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Archiv der Pharmazie



Wiley Online Library : Archiv der Pharmazie



Published: 2018-02-01T00:00:00-05:00

 



Synthesis, docking, in vitro and in vivo antidiabetic activity of pyrazole-based 2,4-thiazolidinedione derivatives as PPAR-γ modulators

2018-02-05T06:00:43.990666-05:00

The design, synthesis, structure–activity relationship, and biological activity of 2,4-thiazolidinedione derivatives as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators for antidiabetic activity are reported. Fifteen 2,4-thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR-γ by the Glide XP module of Schrodinger. Eight derivatives (5a, 5b, 5d, 5f, 5i, 5l, 5n, 5o) having Glide XP scores > −8 as compared to the standard drug, rosiglitazone (Glide XP score = −9.165), showed almost similar interaction with the amino acids such as HIS 449, TYR 473, TYR 327, HIS 323, and SER 289 in the molecular docking studies. These eight derivatives were further screened for PPAR-γ transactivation and in vivo blood glucose lowering activity in the streptozotocin-induced diabetic rat model. Compounds 5o, 5n, 5a, 5i, and 5b showed 52.06, 51.30, 48.65, 43.13, and 40.36% PPAR-γ transactivation as compared to the reference drugs rosiglitazone and pioglitazone with 85.30 and 65.22% transactivation, respectively. The data analysis showed significant blood glucose lowering effects (hypoglycemia) of compounds 5o, 5n, and 5a (140.1 ± 4.36, 141.4 ± 6.15, and 150.7 ± 4.15, respectively), along with reference drugs pioglitazone (135.2 ± 4.91) and rosiglitazone (141.1 ± 5.88) as compared to the diabetic control. Furthermore, the most potent compound 5o also elevated the PPAR-γ gene expression by 2.35-fold as compared to rosiglitazone (1.27-fold) and pioglitazone (1.6-fold). It also significantly lowered the AST, ALT, and ALP levels and caused no damage to the liver. A series of 2,4-thiazolidinedione derivatives were screened for their activity as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators, by molecular docking, PPAR-γ transactivation, and in vivo blood glucose lowering studies, in comparison to rosiglitazone and pioglitazone. The most potent compound 5o elevated the PPAR-γ gene expression by 2.35-fold versus 1.27-fold for rosiglitazone and 1.6-fold for pioglitazone.



Design, synthesis, and biological evaluation of novel 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives as cytotoxic agents and COX-2/LOX inhibitors

2018-02-05T05:55:43.00539-05:00

A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a–l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX-2 rather than COX-1, and the IC50 values (0.25–1.7 µM) were lower than that of indomethacin (IC50 = 9.47 µM) and somewhat higher than that of celecoxib (IC50 = 0.071 µM). The selectivity index for COX-2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC50 values of 0.02–74.03 µM, while the IC50 of the reference zileuton was 0.83 µM. The most active compound 4c (4-chlorobenzoxazole derivative) was found to have dual COX-2/LOX activity. All the synthesized compounds were docked inside the active site of the COX-2 and LOX enzymes. They linked to COX-2 through the N atom of the azole scaffold, while CO of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site. A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a–l was synthesized and evaluated for their in vitro cytotoxic activities. Assessment of the cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities revealed 4c as the most active compound with dual COX-2/LOX activity. All the synthesized compounds were docked inside the active site of the COX-2 and LOX enzymes.



Cover Picture: Arch. Pharm. Chem. Life Sci. (2/2018)

2018-02-01T05:31:44.543619-05:00







Biological evaluation and pharmacophore modeling of some benzoxazoles and their possible metabolites

2018-01-23T06:46:03.045499-05:00

A series of benzoxazole derivatives and some possible primary metabolites were evaluated as anticancer agents. In vitro anti-proliferative activities of the compounds were tested using the SRB assay on cancerous (HeLa) and non-cancerous (L929) cell lines. It was found that 17 of 21 tested compounds had cytotoxic activity on HeLa cells and the cytotoxic activities of the compounds were 15–700 times higher than on L929 cells. We generated two distinct pharmacophore models for the cytotoxic activities of the compounds on HeLa and L929 cells. While active compounds such as camptothecin and X8 fitted the two models generated for both cell lines, selective cytotoxic compounds such as XT3B fitted only the model generated for HeLa cells. Evaluation of the genotoxic activities of the cytotoxic compounds with the alkaline comet assay revealed that compounds X17 and XT3 showed strong genotoxic effects against HeLa cells at low concentrations whereas they had no genotoxic effect on L929 cells. Due to the selective ability for inducing DNA strand breaks only on cancerous cells, the compounds were identified as effective derivatives for anticancer candidates. A series of benzoxazole derivatives and some possible primary metabolites were evaluated as anticancer agents. Of the 21 tested compounds, 17 showed 15–700 times higher cytotoxic activity on HeLa cells than on L929 cells. Two distinct pharmacophore models were generated for the cytotoxic activities of the compounds on HeLa and L929 cells, with active compounds fitting both models and selective compounds, such as XT3B, fitting only the model generated for HeLa cells.



Synthesis and elastase inhibition activities of novel aryl, substituted aryl, and heteroaryl oxime ester derivatives

2017-12-18T07:42:17.241351-05:00

Fifteen novel aryl, substituted aryl and heteroaryl γ-hydroxy- (2a–e), γ-methoxyimino- (3a–e), and γ-benzyloxyimino- (4a–e) butyric acid methyl esters were investigated for their enzyme inhibition, and the synthesis of 10 compounds (3a–e, 4a–e) is given in this study. The other five compounds (2a–e) were synthesized before in another study. Compounds 3a–e and 4a–e were synthesized in this work as original compounds and characterized by 1H and 13C NMR, IR, mass, and elemental analyses. Their (E/Z)-isomerisation ratios were analyzed by 1H and 13C NMR. All of them are of pure (E)-configuration. Due to the literature survey, the elastase inhibition activity was not studied for these compounds. Elastase inhibition ability was investigated in this work for five γ-hydroxy- (2a–e), five γ-methoxy- (3a–e), and five γ-benzyloxyimino- (4a–e) butyric acid methyl esters. All these 15 compounds showed elastase inhibition activity. Compound 2b was the best one and exhibited a better activity than the standard ursolic acid whereas compound 2a worked like the standard. All these compounds can be novel elastase inhibitor agents in the pharmaceutical and cosmetic industries. The elastase inhibition ability of novel aryl, substituted aryl, and heteroaryl oxime ester derivatives was investigated for the first time, compared to that of the standard ursolic acid. The obtained results mark all these compounds as novel elastase inhibitor agents in the pharmaceutical and cosmetic industries.



Design, synthesis, and molecular docking of novel indole scaffold-based VEGFR-2 inhibitors as targeted anticancer agents

2018-01-11T09:06:02.8704-05:00

A series of new indole derivatives 1–18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR-2 active site using sorafenib as a reference VEGFR-2 inhibitor. Based on the molecular docking results, compounds 5a, 5b, 6, 7, 14b, 18b, and 18c were selected to be evaluated for their VEGFR-2 inhibitory activity. Compound 18b exhibited a broad-spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR-2 inhibitor with an IC50 value of 0.07 μM, which is more potent than that of sorafenib (0.09 μM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR-2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046. A series of new indole derivatives 1–18 were synthesized and tested for their cytotoxic activity on a panel of tumor cell lines. Compound 18b showed broad-spectrum anti-proliferative activity on 47 cell lines and was also the most potent VEGFR-2 inhibitor (IC50 = 0.07 vs. 0.09 µM of sorafenib). Molecular docking was carried out to study the binding pattern and binding affinity in the VEGFR-2 active site.



Design, synthesis, and evaluation of new α-aminonitrile-based benzimidazole biomolecules as potent antimicrobial and antitubercular agents

2018-01-22T07:05:42.425505-05:00

The study explores the one-pot synthesis of novel α-aminonitriles by reacting 4-[(1H-benzimidazol-2-yl)methoxy]benzaldehyde, substituted anilines and sodium cyanide using a catalytic amount of copper dipyridine dichloride (CuPy2Cl2) and employing the Strecker reaction under mild conditions. All the synthesized compounds were screened for antimicrobial and antitubercular activity. The promising lead compounds 4d and 4e were identified, with MIC values ranging between 3.9 and 7.8 µg/mL against different bacterial strains. Compounds 4c–e and 4g also showed good antifungal activities against the tested fungal strain. Among those tested, compound 4e exhibited excellent antitubercular activity (MIC 0.05 μg/mL) with a low level of cytotoxicity, suggesting that compound 4e is a promising lead for subsequent investigations in search for new antitubercular agents. Novel α-aminonitriles were synthesized by a one-pot strategy and screened for their antimicrobial and antitubercular activities. Compounds 4d and 4e were identified as promising leads, with MIC values ranging between 3.9 and 7.8 μg/mL against different bacterial strains. Compound 4e also exhibited excellent antitubercular activity (MIC = 0.05 µg/mL) with a low level of cytotoxicity.



Design, synthesis, and pharmacological evaluation of fluorinated azoles as anti-tubercular agents

2018-01-02T04:10:39.301954-05:00

Design, synthesis, and biological screening of 2,2-dimethyl-2,3-dihydrobenzofuran tethered 1,3,4-oxadiazole derivatives as anti-tubercular agents were described. The synthesis of the target compounds was conducted by a series of reaction schemes. All the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectrometry. The therapeutic potential of the synthesized compounds was confirmed by molecular docking studies. Among the synthesized compounds, 12a, 12c, 12d, 12e, 12g, and 12j were found to be more active against non-replicating than against replicating cultures of Mycobacterium tuberculosis H37Ra ex vivo and in vitro. These compounds exhibit minimum inhibitory concentration (MIC) values in the range of 2.31–23.91 μg/mL. The cytotoxicity study was conducted against the cell lines THP-1, A549 and PANC-1, and the compounds were observed to be non-toxic to host cells. Molecular docking was conducted with InhA (FabI/ENR) and suggested the antimycobacterial potential of the synthesized compounds. The investigation presented here was found to be adventitious for the development of new therapeutic agents against Mycobacterium infection. New 2,2-dimethyl-2,3-dihydrobenzofuran tethered 1,3,4-oxadiazole derivatives were screened for their activity as anti-tubercular agents. Compounds 12a, 12c, 12d, 12e, 12g, and 12j were found to be more active against non-replicating than against replicating cultures of Mycobacterium tuberculosis H37Ra ex vivo and in vitro. The therapeutic potential of the synthesized compounds was confirmed by molecular docking studies.



Oxaprozin prodrug as safer nonsteroidal anti-inflammatory drug: Synthesis and pharmacological evaluation

2017-12-28T08:50:22.33579-05:00

Oxaprozin is a popular non-steroidal anti-inflammatory drug (NSAID) and its chronic oral use is clinically restricted due to its gastrointestinal (GI) complications. In order to circumvent the GI complications, oxaprozin was amended as a prodrug in a one-pot reaction using N,N-carbonyldiimidazole as an activating agent. Dextran of average molecular weight (60,000–90,000 Da) was exploited as a carrier in the process of oxaprozin prodrug production by esterification. The structural profiles of the synthesized oxaprozin prodrug were characterized by FT-IR and NMR spectroscopy. The oxaprozin prodrug possessed optimal molecular weight, lipophilicity, partition coefficient, protein binding, and degree of substitution of 52.4%. The release of oxaprozin upon hydrolysis of the prodrug in both simulated gastric fluid and simulated intestinal fluid followed first-order kinetics with 55.2 min of half-life. Varied ADME properties of the prodrug resulted upon Schrodinger's QikProp tool application. Oxaprozin prodrug displayed significant analgesic, antipyretic, and anti-inflammatory activities, with a remarkable decrease in the ulcer index and being devoid of antigenicity in experimental animals. Thus, it is evident that oxaprozin prodrug is a safer oral NSAID without causing any ulcerations. Oxaprozin was produced as a prodrug in a one-pot reaction using N,N-carbonyldiimidazole as an activating agent. The release of oxaprozin upon hydrolysis of the prodrug in both simulated gastric and intestinal fluid followed first-order kinetics. Oxaprozin prodrug displayed significant analgesic, antipyretic, and anti-inflammatory activities, with a low ulcer index and no antigenicity.



Synthesis and biological evaluation of phloroglucinol derivatives possessing α-glycosidase, acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase inhibitory activity

2018-01-11T09:06:27.523923-05:00

A series of novel phloroglucinol derivatives were designed, synthesized, characterized spectroscopically and tested for their inhibitory activity against selected metabolic enzymes, including α-glycosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCA I and II). These compounds displayed nanomolar inhibition levels and showed Ki values of 1.14–3.92 nM against AChE, 0.24–1.64 nM against BChE, 6.73–51.10 nM against α-glycosidase, 1.80–5.10 nM against hCA I, and 1.14–5.45 nM against hCA II. A series of novel phloroglucinol derivatives were designed, synthesized, and tested for their inhibitory activity against α-glycosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCA I and II). All the compounds showed low nanomolar inhibition levels. Effective enzyme inhibition required the presence of a para-substituted phenyl; a bis-structure further increased the inhibitory activity.