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Archiv der Pharmazie



Wiley Online Library : Archiv der Pharmazie



Published: 2017-11-01T00:00:00-05:00

 



6-Nitroazolo[1,5-a]pyrimidin-7(4H)-ones as Antidiabetic Agents

2017-11-20T02:25:25.49045-05:00

Prevention of the formation of advanced glycation end-products (AGEs) is a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In these terms, new synthetic approaches to 6-nitroazolo[1,5-a]pyrimidines have been developed on the basis of the promising antiglycation activity of their structural analogues, such as azolo[5,1-c][1,2,4]triazine-4(1H)-ones. A number of nitroazolopyrimidines were obtained by using nitration, chlorodeoxygenation, and amination reactions, and their antidiabetic properties were elucidated in vitro. It was shown that triazolo[1,5-a]pyrimidine-7(4H)-ones exhibit a higher antiglycation activity than the corresponding 7-alkylamino analogs and aminoguanidine, as the reference compound. It is suggested that this kind of activity can be associated with the chelating properties possessed by the synthesized 6-nitro-7-oxoderivatives. Furthermore, the compounds obtained were tested for their inhibitory activity against dipeptidyl peptidase 4 (DPP4), glycogen phosphorylase, and α-glucosidase in vitro, but their activities proved to be significantly inferior to those of the reference compounds. The compounds of the new 6-nitroazolo[1,5-a]pyrimidine series show promising antiglycation activity. In particular, 2-(α-furyl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one demonstrated inhibition of the formation of advanced glycation end-products (IC50 = 50.35 μM) at one order of magnitude higher than that of the reference compound, aminoguanidine (IC50 = 765.00 μM).



Synthesis, antitumor activity evaluation, and DNA-binding study of coumarin-based agents

2017-11-17T02:26:57.434628-05:00

A novel series of coumarin-thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1H NMR, 13C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60-cell line panel according to the US NCI-DTP protocol or a selection of human tumor cell lines: breast cancer (MCF-7), liver cancer (HepG-2), and colorectal cancer (HCT-116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with KSV = 4.27 × 105 M−1. Moreover, the results for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with KSV 4.27 × 105, 3.96 × 105, and 3.51 × 105 M−1, respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60-cell line panel, the leukemia HL-60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61% growth, followed by the lung carcinoma cell line NCI-H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC50 value of 24.9 μg/mL against the HepG-2 cell line. Novel coumarin-thiadiazole heterocycle derivatives were evaluated with regard to their DNA-binding/cleavage and tumor cell line inhibition activities. Compounds 4c and 4e showed dual DNA binding mode. Compound 14a was the most active regarding DNA cleavage as well as in leukemia cell line inhibition, resulting in 61% growth.



2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles: An Overview on Synthetic Strategies and Biological Activity

2017-11-16T01:40:35.993547-05:00

2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles represent an important class of ATP-competitive protein kinase inhibitors, offering the possibility of multiple interactions with different regions of the target enzyme. The necessity of exploring the effects of diverse chemical decorations around the imidazole core prompted the design of several synthetic routes aimed at achieving both efficiency and flexibility. Additionally, the optimization of established protocols and the extensive use of transition metal-catalyzed cross-coupling reactions have been broadening the spectrum of preparative methodologies within the last decade. This review summarizes the progress in the development of synthetic strategies leading to 2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and 1-alkyl-2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and offers a glance at the biological activities of this class of compounds. Many examples of 2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and 1-alkyl-2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles have been reported as ATP-competitive inhibitors of different protein kinases. This review focuses on how diverse synthetic strategies offer high flexibility in varying the substitution pattern of this class of molecules, providing the optimal moieties for potent and selective inhibition of the desired target enzyme.



Synthesis and Carbonic Anhydrase Inhibition of Tetrabromo Chalcone Derivatives

2017-11-14T04:30:26.783407-05:00

In the present study, human carbonic anhydrase (hCA) enzyme was purified and characterized from fresh blood human red cells by Sepharose-4B-l-tyrosine-sulfanilamide affinity gel chromatography. Secondly, a series of new tetrabromo chalcone derivatives containing 4,7-methanoisoindol-1,3-dione (2a–i) were synthesized from the addition of Br2 to related chalcone derivatives (1a–i). The structures of the new molecules (2a–i) were confirmed by means of 1H NMR, 13C NMR and elemental analysis. Finally, the inhibitory effects of 2a–i on CA activities were investigated using the esterase method under in vitro conditions. The compounds 2a–i exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 11.30–21.22 nM against hCA I and in the range of 8.21–12.86 nM against hCA II. Our findings suggest that the new compounds 2a–i have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor, with obtained Ki values of 34.50 and 28.93 nM against the hCA I and II isozymes, respectively. In addition to the inhibition assays, molecular modeling approaches were implemented for prediction of the binding affinities of compounds 2a and 2c, which had the highest inhibition effects, against the hCA I and II isozymes. New tetrabromo chalcone derivatives containing 4,7-methanoisoindol-1,3-dione (2a–i) were synthesized from the addition of Br2 to related chalcone derivatives and tested for their inhibitory activity on human carbonic anhydrase (hCA) purified from red blood cells. The new compounds 2a–i show higher inhibitory activity than the clinical CA inhibitor acetazolamide (AZA).



Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors

2017-11-13T04:10:47.450436-05:00

Novel series of phthalazine derivatives 6–11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF-7 breast cancer cells with IC50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib as reference drug with IC50 of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with IC50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way. Novel series of phthalazine derivatives were designed, synthesized, and evaluated for their anticancer activity against HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the most promising activities (IC50 (HCT-116) = 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 µM, respectively) compared to sorafenib as reference drug.



Rational Optimization of Tumor Suppressor-Derived Peptide Inhibitor Selectivity between Oncogene Tyrosine Kinases ErbB1 and ErbB2

2017-11-13T04:10:31.31698-05:00

The tumor-suppressor protein Mig-6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2. Despite their highly homologous nature, these two kinases are separately involved in the development of different types of human cancer. Here, we utilized a rational strategy to iteratively optimize the interaction specificity of the two kinases with a Mig-6 derived peptide by exploiting structural diversity space. Instead of traditionally improving the peptide binding potency, the optimization attempts to maximize the affinity difference between peptides binding to ErbB1 and ErbB2. The computational design was also substantiated by using fluorescence-based assays. Consequently, we successfully designed three peptides, HSLTPTQSF, THLMNLLRI, and NSGCPMHK, with high or moderate selectivity for ErbB1 over ErbB2 (3.1-, 6.3-, and 3.0-fold, respectively) and two peptides, PCMTDFLFT and WVIFPSQTN, with moderate or modest selectivity for ErbB2 over ErbB1 (3.5- and 1.6-fold, respectively). The method is expected to be used for the rational molecular design of selective peptide entities for other protein systems. The tumor suppressor Mig-6-derived peptide selectivity between the human receptor tyrosine kinases ErbB1 and ErbB2 was improved by using an iteration optimization algorithm. The optimization attempts to maximize the affinity difference between peptide binding to ErbB1 and ErbB2. A number of peptides were successfully designed to have high selectivity for the two kinases.



Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors

2017-11-07T10:01:40.605328-05:00

Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore, there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the synthesis and characterization of ten benzyl benzamides 8a–j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a percent inhibition of 82.2% at 10 μM concentration and an IC50 value of 1.3 μM. The docking study shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by a hydrophobic lining. Furthermore, the scaffold of 8a–j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities. New cholesteryl ester transfer protein (CETP) inhibitors capable of raising the high-density lipoprotein levels may be a novel approach for the prevention of cardiovascular disease. Ten new benzyl benzamides (8a–j) were characterized for their CETP inhibitory activities. The scaffold of 8a–j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities.



Practical Synthesis of α-Amyrin, β-Amyrin, and Lupeol: The Potential Natural Inhibitors of Human Oxidosqualene Cyclase

2017-10-13T07:10:37.677894-05:00

A practical synthesis of α-amyrin (1), β-amyrin (2), and lupeol (3) was accomplished in total yields of 32, 42, and 40% starting from easily available ursolic acid (4), oleanolic acid (5), and betulin (6), respectively. Remarkably, these three natural pentacyclic triterpenes exhibited potential inhibitory activity against human oxidosqualene cyclase. A practical synthesis of α-amyrin (1), β-amyrin (2), and lupeol (3) was accomplished in total yields of 32, 42, and 40% starting from easily available ursolic acid, oleanolic acid, and botulin, respectively. These three natural pentacyclic triterpenes exhibited potential inhibitory activity against human oxidosqualene cyclase.









Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities

2017-10-13T03:31:42.964994-05:00

Thienopyrimidines (TP), comprising a thiophene ring fused with pyrimidine, are famous bioisosteres to purines, an essential part of the human metabolome. This scaffold has become an interesting structural element in the development of pharmaceutical compounds, due to their wide spectrum applications as cytotoxic agents against different types of human cancer cell lines, cGMP phosphodiesterase inhibitors, and anti-viral, anti-inflammatory, and anti-microbial agents. The structural similarity of this scaffold with adenine made it an excellent moiety to be used in the design of kinase inhibitors. This review focuses on the chemistry of thienopyrimidine derivatives, their potential activities against various kinases, and their structure–activity relationship studies. The thienopyrimidine scaffold, which comprises a thiophene ring fused with pyrimidine, is an interesting structural element in the development of pharmaceutical compounds due to its wide spectrum of applications. This review focuses on the chemistry of thienopyrimidine derivatives, their potential activities against various kinases, and their structure–activity relationship studies.



Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis

2017-09-25T01:56:59.138031-05:00

Selective inhibition of Janus kinase 3 (JAK3) has been identified as an important strategy for the treatment of autoimmune disorders. Based on the unique cysteine 909 residue (Cys909) of JAK3 at the gatekeeper position, we have developed a new irreversible covalent inhibitor, III-4, which is highly potent and selective in targeting JAK3. Importantly, III-4 selectively inhibited JAK3 (IC50 = 57 ± 1.21 nM) over other JAKs (IC50 > 10 µM) and Cys909 kinome members (IC50 > 1 µM). A cellular selectivity study also confirmed that III-4 preferentially inhibited JAK3 over JAK1 in JAK/STAT signaling. Moreover, the fact that III-4 covalently modified the Cys909 residue in JAK3 was clearly validated by mass spectrometry and covalent docking analysis. Based on the favorable target profiles, the pharmacokinetic properties and its low toxicity, III-4 exhibited better efficacy than tofacitinib in impeding disease progression in CIA mice, without any significant adverse effects. Taken together, III-4 is a potent, selective, and durable inhibitor of JAK3 and has the potential for the treatment of inflammatory disorders and autoimmune diseases, such as rheumatoid arthritis. A new irreversible, covalent JAK3 inhibitor was developed based on Cys909 at the gatekeeper position of the enzyme. The new inhibitor III-4 selectively inhibits JAK3 (IC50 = 57 ± 1.21 nM) versus other JAKs (IC50 > 10 μM) and Cys909 kinome members (IC50 > 1 μM) and is more effective in impeding disease progression in CIA mice than tofacitinib.



Synthesis and Functional Investigations of Computer Designed Novel Cladribine-Like Compounds for the Treatment of Multiple Sclerosis

2017-09-28T11:26:51.010475-05:00

Cladribine (2-CdA) is used as an anti-cancer drug but is currently studied as a potential treatment for use in relapsing-remitting multiple sclerosis (MS). In this study, we computer designed, synthesized, and characterized two novel derivatives of 2-CdA, K1–5d and K2–4c, and investigated their underlying mechanism of beneficial effect using the CCRF-CEM and RAJI cell lines. For this purpose, we first determined their effect on MS and DNA damage and repair-related gene expression profiles using custom arrays along with 2-CdA treatment at non-toxic doses. Then, we determined whether cells underwent apoptosis after treatment with 2-CdA, K1–5d, and K2–4c in CCRF-CEM and RAJI cells, using the DNA fragmentation assay. It was found that both derivatives modulated the expression of the pathway-related genes that are important in inflammatory signaling, apoptosis, ATM/ATR, double-strand break repair, and the cell cycle. Furthermore, 2-CdA, K1–5d, and K2–4c significantly activated apoptosis in both cell lines. In summary, our data demonstrate that although both derivatives act as anti-inflammatory and apoptotic agents, inducing the accumulation of DNA strand breaks and activating the ultimate tumor suppressor p53 in T and B lymphocytes, the K1–5d derivative has shown more promising activities for further studies. Two novel derivatives of cladribine (2-CdA) were synthesized and analyzed for their potential effect on relapsing-remitting multiple sclerosis. K1–5d and K2–4c modulated the expression of genes important in inflammatory signaling, apoptosis, ATM/ATR, double-strand break repair, and the cell cycle. 2–CdA, K1–5d and K2–4c also induced DNA fragmentation in CCRF-CEM and RAJI cells.



New Biguanides as Anti-Diabetic Agents, Part II: Synthesis and Anti-Diabetic Properties Evaluation of 1-Arylamidebiguanide Derivatives as Agents of Insulin Resistant Type II Diabetes

2017-10-13T03:50:24.389322-05:00

New 1-arylamidebiguanide hydrochloride salts were synthesized via reaction of hydrazide derivatives with dicyandiamide in acidic medium. The structure of the obtained derivatives was characterized by spectroscopic and elemental analysis tools. The anti-diabetic properties of the synthesized compounds were determined. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives showed a significant decrease of the elevated glucose in comparison with the anti-diabetic standard drug, metformin. The effects of the synthesized biguanide derivatives on the diabetic properties regarding liver function enzyme activities (AST, ALT, and ALP), lipid profiles (TC, TG, and TL), lipid peroxide, and nitrous oxide as well as histopathological characteristics were investigated and discussed. New 1-substituted biguanides were synthesized and screened for their anti-diabetic activity in comparison to the standard drug metformin. Additionally, liver function enzyme activities, lipid profiles, antioxidant activities, and histopathological characteristics were investigated and discussed.



Design, Synthesis, and Screening of Triazolopyrimidine–Pyrazole Hybrids as Potent Apoptotic Inducers

2017-10-16T01:45:46.445563-05:00

An efficient synthesis of novel 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-5,7-dimethyl-[1,2,4]triazolo[4,3-a]-pyrimidines was accomplished by the oxidation of pyrimidinylhydrazones by using organoiodine(III) reagent. All new triazolopyrimidine derivatives bearing the pyrazole scaffold were screened to evaluate them as a reproductive toxicant in the testicular germ cells of goat (Capra hircus). This study aimed at assessing the cytological and biochemical changes in testicular germ cells after the exposure to triazolopyrimidines in a dose- and time-dependent manner. Histomorphological analysis, fluorescence assays, apoptosis quantification, and terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) assays were performed to determine cytological changes, whereas thiobarbituric acid-reactive substance (TBARS) and ferric reducing antioxidant power (FRAP) assays were carried out to measure the oxidative stress in triazolopyrimidines treated germ cells. The parallel use of these methods enabled us to determine the role of triazolopyrimidines in inducing apoptosis as a consequence of cytogenetic damage and oxidative stress generated in testicular germ cells of goat. Organoiodine(III)-mediated oxidative methodology was used to design and synthesize triazolopyrimidine–pyrazole hybrid derivatives. The newly synthesized compounds were screened for their cytotoxicity and genotoxicity in goat (Capra hircus) testicular germ cells. The cytological changes and oxidative stress levels in treated germ cells were determined to assess the role of triazolopyrimidines in inducing apoptosis by cytogenetic damage and oxidative stress.



Evaluation of β-Aminocarboxylic Acid Derivatives in Hippocampal Excitatory Synaptic Transmission

2017-09-05T07:06:11.936641-05:00

β-Aminocarboxylic acid derivatives (LINS04 series) were screened with the aim to explore their potential functional role in excitatory synaptic transmission in the central nervous system. We used field recordings in rat hippocampal slices to investigate the effects of the LINS04 series on the synaptic transmission at hippocampal CA1 synapses. We found that LINS04008 and LINS04009 increase the size of the evoked field excitatory postsynaptic potential (EPSP) in a dose-dependent manner. The concentration–response curve shows that the efficacy of LINS04008 is highest in the series (EC50 = 91.32 µM; maximum fEPSP 44.97%). The esters LINS04006 and LINS04005 did not affect the synaptic evoked activity. These data provide the first evidence of synaptic activity enhancement by these compounds and the importance of the acidic group to the activity. This set of data may provide direction for a strategic procedure to restore the glutamate synaptic transmission; however, further studies are needed to establish a more complete picture of how these molecules act on the glutamate transmission, which are in our mind for the next steps. β-Aminocarboxylic derivatives were screened in hippocampal CA1 slices as modulators of glutamatergic neurotransmission. LINS04008 (EC50 = 91.32 μM; maximum evoked field excitatory postsynaptic potential 44.97%) was the most promising stimulant of the synaptic activity, while the ester derivatives LINS04006 and LINS04005 were inactive.



Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease

2017-09-22T07:00:35.708341-05:00

Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC50 values of 0.64–51.09 μM. The preliminary structure–activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC50 (0.64 μM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD. The newly designed sulfonylhydrazones inhibited acetylcholinesterase (AChE) with IC50 values between 0.64 and 51.09 μM. The most active compound, (E)-N′-(4-hydroxy-3-methoxybenzylidene)-4-methoxybenzenesulfonohydrazide (6d), is not cytotoxic to LL24 cells and, due to its drug-likeness, appears suitable for oral absorption and brain penetration.