Archiv der Pharmazie

Some pyrazoles derivatives: Potent carbonic anhydrase, α‐glycosidase, and cholinesterase enzymes inhibitors ()
Abstract A series of substituteed pyrazol‐4‐yl‐diazene derivatives were found to be effective inhibitors against α‐glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with Ki values in the range of 33.72 ± 7.93 to 90.56 ± 27.52 nM for α‐glycosidase, 1.06 ± 0.16 to 9.83 ± 0.74 nM for hCA I, 0.68 ± 0.12 to 7.16 ± 1.14 nM for hCA II, 44.66 ± 10.06 to 78.34 ± 17.83 nM for AChE, and 50.36 ± 13.88 to 88.36 ± 20.03 nM for BChE, respectively. Recently, inhibition of these metabolic enzymes has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances, such as diabetes, glaucoma, obesity, epilepsy, cancer, and neurodegenerative diseases.
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3‐(7‐Azaindolyl)‐4‐indolylmaleimides as a novel class of mutant isocitrate dehydrogenase‐1 inhibitors: Design, synthesis, and biological evaluation ()
Abstract A series of 3‐(7‐azainodyl)‐4‐indolylmaleimides was designed, synthesized, and evaluated for their isocitrate dehydrogenase 1 (IDH1)/R132H inhibitory activities. Many compounds such as 11a, 11c, 11e, 11g, and 11s exhibited favorable inhibitory effects on IDH1/R132H and were highly selective against the wild‐type IDH1. Evaluation of the biological activities at the cellular level showed that compounds 11a, 11c, 11e, 11g, and 11s could effectively suppress the production of 2‐hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Preliminary structure–activity relationship (SAR) and molecular modeling studies were discussed based on the experimental data obtained. These findings may provide new insights into the development of novel IDH1/R132H inhibitors.
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Prospecting for cytotoxic and antiprotozoal 4‐aryl‐4H‐chromenes and 10‐aryldihydropyrano[2,3‐f]chromenes ()
Abstract Different studies reported that genetic predisposition or metabolic dysfunction are the risk factors for cancer. Infectious parasitic diseases were listed among factors that predispose to cancer. Because of the resemblance between the life cycle of cancer cells and some parasites, this study aimed to prepare pyran derivatives with cytotoxic and antiprotozoal potencies. Therefore, 7 chromenes, 10 pyranocoumarins, and an unexpected intermediate were obtained from a multi‐reagent one‐pot reaction. These compounds were evaluated for their cytotoxicity on sensitive and resistant leukemia cancer cells lines and against two protozoan parasites, namely Trypanosoma cruzi and Leishmania amazonensis amastigote. Promising cytotoxicity (IC50 values of less than 1 µM) was obtained for two of the synthetic products (12 and 15). Compound 12 induced apoptosis and cell cycle arrest in CCRF‐CEM leukemia cells in G0/G1 while compound 15 and doxorubicin induced apoptosis and arrest in the S and G2/M phases. Ten of these products showed trypanocidal activity, while only five of them were weakly active on L. amazonensis. Three of the obtained pyrans showed significant cytotoxicity and antitrypanocidal activity, simultaneously. Nevertheless, all antiparasitic compounds revealed potency with low selectivity toward THP‐1 cells used as host.
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Xanthine oxidase inhibitory activity of new pyrrole carboxamide derivatives: In vitro and in silico studies ()
Abstract Pyrrole carboxamide rings are rarely used as active scaffold in designing inhibitors for enzymes. Herein, we described the structure–activity relationship for novel xanthine oxidase inhibitors based on the pyrrole carboxamide scaffold. A series of novel‐substituted pyrrole carboxamide derivatives were synthesized and characterized; their in vitro and in silico inhibitory activities were determined against xanthine oxidase. Among these compounds, those which contain no substituent and one methyl group at the para‐position of the phenyl moiety in the main structure, respectively, were found out as most active according to the xanthine oxidase inhibition activity study. In silico techniques reveal why these compounds display more activities than others, based on their binding interactions with xanthine oxidase and the surface scanning results of the enzyme. Furthermore, the binding energy calculations displayed good agreement with the experimental activity values.
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Novel cinnamic acid–tryptamine hybrids as potent butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study ()
Abstract A novel series of cinnamic acid–tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid–tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 ± 0.04 μM. This compound showed a 14‐fold higher inhibitory potency than the standard drug donepezil (IC50 = 7.79 ± 0.81 μM) and inhibited BChE through a mixed‐type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against β‐secretase, which exhibited low activity (inhibition percentage: 38%).
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Editorial Board: Arch. Pharm. Chem. Life Sci. (10/2018) ()
Archiv der Pharmazie, Volume 351, Issue 10, October 2018.
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Cover Picture: Arch. Pharm. Chem. Life Sci. (10/2018) ()
Archiv der Pharmazie, Volume 351, Issue 10, October 2018.
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Overcoming resistance in non‐small‐cell lung cancer: A practical lesson for the medicinal chemist ()
Abstract The introduction of tyrosine kinase inhibitors (TKIs) in the clinical management of oncological patients spread the light on the use of selective, rationally designed small molecules for the treatment of cancer. First‐generation TKIs bared high response against these malignancies, although the unavoidable shadow of resistance limits their long‐term efficacy. Non‐small‐cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, and it is the first cause of cancer deaths worldwide for men and women. Traditional chemotherapy is marginally effective against this form, and erlotinib and gefitinib were introduced as first‐line treatments based on the observation that the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is mutated in several cases and, thus, represents a druggable target. EGFR‐mutant and anaplastic lymphoma kinase (ALK)‐positive patients are more responsive to these treatments, even if secondary mutations causing resistance soon emerged. The efforts of medicinal chemists are currently oriented toward the development of new generations of TKIs overcoming these obstacles. We here overview the novel strategies from the point of view of the medicinal chemist: the rational structure‐based drug design that led to the development of irreversible and non‐ATP‐competitive inhibitors. Such improvements parallel the novel therapeutic strategies adopted in the clinic, which are also discussed.
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Novel sulfamate derivatives of menthol: Synthesis, characterization, and cholinesterases and carbonic anhydrase enzymes inhibition properties ()
Abstract Sulfamates have a large spectrum of biological activities including enzyme inhibition. Eight sulfamates derived from menthol (2a–h) were synthesized. Also, in the other section of this study, novel sulfamate derivatives of menthol were tested against some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carbonic anhydrase I and II enzymes (hCAs I and II). The newly synthesized novel menthol sulfamate and menthol carbonyl sulfamate derivatives showed Ki values in the range of 34.37 ± 8.17 to 53.40 ± 10.61 nM against hCA I, 12.91 ± 4.57 to 38.67 ± 6.22 nM against hCA II, 111.17 ± 52.36 to 522.86 ± 120.08 nM against AChE, and 50.01 ± 11.73 to 109.63 ± 50.08 nM against BChE. As a result, the novel menthol sulfamate and menthol carbonyl sulfamate derivatives can be promising Alzheimer's disease drug candidates and novel hCA I and hCA II enzymes inhibitors.
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Investigations into neuroprotectivity, stability, and water solubility of 7‐O‐cinnamoylsilibinin, its hemisuccinate and dehydro derivatives ()
Abstract Derivatives of the recently described potent neuroprotective 7‐O‐cinnamoylsilibinin ester were prepared: its hemisuccinate to improve water solubility and the dehydrosilibinin ester that was shown to form in assay media to investigate its role in overall neuroprotective effects. 7‐O‐Cinnamoyl‐2,3‐dehydrosilibinin is less neuroprotective than 7‐O‐cinnamoylsilibinin in a murine hippocampal cell line (HT‐22) and we conclude that the dehydrosilibinin derivatives are not the actual carriers of neuroprotective properties, at least in the assay applied. Solubility of the test compounds was determined in shake‐flask experiments and the ester's solubility was greatly improved by introduction of a hemisuccinate at the 23‐position of silibinin. Time–stability curves in assay media were recorded. The hemisuccinate ester did not act as a prodrug to release 7‐O‐cinnamoylsilibinin but is the second ester bond to be cleaved. Nevertheless, it still exhibits significant neuroprotection. Therefore, its greatly increased solubility might effectively counterbalance lower in vitro neuroprotection.
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Concise synthesis and antibacterial evaluation of novel 3‐(1,4‐disubstituted‐1,2,3‐triazolyl)uridine nucleosides ()
Abstract We report herein a simple and efficient synthesis of a new series of antibacterial uridine nucleosides. The strategy involved a sequential silylation/N‐glycosylation/N‐propargylation procedure of uracil 1 for preparing the dipolarophile 5 in good yield. A series of novel uridine‐[1,2,3]triazole nucleosides 6a–j were efficiently synthesized via the copper‐catalyzed azide–alkyne cycloaddition (CuAAC) from dipolarophile 5 with different selected azides. The reactions were carried out under both conventional and ultrasonic irradiation conditions. In general, improvements were observed when reactions were carried out under sonication. Their antibacterial potential has been evaluated by means of a micro‐dilution assay against either Gram‐positive or Gram‐negative bacteria. Compounds 6i and 6j have shown significant bactericidal activity against Staphylococcus aureus (MIC = 10 and 6 μM, respectively), and 6h against Escherichia coli (MIC = 8 μM). Moreover, antibacterial kinetic assays showed that 6i and 6j significantly reduced the S. aureus growth rate at the MIC concentration, after 6 h, compared to their deprotected analogs, 6k and 6l, respectively. Compound 6h also significantly reduced the growth of E. coli. These antibacterial effects may be related to the penetrating properties of these compounds, as revealed by the leakage of nucleic acids from the sensitive strains.
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Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments ()
Abstract Hybrid inhibitors of acetyl‐ and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin–donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase.
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Pyrazinoates as antiparasitic agents against Trypanosoma cruzi ()
Abstract This work reports a repurposing study of pyrazinoic acid (1) and methyl (2), ethyl (3) and 2‐chloroethyl (4) ester derivatives with antimycobacterial activity, in assays against Trypanosoma cruzi. The compounds and benznidazole, the standard antitrypanosoma drug, were evaluated in concentrations ranging from 100 to 6.25 μg/mL. The results showed that compounds 2 and 3 (EC50 = 182 and 447 μM) significantly reduced the infection rate of the parasite into the mammalian cells at 100 μg/mL (p <� 0.05) in a similar way to benznidazole. In addition, all the compounds also significantly reduced the number of intracellular parasites (compound 1 at 50 μg/mL, and compounds 2–4 at 100 μg/mL, p <� 0.05) in comparison to the control. Compounds 1 and 2 were more effective than benznidazole at 50 μg/mL (p <� 0.001). Moreover, compounds 1–4 did not show significant cytotoxicity against THP‐1, J774, and HeLa cells (>1000 μM), indicating that they possess considerable selectivity against the parasites. This report represents the first study of such compounds against T. cruzi, indicating the potential of pyrazinoates as antiparasitic agents.
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Synthesis of androgen receptor antagonists containing a pentafluorosulfanyl (SF5) moiety ()
Abstract A novel scaffold of pentafluorosulfanyl (SF5)‐containing enzalutamide analogues was discovered for potent androgen receptor (AR) antagonists through rational drug design. Several compounds showed good biological profiles in AR binding. Of the derivatives studied, compound 8a had potent AR antagonist activity (IC50 = 7.1 ± 1.0 µM) and high efficacy (104.5 ± 12.8%). It exhibited an inhibitory effect comparable to that of enzalutamide (inhibition = 66.0 and 77.9%, respectively) in a prostate cancer cell line. The results point to the potential of using this scaffold to develop new AR antagonists.
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