6% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3-carboxylic acid (9a-c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3-carboxylic acids (9a-c) exhibited AI activities (ID(50)=85.2-104.4 mg/kg po range) between that exhibited by the reference drugs aspirin (ID(50)=128.7 mg/kg po) and celecoxib (ID(50)=10.8 mg/kg po). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO-coxibs) offers a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects.     

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 of new 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles: A search for novel nitric oxide donor anti-inflammatory agents

A group of 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles (12a–f) was synthesized and evaluated as anti-inflammatory agents. While all the compounds (20 mg/kg) showed significant anti-inflammatory activity after 3 h of inflammation induction (69–89%) as compared to celecoxib (80%), 1-(4-methanesulfonylphenyl)-5-(4-methylaminomethylphenyl)-3-trifluoromethyl-1H-pyrazole (12a) was found to be the most effective one (89%). The synthesis of model hybrid nitric oxide donor N-diazen-1-ium-1,2-diolate derivatives of 1-(4-methanesulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles (10a–f) requires further investigation since the reaction of N-(4-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)ethanamine (12b) or 1-(4-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)piperazine (12c) with nitric oxide furnished N-nitroso derivatives (13 and 14), respectively, rather than the desired N-diazen-1-ium-1,2-diolate derivatives (10b and 10c).     

Novel (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic ester prodrugs possessing a diazen-1-ium-1,2-diolate moiety: design, synthesis, cyclooxygenase inhibition, and nitric oxide release studies

A novel group of hybrid nitric oxide-releasing anti-inflammatory drugs (11) possessing a 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, or 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, nitric oxide (.NO) donor moiety attached via a one-carbon methylene spacer to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. These ester prodrugs (11) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC(50)=0.94-31.6 microM range). All compounds released .NO upon incubation with phosphate buffer (PBS) at pH 7.4 (3.2-11.3% range). In comparison, the percentage of .NO released was significantly higher (48.6-75.3% range) when these hybrid ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both .NO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases. O(2)-[(E)-2-(4-Acetylaminophenyl)-3-(4-methanesulfonylphenyl)acryloyloxymethyl]-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11f) is a moderately potent (IC(50)=0.94 microM) and selective (SI>104) COX-2 inhibitor that released 73% of the theoretical maximal release of two molecules of .NO/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester .NO-donor prodrugs offer a potential drug design concept for the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular side effects.     

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).     

A diazen-1-ium-1,2-diolate analog of 7-azabenzobicyclo[2.2.1]heptane: Synthesis,nitric oxide and nitroxyl release,in vitro hemodynamic,and anti-hypertensive studies

1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate (16) was designed with the expectation that it would act as a dual nitric oxide (NO) and nitroxyl (HNO) donor that is not carcinogenic or genotoxic. Compound 16, with a suitable half-life (17.8 min) in PBS at pH 7, released NO (19%) and HNO (22%) during a 2 h incubation in PBS at pH 7. In addition, compound 16 exhibited a significant in vitro positive inotropic effect, increased the rates of contraction and relaxation, and increased coronary flow rate, but did not induce a chronotropic effect. Furthermore, compound 16 (13.7 mg kg^?1, po dose) provided a significant reduction in the blood pressure of mice up to 3 h post-drug administration. All these data suggest that compound 16 constitutes an attractive ‘lead-compound’ that could have potential applications to treat cardiovascular disease(s) such as congestive heart failure.     

Synthesis and biological evaluation of 1,4-dihydropyridine calcium channel modulators having a diazen-1-ium-1,2-diolate nitric oxide donor moiety for the potential treatment of congestive heart failure

A group of racemic 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-nitropyridines possessing nitric oxide donor O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino, or 4-ethylpiperazin-1-yl)diazen-1-ium-1,2-diolate, C-5 ester substituents were synthesized by coupling the respective 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-nitropyridine-5-carboxylic acids with either O(2)-acetoxymethyl-1-[N-(2-methylsulfonyloxyethyl)-N-methylamino]diazen-1-ium-1,2-diolate, or O(2)-acetoxymethyl-1-[4-(2-methylsulfonyloxyethyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. Compounds having a C-4 2-pyridyl, 4-pyridyl, 2-trifluoromethylphenyl, or benzofurazan-4-yl substituent exhibited more potent smooth muscle calcium channel antagonist activity (IC(50)'s in the 0.37-1.09 microM range) than related analogs having a C-4 3-pyridyl substituent (IC(50)'s=3.03-9.14 microM range) relative to the reference drug nifedipine (IC(50)=9.13 nM). The point of attachment of C-4 isomeric pyridyl substituents was a determinant of smooth muscle calcium channel antagonist activity where the relative potency profile was 4-pyridyl>2-pyridyl>3-pyridyl. Replacement of the C-5 methyl ester substituent of methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate (Bay K 8644) by an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate, or O(2)-acetoxymethyl-1-(4-ethylpiperazin-1-yl)diazen-1-ium-1,2-diolate, C-5 ester substituent provided compounds, which exhibited a lower, yet respectable, cardiac positive inotropic effect (IC(50)'s=4.82 and 4.05 microM, respectively) relative to the reference drug Bay K 8644 (IC(50)=0.30 microM). All compounds released nitric oxide upon incubation with either phosphate buffer at pH7, or porcine liver esterase. However, the percentage nitric oxide released was up to 3-fold higher (76%) when these O(2)-acetoxymethyl-1-(alkylamino)diazen-1-ium-1,2-diolates were incubated with guinea pig serum. These results suggest that *NO would be released in vivo, upon cleavage by nonspecific serum esterases, preferentially in the vascular endothelium where it may enhance smooth muscle calcium channel antagonist activity.     

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.     

Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: Design,synthesis, pharmacological investigations and docking studies

The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6–8) of some acidic NSAIDs (1–3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6–8) were confirmed by IR, ¹H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6–8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t_1/2 ≈ 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6–8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4 days. In addition, docking of the mutual ester prodrugs (6–8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.     

Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery

A small library of amino acid ester prodrugs of 6-β-naltrexol (NTXOL, 1) was prepared in order to investigate the candidacy of these prodrugs for microneedle-enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized (6a–f). 6b, 6d, and 6e were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. The lead compound (6e) exhibited the most rapid bioconversion to NTXOL in human plasma (t_1/2 = 2.2 ± 0.1 h).     

New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase

New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC₅₀ = 14.8, 24.8, 23.6 and 20.7 μM, respectively) compared to the parent ciprofloxacin (IC₅₀ >100 μM) and doxorubicin as a positive control (IC₅₀ = 1 μM). The flow cytometric analysis for 2b showed dose dependent G₂/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G₂/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G₂/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.     

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 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.     

Inhibitory effect of resveratrol dimerized derivatives on nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells

Four types of resveratrol dimerized analogues were synthesized and evaluated in vitro on LPS-induced NO production in RAW 264.7 cells. The results showed that several compounds, especially those containing 1,2-diphenyl-2,3-dihydro-1H-indene core (type I), exhibited good inhibitory activities. Among 25 analogues, 12b showed a significant inhibitory activity (49% NO production at 10 μM, IC₅₀ = 3.38 μM). Further study revealed that compound 12b could suppress LPS-induced iNOS expression, NO production, and IL-1β release in a concentration-dependently manner. The mechanism of action (MOA) involved for its anti-inflammatory responses was through signaling pathways of p38 MAPK and JNK1/2, but not ERK1/2.     

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.