Archiv der Pharmazie

Design, Synthesis, and Screening of Triazolopyrimidine–Pyrazole Hybrids as Potent Apoptotic Inducers ()
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.
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Practical Synthesis of α-Amyrin, β-Amyrin, and Lupeol: The Potential Natural Inhibitors of 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 (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.
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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 ()
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.
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Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities ()
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.
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Synthesis and Functional Investigations of Computer Designed Novel Cladribine-Like Compounds for the Treatment of Multiple Sclerosis ()
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.
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Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis ()
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.
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Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease ()
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.
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Evaluation of β-Aminocarboxylic Acid Derivatives in Hippocampal Excitatory Synaptic Transmission ()
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.
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Cover Picture: Arch. Pharm. Chem. Life Sci. (10/2017) ()

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Editorial Board: Arch. Pharm. Chem. Life Sci. (10/2017) ()

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Delivery of Therapeutic Proteins Using Electrospun Fibers—Recent Developments and Current Challenges ()
Proteins play a vital role within the human body by regulating various functions and even serving as structural constituent of many body parts. In this context, protein-based therapeutics have attracted a lot of attention in the last few decades as potential treatment of different diseases. Due to the steadily increasing interest in protein-based therapeutics, different dosage forms were investigated for delivering such complex macromolecules to the human body. Here, electrospun fibers hold a great potential for embedding proteins without structural damage and for controlled release of the protein for therapeutic applications. This review provides a comprehensive overview of the current state of protein-based carrier systems using electrospun fibers, with special emphasis on discussing their potential and key challenges in developing such therapeutic strategies, along with a prospective view of anticipated future directions. Electrospun fibers hold great potential for embedding proteins for controlled release of the protein for therapeutic applications. This review provides a comprehensive overview of the current state of protein-based carrier systems using electrospun fibers with special emphasis on their potential and the key challenges in developing such therapeutic strategies.
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The Effect of Carboxamide/Sulfonamide Replacement in Arylpiperazinylalkyl Derivatives on Activity to Serotonin and Dopamine Receptors ()
A series of carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1-(2,3-dichlorophenyl)piperazine (2,3-DCPP) analogs were prepared and tested for their affinity to bind to serotonin 5-HT1A/5-HT6/5-HT7 and dopamine D2 receptors. This chemical modification let us explore the impact of the replacement of the carboxamide by the sulfonamide group on the affinity changes. In both the o-OMe-PhP and 2,3-DCPP series, the relative activities of the carboxamides versus sulfonamides toward the 5-HT1A/5-HT6/5-HT7 and D2 receptors show similar trends. Varied or similar activities for particular receptors were found for the carboxamides/sulfonamides with p-xylyl spacer, while of the two classes of carboxamides and sulfonamides examined, benzyl derivatives of the sulfonamides displayed the highest serotoninergic affinity, in particular to the 5-HT7 receptors (Ki 8–85 nM). The Ki values revealed that, irrespective of the carboxamide/sulfonamide zone, both p-xylyl and benzyl derivatives had the highest affinity for the dopamine D2 receptor (i.e., 16 out of 24 compounds investigated have an affinity below 100 nM). A molecular modeling study of carboxamide 9a and sulfonamide 9b showed that their binding effects to each of 5-HT1AR and D2R created binding modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a in complexes with a 5-HT1AR (9aI) and D2R (9aII) are over 83%, while the respective similarities of sulfonamide 9b structures (9bI/9bII) are only about 40%. New carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine and 1-(2,3-dichlorophenyl)piperazine analogs were tested for their affinity to the serotonin 5-HT1A/5-HT6/5-HT7 and dopamine D2 receptors, allowing exploration of the impact of the replacement of the carboxamide by the sulfonamide group on receptor affinity. Benzyl derivatives of the sulfonamides displayed the highest serotoninergic affinity.
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Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues ()
Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2•−). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2–C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π–π interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity. Compound C8, one of the 18 designed compounds with chemical relationship to the NOX2 inhibitor diapocynin (C1), forms π–π interactions with the NOX2 subunit p47phox and exhibits antioxidant properties by inhibiting ROS production in endothelial cells. Targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity.
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Design, Synthesis, and Biological Evaluation of New Peptide Analogues as Selective COX-2 Inhibitors ()
A new class of peptide derivatives possessing SO2Me and N3 pharmacophores at the para position of a phenyl ring bound to different aromatic amino acids were synthesized based on solid-phase synthesis methodology, and evaluated as selective cyclooxygenase-2 (COX-2) inhibitors. One of the analogues, i.e., compound 2a as the representative of this series, was recognized as the highest selective COX-2 inhibitor with a COX-2 selectivity index of >500. The structure–activity relationships (SARs) acquired indicated that compound 2a containing a 4-(methylsulfonyl)benzoyl group as a pharmacophore and tyrosine as a ring bearing amino acid in the second position and glutamic acid as the C-terminal amino acid can give the essential geometry to provide selective COX-2 inhibitory activity. Antiproliferative activity of the synthesized peptides (1a–7b) was also determined against four different human cancer cell lines, including MCF-7, HepG2, A549, and HeLa. According to our results, A549, HepG2, and MCF7 seemed to be more sensitive cell lines than HeLa cells encountering these compounds, which gave inhibitory action with IC50 values from 4.8 to 64.4 µM. In this regard, compounds 3a and 2b displayed the best inhibitory activity against the cell lines. Moreover, a good correlation was observed between the antiproliferative potency and the COX-2 inhibitory activity of compounds 1a, 2a, 2b, and 5b. Such findings suggest that one of the mechanism of anticancer activity of these peptides may be through the COX-2 inhibitory action. A new class of peptide derivatives possessing SO2Me and N3 pharmacophores at the para position of a phenyl ring bound to different aromatic amino acids were synthesized by solid-phase synthesis methodology and evaluated as selective cyclooxygenase-2 (COX-2) inhibitors and anticancer agents. Compounds 3a and 2b displayed the best potency against the studied cancer cell lines. Compounds 1a, 2a, 2b, and 5b showed good correlation between their antiproliferative and COX-2 inhibitory activity.
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Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti-Hyperlipidemic and Antioxidant Agents ()
Hyperlipidemia and oxidative stress have been implicated as contributing factors to the development of atherosclerosis and cardiovascular diseases (CVDs). Currently, a large number of antihyperlipidemic medications are conveniently available in the market. Nonetheless, the majority of antihyperlipidemics lack the desired safety and efficacy. Thus, the present study was undertaken to evaluate the potential effect of novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives in controlling hyperlipidemia and oxidative stress using the Triton WR-1339-induced hyperlipidemic rat model for antihyperlipidemic activity and the DPPH radical scavenging assay for antioxidant activity. This study revealed the antihyperlipidemic activities of some of the newly synthesized, novel carboxamide derivatives, mainly C4 and C12 (p <� 0.05). The majority of the compounds displayed a relatively low or no DPPH radical scavenging effect, with C20 possessing the best radical scavenging effect (22%) among all. This research opens the door for new potential antihyperlipidemic compounds derived from isonicotinic acid. N-(3-Benzoylphenyl)pyridine-4-carboxamide (C4) was found to have promising lipid-lowering and antioxidant effects, which may create a protective effect against CVDs, by reducing the LDL-C levels and diminishing the generation of reactive oxygen species. Novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives were studied for their activities in controlling hyperlipidemia and oxidative stress. N-(3-Benzoylphenyl)pyridine-4-carboxamide showed promising lipid-lowering and antioxidant effects, which may provide protection against cardiovascular diseases.
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Molecular Engineering of Tetracyclic 2,3-Dihydro-1H-benzo[2,3]-benzofuro[4,5-e][1,3]oxazine Derivatives: Evaluation for Potential Anticancer Agents ()
Water-mediated one-pot Mannich type condensation of dibenzo[b,d]furan-2-ol with different amines resulted in a large library of novel 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives in moderate to excellent yields. The ortho-aminomethylation of the dibenzofuranols proceeded smoothly in the presence of various aromatic/aliphatic amines and paraformaldehyde, followed by cyclization. All the newly synthesized tetracyclic 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives were chemically characterized and screened for their cytotoxicity activity by cell viability assay (MTT test) against three human cancer cell lines and antibacterial activity by determining the minimum inhibitory concentration (MIC) against four bacterial strains. Among all the derivatives, MCV-24 showed promising anticancer activity by inhibiting the cell proliferation of an ovarian cancer cell line (SKOV3) with an IC50 value at 7.5 µM, whereas MCV-24 to MCV-30 derivatives showed moderate activity against a lung cancer cell line (A549) with an IC50 value ranging from 11 to 15.9 µM. Besides MCV-29, -30, and -31 also exhibited broad-spectrum antibacterial activity. Among all new compounds, MCV-24–30 showed promising anticancer and MCV-29–31 antibacterial activity. Water-mediated one-step Mannich type condensation of dibenzo[b,d]furan-2-ol with different amines gave a large library of novel 2,3-dihydro-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives. Among these, MCV-24 showed promising anticancer activity by inhibiting the cell proliferation of the SKOV3 ovarian cancer cell line at IC50 = 7.5 μM. Derivatives MCV-24 to MCV-30 showed moderate activity against the lung cancer cell line A549.
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Design, Synthesis, and Pharmacological Screening of Pyridazinone Hybrids as Anticonvulsant Agents ()
A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized in accordance with the pharmacophoric requirements essential for the anticonvulsant activity. The synthesized compounds were evaluated for anticonvulsant activity on mice by the gold standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models. Among the compounds tested, SS-4F showed significant anticonvulsant activity in both the screens with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screens, respectively. Compound SS-4F emerged as safer and effective anticonvulsant due to its several-fold higher protective indices. Further, the gamma-aminobutyric acid (GABA) estimation result showed a marked increase in the GABA level (1.7-fold) as compared to the control, which was further confirmed by good binding properties with the GABAA receptor. A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized, and evaluated for anticonvulsant activity on mice based on the standard MES and scPTZ-induced seizure models. Compound SS-4F showed significant anticonvulsant activity with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screen, respectively. It also had the highest protective indices.
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