Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.     

Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

A group of 4,5‐diphenylisoxazoles ( 11a–p ), 3,4‐diphenyl‐5‐trifluoromethylisoxazoles ( 15, 21 ), and 4,5‐diphenyl‐3‐methylsulfonamidoisoxazole ( 23 ) possessing a variety of substituents (H, F, MeS, MeSO, MeSO₂) at the para‐position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX‐2 inhibitory antiinflammatory (AI), agents. Although the 4,5‐diphenylisoxazole group of compounds (11a–p) exhibited potent analgesic and AI activities, those compounds evaluated ( 11a, 11b, 11m ) were more selective inhibitors of COX‐1 than COX‐2, with the exception of 4‐(4‐methylsulphonylphenyl)‐5‐phenylisoxazole ( 11n ) that showed a modest COX‐2 selectivity index (SI) of 2.1. In contrast, 3‐(4‐methylsulphonylphenyl)‐4‐phenyl‐5‐trifluoromethylisoxazole ( 15 ), which retained good analgesic and AI activities, was a highly potent and selective COX‐2 inhibitor (COX‐1 IC₅₀ > 500 μM; COX‐2 IC₅₀ < 0.001 μM) with a COX‐2 SI of > 500,000, relative to the reference drug celecoxib (COX‐1 IC₅₀ = 22.9 μM; COX‐2 IC₅₀ = 0.0567 μM) with a COX‐2 SI of 404. The 3‐phenyl‐4‐(4‐methylsulphonylphenyl) regioisomer ( 21 ) was a less potent inhibitor (COX‐1 IC₅₀ = 252 μM; COX‐2 IC₅₀ = 0.2236 μM) with a COX‐2 SI of 1122, relative to the regioisomer ( 15 ). The related compound 4,5‐diphenyl‐3‐methylsulfonamidoisoxazole ( 23 ) exhibited similar (to 21 ) potency and COX‐2 selectivity (COX‐1 IC₅₀ > 200 μM; COX‐2 IC₅₀ = 0.226 μM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX‐2 inhibitor (15) in the active site of the human COX‐2 enzyme showed the C‐5 CF₃ substituent is positioned 3.37 Å from the phenolic OH of Tyr³⁵⁵, and 6.91 Å from the Ser⁵³⁰ OH. The S‐atom of the MeSO₂ substituent is positioned deep (7.40 Å from the entrance) inside the COX‐2 secondary pocket (Val⁵²³). These studies indicate a C‐5 CF₃ ( 15, 21 ), or C‐3 NHSO₂Me ( 23 ), central isoxazole ring substituent is crucial to selective inhibition of COX‐2 for this class of compounds. Drug Dev. Res. 51:273–286, 2000. © 2001 Wiley‐Liss, Inc.     

Biological Evaluation of 2‐(4‐Amino‐Phenyl)‐3‐(3,5‐Dihydroxylphenyl) Propenoic Acid

Abstract: 2‐(4‐Aminophenyl)‐3‐(3,5‐dihydroxylphenyl) propenoic acid (CSN‐07001) is a new compound based on the combination of resveratrol and propenoic acid derivatives. In vitro cyclooxygenase (COX)/5‐lipoxygenase (5‐LOX) inhibition assays showed that the test compound exhibited a dual inhibitory activity against the COX (COX‐1 IC₅₀ = 2.20 μM, COX‐2 IC₅₀ = 1.76 μM) and 5‐LOX (IC₅₀ = 0.28 μM) enzymes. Further, the enhanced COX‐1/COX‐2/5‐LOX expression in lipopolysaccaride‐induced lung inflammation in mice was also suppressed by CSN‐07001 in a concentration‐dependent manner. In vivo studies showed that CSN‐07001 exhibited potent anti‐inflammatory and antinociceptive effects in different experimental models. We further examined the risk of gastric damage induced by CSN‐07001. The test compound was gastric‐sparing in that it elicited markedly fewer stomach lesions than indomethacin in rats. Taken together, our data indicate that CSN‐07001 exhibits a novel class of dual inhibitors of COX and 5‐LOX having therapeutic potential as non‐steroidal anti‐inflammatory agents with an enhanced gastric safety profile.     

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis,Molecular Modeling Studies,and Identification as Stereoselective Inhibitors of HIV‐1

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 _S , 11 _S , and 12 _S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC₅₀) = 123.8 µM (selectivity index, SI > 3), IC₅₀ = 12.1 µM (SI > 29), IC₅₀ = 17.4 µM (SI > 19), respectively. Enantiomers 8 _R , 11 _R , and 12 _R were inactive against the HIV‐1 strain III_B. Hydrazones 8 _S , 11 _S , and 12 _S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT.     

Design,syntheses, and evaluation of novel 1,1‐dihalo‐2,3‐diphenylcyclopropanes as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

A group of (Z)‐ and (E)‐1,1‐dihalo‐2‐(4‐substituted‐phenyl)‐3‐phenylcyclopropane [ (Z)‐10 , (E)‐11 ] stereoisomers having a variety of substituents (H, Br, Cl, F, NO₂, SO₂Me) at the para‐position of the C‐2 phenyl ring in conjunction with either two chloro or bromo substituents at C‐1 were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of compounds ( 10‐11 ) exhibited significant analgesic activity since 4% NaCl‐induced abdominal constriction was reduced by 44–73% at 30 min, and 48–77% at 60 min, post‐drug administration relative to the reference drugs aspirin and celecoxib (58 and 32% inhibition at 30 min post‐drug administration) for a 50 mg/kg intraperitoneal dose. In the 1,1‐dichloro group of compounds, a Cl or MeSO₂ substituent at the para‐position of the C‐2 phenyl ring generally provided superior analgesic activity. The most active analgesic compound, (E)‐1,1‐dichloro‐2‐(4‐methanesufonylphenyl)‐3‐phenylcyclopropane ( 11h ) inhibited abdominal constriction by 72 and 77% at 30 and 60 min post‐drug administration, respectively. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of ( Z)‐10 and ( E)‐11 compounds exhibited AI activities in the inactive‐to‐moderate activity range (1.5–45% inhibition) for a 50 mg/kg oral dose. The AI potency order, with respect to the para‐substitutent on the C‐2 phenyl ring, for the ( Z)‐10 compounds was NO₂ > MeSO₂ ≈ H ≥ Cl, and for the ( E)‐11 compounds was H ≥ MeSO₂ > Cl ≈ Br. (E)‐1,1‐dibromo‐2‐(4‐methanesufonylphenyl)‐3‐phenylcyclopropane ( 11l ), which was the most active AI compound, reduced inflammation by 45 and 37% at 3 and 5 h post‐drug administration, respectively. The ( E)‐11 stereoisomer was generally a more potent AI agent than the corresponding ( Z)‐10 stereoisomer. In vitro COX‐1 and COX‐2 inhibition studies showed that (E)‐1,1‐dichloro‐2‐(4‐nitrophenyl)‐3‐phenylcyclopropane ( 11c ) inhibited COX‐1 (IC₅₀ = 278.8 μM) and COX‐2 (IC₅₀ = 80.5 μM) for a COX‐2 selectivity index of 3.5, whereas (E)‐1,1‐dichloro‐2‐(4‐methanesulfonylphenyl)‐3‐phenylcyclopropane ( 11h ) was a more potent inhibitor of COX‐1 and COX‐2, but it was more selective for COX‐1 (COX‐1 IC₅₀ = 0.59 μM, COX‐2 IC₅₀ = 3.04 μM). A molecular modeling (docking) study for (E)‐1,1‐dichloro‐2‐(4‐methanesulfonylphenyl)‐3‐phenylcyclopropane ( 11h ) on the active site of the human COX‐2 isozyme shows it binds in the center of the active site with the 1,1‐dichloro substituents oriented in the direction of the mouth of the channel towards Arg¹²⁰, and the C‐2 MeSO₂ moiety oriented towards the apex of the active site with the S‐atom of the MeSO₂ substituent positioned about 6.56 Å inside the entrance to the secondary pocket (Val⁵²³) of COX‐2. In contrast, the corresponding (Z)‐10h stereoisomer assumes a different position in the COX‐2 binding site where the S‐atom of the MeSO₂ moiety is near (4.02 Å) the Ser⁵³⁰ OH, but a much greater distance from the COX‐2 secondary pocket (Val⁵²³). The results from these docking studies are consistent with the observation that (E)‐11h is an inhibitor of both COX isozymes, whereas the (Z)‐10h stereoisomer is an inactive COX inhibitor (COX‐1 IC₅₀ > 100 μM, COX‐2 IC₅₀ > 200 μM). Drug Dev. Res. 55:79–90, 2002. © 2002 Wiley‐Liss, Inc.     

Synthesis and kinetics studies of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazide derivatives as potent antidiabetic agents

A novel series of N′‐(2‐(3,5‐disubstituted‐4H‐1,2,4‐triazol‐4‐yl)acetyl)‐6/7/8‐substituted‐2‐oxo‐2H‐chromen‐3‐carbohydrazides were synthesized and studied for their α‐glucosidase inhibition activity. Most of the synthesized compounds exhibited potential α‐glucosidase inhibition activity with IC₅₀ values ranging from 0.96 ± 0.02 to 32.86 ± 0.73 µg/ml. Among them, compounds 3e and 4e , having a methoxy group on the coumarin ring, proved to be the most potent ones, showing an enzyme inhibition activity with IC₅₀ = 0.96 ± 0.02 and 1.44 ± 0.06 µg/ml, respectively. The kinetic study through Lineweaver–Burk plots revealed that the inhibition mechanism of the most active compounds 3d, 3e, 4d , and 4e , on the α‐glucosidase activity, was found to be in the competitive mode.     

Design,syntheses, and evaluation of 2,3‐diphenylcycloprop‐2‐en‐1‐ones and oxime derivatives as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

A group of 2,3‐diphenylcycloprop‐2‐enes having a variety of substituents at the para‐position of the C‐2 phenyl ring (H, F), and C‐3 phenyl ring (H, F, SMe, SOMe, SO₂Me), in conjunction with either a C‐1 carbonyl, oxime, oxime acetate, benzoyl hydrazone, or hydrogen substituent were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of cycloprop‐2‐ene compounds exhibited significant analgesic activity, since 4% NaCl‐induced abdominal constriction was reduced by 43–90% at 30 min, and 41–100% at 60 min, after drug administration relative to the reference drugs aspirin and celecoxib (58% and 32% inhibition at 30 min after drug administration) for a 50 mg/kg intraperitoneal dose. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of cycloprop‐2‐ene compounds exhibited AI activities in the inactive‐to‐modest activity range (0–26% inhibition) for a 50 mg/kg oral dose. The AI potency order for a group of 2,3‐diphenylcycloprop‐2‐enes with respect to the C‐1 substituent was oxime>hydrogen>carbonyl>benzoyl hydrazone. 2,3‐Diphenylcycloprop‐2‐en‐1‐one oxime ( 20 ) was the most active AI agent, inducing a 26% reduction in inflammation, relative to the reference drugs ibuprofen and celecoxib, which showed 52% and 58% reductions in inflammation, at 5 h after drug administration. In vitro COX‐1 and COX‐2 inhibition studies showed that 2,3‐diphenylcycloprop‐2‐en‐1‐one oxime ( 20 ) is a selective COX‐2 inhibitor (COX‐1 IC₅₀>100 μM; COX‐2 IC₅₀=2.94 μM; COX‐2 selectivity index>34). A molecular modeling study that docked the oxime ( 20 ) in the active site of the human COX‐2 isozyme showed that it binds in the vicinity of the mouth of the COX‐2 binding site with the O‐atom of the oxime (=N–OH) moiety separated from the NH₂ group of Arg¹²⁰ by about 3.65 Å. This orientation of the oxime compound ( 20 ) in the COX‐2 binding site could be due to a potentially strong ionic interaction between the =NOH oxime moiety and the guanidinium moiety of Arg¹²⁰. Drug Dev. Res. 57:6–17, 2002. © 2002 Wiley‐Liss, Inc.     

Synthesis and evaluation as PDE4 inhibitors of pyrimidine‐2,4‐dione derivatives

A series of nitraquazone analogs with a pyrimidindione core was synthesized and tested for inhibitory activity on PDE4, selectivity versus PDE3 and PDE5 and for affinity towards the rolipram high‐affinity binding site (HARBS). The 5‐anilino derivatives 13–18 showed the best profile combining appreciable PDE4 inhibitory activity (IC₅₀ = 5–14 µM) with a good selectivity toward PDE3 and PDE5. The same compounds demonstrate low affinity for the HARBS site with IC₅₀ values of 12–69 µM (IC₅₀ for Rolipram = 3.6 nM). Drug Dev Res 72: 274–288, 2011. © 2010 Wiley‐Liss, Inc.     

Design,synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC₅₀ values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC₅₀ value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC₅₀ values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC₅₀ values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC₅₀ values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC₅₀ = 0.8 µM). These promising derivatives, 3f , 3h , and 3j , were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.     

Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

A group of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates ( 10–15 ), and the related acetamide derivative ( 16 ), that possess a variety of C‐7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic‐antiinflammatory agents. The effect of the C‐7 substituent(s) and the nature of the acetic acid ester (R¹ = Ome) or acetamide (R¹ = NH₂) moiety on analgesic activity was determined using a 4% NaCl‐induced abdominal constriction assay. Compounds 10–16 inhibited writhing by 36–82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C‐7 substituents was a determinant of analgesic activity in the 7,7‐dihalo group of compounds where the relative activity profile was 7‐Cl₂ > 7‐Br₂ > 7‐F₂ > 7‐Cl,7‐F, and for 7‐monohalo compounds where the potency order was 7‐Br > 7‐Cl. Elaboration of the 7,7‐dibromo methyl acetate ester ( 10 ) to the corresponding acetamide derivative ( 16 ) enhanced analgesic activity. The nature of the 7‐halo substituent(s) in the 7,7‐dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan‐induced rat paw edema assay, where the relative potency order was 7‐Br₂ > 7‐Cl₂ > 7‐F₂ > 7‐Cl,7‐F. The most potent 7,7‐dibromo compound ( 10 ) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX‐2 (IC₅₀ = 26.4 μM) and COX‐1 (IC₅₀ = 227 μM) for a COX‐2 selectivity index of 8.6. Docking 10 in the active site of human COX‐2 showed it binds in the center of the COX‐2 binding site with the C‐5 phenyl ring oriented toward the acetylation site (Ser⁵³⁰), and the phenyl group of the C‐4 benzoyl moiety oriented in the vicinity of the COX‐2 secondary binding pocket near Val⁵²³. Drug Dev. Res. 49:75–84, 2000. © 2000 Wiley‐Liss, Inc.     

Trimethyl‐4‐oxo‐4,5,6,7‐tetrahydroindazole‐1‐acetic Acid: A New Lead Compound with Selective COX‐2 Inhibitory Activity

A novel series of 3,6,6‐trimethyl‐4‐oxo‐4,5,6,7‐tetrahydroindazole‐1‐acetic acid derivatives was designed and synthesized by a new one‐step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase‐2 (COX‐2) and cyclooxygenase‐1 (COX‐1) enzymes in vitro. Among the synthesized compounds, the 2‐(3,6,6‐trimethyl‐4‐oxo‐4,5,6,7‐tetrahydroindazol‐1‐yl)acetic acid 4 emerged as the most potent COX‐2 inhibitor (IC₅₀ value: 150 nM) with the highest selectivity index (COX‐1/COX‐2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX‐2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization.     

Synthesis,molecular docking,and pharmacological evaluation of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives as selective COX‐2 inhibitors and anti‐inflammatory agents

A series of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives ( 3am ) was synthesized and evaluated for their 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 potential by the carrageenan‐induced rat paw edema method. Out of 13 newly synthesized compounds, 3a , 3b , 3d , 3g , 3j , and 3k were found to be the most potent COX‐2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti‐inflammatory activity of these six compounds ( 3a , 3b , 3d , 3g , 3j , and 3k ) was assessed by the carrageenan‐induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti‐inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX‐2, to understand the binding mechanism of these inhibitors to the active site of COX‐2.

     

Synthesis and In‐Vitro Anti‐Hepatitis‐B Virus Activity of 6H‐[1]Benzothiopyrano[4,3‐b] quinolin‐10‐ols

A series of 9‐methoxy‐6H‐[1]benzothiopyrano[4,3‐b]quinolin‐10‐ols with a Mannich side chain were synthesized and evaluated for their anti‐Hepatitis B virus (HBV) activity in HepG2.2.15 cells. Some compounds showed significant anti‐HBV activity with IC₅₀ values less than 41 μM. Among them, compound 9b was the most effective anti‐HBV agent (IC₅₀ = 1.7 μM, SI = 60.3).     

Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: Design,synthesis, molecular docking,and anticancer evaluations

A novel series of benzoxazole/benzothiazole derivatives 4a–c – 11a–e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT‐116, and MCF‐7 cells, with IC₅₀ values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f , and 9c showed the highest anticancer activities against HepG2 cells with IC₅₀ values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT‐116 cells with IC₅₀ values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF‐7 cells with IC₅₀ values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC₅₀ values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a–c, 9b,c,e,f,h , and 11c,e were further evaluated for their VEGFR‐2 inhibition. Compounds 4c and 4b potently inhibited VEGFR‐2 at IC₅₀ values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC₅₀ value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Design and synthesis of pyrazole–pyrazoline hybrids as cancer‐associated selective COX‐2 inhibitors

In continuation of our previous work on cancer and inflammation, 15 novel pyrazole–pyrazoline hybrids ( WSPP1 – 15 ) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in ¹H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (H_A, H_M, and H_X) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF‐7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5‐Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC₅₀ values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC₅₀ value of more than 50 µM. The derivatives were also evaluated for their in vitro anti‐inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti‐inflammatory activities were further studied for COX‐2 inhibition. The manifestation of a higher COX‐2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX‐2 also exhibited a better spectrum of activity against various cancer cell lines.     

The application of tandem aza-wittig reaction to synthesize artemisinin-guanidine hybrids and their anti-tumor activity

Three series of novel artemisinin–guanidine hybrids 4a–4f , 8a–8h and 9a–9h have been facilely synthesized via four‐component reaction (aza‐Wittig reaction) and evaluated for their anti‐tumor activities against A549, HT‐29 and MDA‐MB‐231 cell lines in vitro. All of the tested compounds showed enhanced anti‐tumor activities with IC₅₀ values ranging from 0.02 µM to 12.0 µM as compared to DHA (dihydroartemisinin). Among them, artemisinin derived dimers, compounds 9b (IC₅₀ = 0.05 µM), 9d (IC₅₀ = 0.06 µM) and 9f (IC₅₀ = 0.02 µM) were found to be most active against HT29 cells.     

Design,synthesis, molecular docking,and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors

Novel series of benzoxazole s 4 _a‐f ‐16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 _e was found to be the most potent against HepG2, HCT‐116, and MCF‐7 with IC₅₀ = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5 _c , 5 _f , 6 _b , 5 _d , and 6 _c showed the highest anticancer activities against HepG2 cells with IC₅₀ of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT‐116 cells with IC₅₀ of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF‐7 cells with IC₅₀ of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC₅₀ of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5 _c‐f and 6 _b,c were further evaluated for their vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibition. Compounds 5 _e and 5 _c potently inhibited VEGFR‐2 at lower IC₅₀ values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC₅₀ = 0.1 ± 0.02 µM). Compound 5 _f potently inhibited VEGFR‐2 at low IC₅₀ value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR‐2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.     

Synthesis and calcium channel modulation effects of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates possessing ortho‐, meta‐, and para‐CH2S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents

A group of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐phenylpyridine‐5‐carboxylates ( 13–15 ) possessing ortho‐, meta‐, and para‐CH₂S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents were synthesized using a modified Hantzsch reaction. Calcium channel (CC) modulating activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro assays. This class of –CH₂S(O)nMe and –S(O)nMe (n = 0–2) compounds ( 13–15a–f ) exhibited weaker CC antagonist activity on GPILSM (IC₅₀ = > 1.1 × 10^–5 to 4.1 × 10^–6 M range) than the reference drug nifedipine (IC₅₀ = 1.4 × 10^–8 M). The oxidation state of the sulfur atom was a determinant of smooth muscle CC antagonist activity where the relative activity profile was generally thio ( 13 , ‐CH₂SMe, ‐SMe) and sulfonyl ( 15 , ‐CH₂SO₂Me, ‐SO₂Me) > sulfinyl ( 14 , ‐CH₂SOMe, ‐SOMe). The point of attachment of the phenyl substituent was a determinant of activity for the –CH₂SMe ( 13a–c ), ‐CH₂SOMe ( 14a–c ) and SOMe ( 14d–f ) isomers where the relative potency order was meta and para > ortho. Compounds in this group ( 13–15 ), unlike Bay K 8644 (EC₅₀ = 2.3 × 10^–7 M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta‐CH₂SMe ( 13b ), ortho‐CH₂SMe ( 13c ), meta‐SMe ( 13e ), and ortho‐CH₂SO₂Me ( 15c ) C‐4 phenyl derivatives exhibited respectable in vitro cardiac positive inotropic activities (EC₅₀ = 1.00 × 10^–6 to 7.57 × 10^–6 M range) relative to the reference drug Bay K 8644 (EC₅₀ = 7.70 × 10^–7 M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel agonist on smooth muscle (GPILSM), compounds 13b (IC₅₀ = 4.11 × 10^–6 M), 13c (IC₅₀ = 2.29 × 10^–5 M), 13e (IC₅₀ = > 1.20 × 10^–5 M) and 15c (IC₅₀ = 6.22 × 10^–6 M) exhibited a desirable simultaneous calcium channel antagonist effect on smooth muscle at a similar ( 13b , 15c ), or lower ( 13c , 13e ), concentration relative to its cardiac agonist EC₅₀ value. Model compounds such as 13b , 13c , 13e , and 15c , that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulators that offer a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:177–186, 2000. © 2001 Wiley‐Liss, Inc.     

Synthesis and Evaluation of Benzophenone O‐Glycosides as α‐Glucosidase Inhibitors

The first total synthesis of benzophenone O‐glycosides (iriflophenone 2‐O‐α‐L ‐rhamnopyranoside: 1 and aquilarisinin: 2 ) isolated from the leaves of Aquilaria sinensis and related new derivatives ( 3 – 12 ) was accomplished through suitable protecting group manipulations and glycosylation starting from commercially available L ‐rhamnose, D ‐glucose, D ‐galactose, D ‐mannose, D ‐xylose, and 1,3,5‐trihydroxybenzene. All synthesized benzophenone O‐glycosides were evaluated for their inhibitory activities against α‐glucosidase. Of these, benzophenone O‐glycosides 4 and 10 exhibited the most potent inhibitory activity in vitro against α‐glucosidase with IC₅₀ values of 168.7 ± 13.9 and 210.1 ± 23.9 µM, respectively, when compared with that of the positive control acarbose with an IC₅₀ value of 569.3 ± 49.7 µM.     

Syntheses,calcium channel modulation effects,and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

A group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH₂)_n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl ( 16 ), 2‐pyridyl ( 17 ), or benzofurazan‐4‐yl ( 20 ) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC₅₀ values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl ( 18 ), or 4‐pyridyl ( 19 ) substituent with IC₅₀ values > 29.91 μM, relative to the reference drug nifedipine (IC₅₀=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d , 17a–d , and 20a–d having alkyl spacer groups of variable chain length [–CO₂(CH₂)_nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O²‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate ( 16b , EC₅₀=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC₅₀=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 ( 3 , EC₅₀=9.40 μM). The O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable ?NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l ‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.