Archiv der Pharmazie

Design, synthesis, and molecular docking study of 3H‐imidazole[4,5‐c]pyridine derivatives as CDK2 inhibitors ()
Abstract A novel series of imidazo[4,5‐c]pyridine‐based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti‐proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC50 values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC50 = 21 nM) and in vitro anti‐proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti‐proliferation activities. Therefore, the pyridin‐3‐ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti‐cancer therapy.
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Design, synthesis, and antitumor evaluation of quinoline‐imidazole derivatives ()
Abstract A series of compounds bearing quinoline‐imidazole (8a–e, 9a–e, 10a–e, 11a–e, and 12a–e) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC‐3, HepG2, and MCF‐7 cells by the MTT method, with NVP‐BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC‐3 cells, with half‐maximal inhibitory concentration (IC50) values of 2.42 ± 1.02 µM, 6.29 ± 0.99 µM, and 5.11 ± 1.00 µM, respectively, which was equal to NVP‐BEZ235 (0.54 ± 0.13 µM, 0.36 ± 0.06 µM, 0.20 ± 0.01 µM). Besides, the IC50 value of 12a against the cell line WI‐38 (human fetal lung fibroblasts) was 32.8 ± 1.23 µM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K‐Akt‐mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP‐BEZ235, suggesting there may be some other mechanisms of action. The structure–activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C‐6 of the quinoline ring was replaced by a bromine atom.
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Probing chemical space of tick‐borne encephalitis virus reproduction inhibitors with organoselenium compounds ()
Abstract Tick‐borne encephalitis virus (TBEV), a member of the genus Flavivirus, is the leading cause of arboviral neuroinfections in Europe. Only a few classes of the nucleoside and non‐nucleoside inhibitors were investigated against TBEV reproduction. Paving the way to previously unexplored areas of anti‐TBEV chemical space, we assessed the inhibition of TBEV reproduction in the plaque reduction assay by various compounds derived from cyanothioacetamide and cyanoselenoacetamide. Compounds from seven classes, including 4‐(alkylthio)‐2‐aryl‐3‐azaspiro[5.5]undec‐4‐ene‐1,1,5‐tricarbonitriles, 3‐arylamino‐2‐(selenazol‐2‐yl)acrylonitriles, ethyl 6‐(alkylseleno)‐5‐cyano‐2‐oxo‐1,2‐dihydropyridine‐3‐carboxylates, 6‐(alkylseleno)‐2‐oxo‐1,4,5,6‐tetrahydropyridine‐3‐carbonitriles, 2‐(alkylseleno)‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carbonitriles, 8‐selenoxo‐3,5,7,11‐tetraazatricyclo[7.3.1.02,7]tridec‐2‐ene‐1,9‐dicarbonitriles, and selenolo[2,3‐b]quinolines, inhibited TBEV reproduction with EC50 values in the micromolar range while showing moderate cytotoxicity and no inhibition of enterovirus reproduction. Thus, new scaffolds with promising anti‐TBEV activity were found.
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Synthesis of substituted fluorobenzimidazoles as inhibitors of 5‐lipoxygenase and soluble epoxide hydrolase for anti‐inflammatory activity ()
Abstract A new series of 4‐((5‐fluoro‐6‐(substituted)‐1H‐benzo[d]imidazol‐2‐ylthio)methyl)‐benzoic acids 4a–o and 2‐(5‐fluoro‐6‐(substituted)‐1H‐benzo[d]imidazol‐2‐ylthio)‐2‐methylpropanoic acids 8a–e were synthesized, and their inhibitory potencies against soluble epoxide hydrolase (sEH) and 5‐lipoxygenase (5‐LOX) were investigated. These molecules were designed based on the combination of 5‐LOX and sEH pharmacophores, resulting in hybrid analogs with potent sEH and 5‐LOX inhibitory activity. Compound 4g showed remarkable activity with IC50 values of less than 1 μM (0.9 μM) against 5‐LOX, while compound 4k displayed promising activity against sEH with IC50 ≤ 1 μM (0.7 μM). These compounds were evaluated for their in vivo potential using the carrageenan‐induced rat paw edema assay. Based on the obtained results, the structure–activity relationship was established and a correlation between the activities was observed. Compounds 4f, 4g, 4k, 4n, and 8e showed potent anti‐inflammatory activity and significant inhibition of edema (64.13, 67.39, 66.30, 65.21, and 58.69%, respectively) at a dose of 100 mg/kg, comparable to the standard drug ibuprofen (70.65%) at 3 h.
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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 ()
Abstract 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.
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Anticancer activity of dihydropyrazolo[1,5‐c]quinazolines against rat C6 glioma cells via inhibition of topoisomerase II ()
Abstract The design and synthesis of dihydropyrazolo[1,5‐c]quinazolines (1a–h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling.
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Editorial Board: Arch. Pharm. Chem. Life Sci. (6/2018) ()
Archiv der Pharmazie, Volume 351, Issue 6, June 2018.
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Cover Picture: Arch. Pharm. Chem. Life Sci. (6/2018) ()
Archiv der Pharmazie, Volume 351, Issue 6, June 2018.
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Molecular insights into trypanothione reductase‐inhibitor interaction: A structure‐based review ()
Abstract Information on how small molecules bind to the target enzyme has the potential to impact immensely on how medicinal chemists go about antiparasitic drug discovery. In this review, for the first time, we intend to make an assessment of the structural aspects of trypanothione reductase as drug target, and its complexes with several reversible drugs from the Protein Data Bank (PDB). We attempt to reveal the mechanism of these interactions by careful accounting of the X‐ray structures and their possible roles in biological activity to treat Trypanosomatidae diseases. We focus on some of the outstanding findings from structures that are relevant to anti‐trypanocidal drug discovery. We also review new interesting compounds that have appeared in the literature based on these X‐ray structures.
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Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors ()
Abstract B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib. Constantly emerging agents exhibiting superior efficacy and safety in preclinical and clinical studies provide promising therapeutics for the treatment of B cell malignancies.
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Reagent‐induced asymmetric induction in addition reaction of reduced glutathione onto bis‐Mannich chalcones ()
Abstract The stereochemistry of non‐enzyme catalyzed nucleophilic addition of GSH to 4′‐hydroxychalcone 1 and its bis‐Mannich derivative 2 was investigated at different pH values (pH 3.2, 6.1, 7.4, and 8.0). The stereochemical outcome of the reactions was evaluated by HPLC‐UV‐Vis method. Under strongly acidic conditions (pH 3.2), an unexpected diastereoselective addition of GSH onto the bis‐Mannich derivative 2 was observed. Such a selectivity could not be observed in the similar reaction of 2 with N‐acetylcysteine. The observed stereoselectivity can be rationalized by ion‐pair formation between the protonated Mannich nitrogens and the deprotonated GSH(glutamate)‐carboxylate. To the best of our knowledge, this is the first example of reagent‐induced asymmetric induction in Michael‐type additions of thiols.
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Synthesis, evaluation, and molecular docking studies of aryl urea‐triazole‐based derivatives as anti‐urease agents ()
Abstract Considering the importance of urease inhibitors in the treatment of ureolytic bacterial infections, in this work, the synthesis of novel, aryl urea‐triazole‐based derivatives as effective urease inhibitors is described. Dichloro‐substituted derivative 4o, with IC50 = 22.81 ± 0.05 μM, is found to be the most potent urease inhibitor, determined by Berthelot colorimetric assay. Docking studies were also carried out for compound 4o to confirm the effective interactions with the urease active site.
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Expanding the chemical space of anti‐HCV NS5A inhibitors by stereochemical exchange and peptidomimetic approaches ()
Abstract Here we report a series of potent anti‐HCV agents bearing a symmetrical benzidine l‐prolinamide backbone with different capping groups including alkyl/aryl carbamates of natural and unnatural valine and leucine amino acids. All compounds were investigated for their inhibitory activity in an HCV replicon assay on genotype 1b. The novel compounds share some chemical and clinical attributes of commercially available NS5A inhibitors. Compounds 5 and 6 with unnatural capping residue and ethyl and isobutyl carbamates showed EC50 values in the picomolar range with a low toxicity profile and selectivity indices of several orders of magnitude. These findings enlarge the chemical space from which NS5A inhibitors may be discovered by adopting unnatural amino acids, amino acids other than valine and carbamates other than methyl as the capping groups.
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New tacrine–acridine hybrids as promising multifunctional drugs for potential treatment of Alzheimer's disease ()
Abstract The synthesis, biological tests, and computer modeling of a series of novel promising tacrine hybrids for the therapy of Alzheimer's disease are reported. Firstly, new tacrine–acridine hybrids with different carbon linker lengths were synthesized. Secondly, all the compounds were tested in vitro for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme activity. After that, the most promising compound 3d was tested using the amyloid‐β aggregation assay. To evaluate possible toxic effects, cytotoxicity tests were conducted. The most active compound 3d (IC50 = 7.6 pM for AChE and 1.7 pM for BuChE) appeared to be a much more active inhibitor than tacrine (IC50 = 89.9 nM for AChE and 14.9 nM for BuChE). At the highest concentration (100 μM), 3d exhibited 57.77% activity, retaining it as the concentration decreased: 50 μM – 54.74%, 20 μM – 48.28%, 10 μM – 31.66%. The compound showed no significant cytotoxic effect at the tested concentrations. At the end, docking studies using methods of computer modeling were performed to visualize the binding mode of the inhibitor 3d. It showed dual‐binding mode for AChE, by binding to the catalytic anionic site and the peripheral anionic site simultaneously. Thus, compound 3d is a promising multitarget hybrid that can be used for the treatment of Alzheimer's disease.
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Synthesis and glutathione reductase inhibitory properties of 5‐methyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one's aryl Schiff base derivatives ()
Abstract Glutathione reductase (GR) is responsible for the existence of the reduced glutathione (GSH) molecule, a crucial antioxidant against oxidative stress reagents. The antimalarial activities of some redox active compounds are attributed to their inhibition of antioxidant flavoenzyme GR, and inhibitors are therefore expected to be useful for the treatment of malaria. In this work, a fast and effective synthesis and the GR inhibitory properties of 5‐methyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one's aryl Schiff base derivatives are reported. For this aim, the triazol nucleus was obtained, which was substituted with identical groups: ester, hydrazide, and Schiff base system at the N‐2 and N‐4 nitrogen atoms. The majority of the reactions were carried out by utilizing both microwave and conventional methods in order to compare their yields and reaction times. Beside this, the occuring E/Z geometrical isomers from the CN double bond and the cis/trans amide conformers at the CONH single bond were studied. In the biological activity section of this work, it was found that all synthesized compounds have better inhibitory activity than N,N‐bis(2‐chloroethyl)‐N‐nitrosourea against GR; especially, two molecules, 6e and 6f, are the best among them. The evidence indicates that these Schiff base derivatives, with triazole ring, are strong GR inhibitors and novel antimalaria candidates.
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Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐b]pyrazole‐7‐carboxamides ()
Abstract The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2‐b]pyrazole‐7‐carboxamides were investigated. Following a hit‐to‐lead optimization exploiting 2D and 3D cultures of MCF‐7 human breast, 4T1 mammary gland, and HL‐60 human promyelocytic leukemia cancer cell lines, a 67‐membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub‐micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL‐60 sensitivity (IC50 = 0.183 μM).
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Antileishmanial activity, structure–activity relationship of series of 2‐(trifluoromethyl)benzo[b][1,8]naphthyridin‐4(1H)‐ones ()
Abstract Trifluoromethyl‐substituted quinolones and their analogues have emerged as an interesting platform in the last 6 years to design antiparasite agents. Many of their derivatives have been demonstrated to display excellent efficacy against flagellate parasites such as Plasmodium spp. In order to identify new analogues of trifluoromethyl‐substituted quinolones to treat the American cutaneous leishmaniasis, we evaluated the antiproliferative activity of a series of 2‐(trifluoromethyl)benzo[b]‐[1,8]naphthyridin‐4(1H)‐ones on the Leishmania braziliensis and Leishmania mexicana parasites. The mentioned derivatives have never been evaluated against any parasite strain. In general, an in vitro evaluation on L.(L)mexicana and L.(V)braziliensis showed that L.(L)mexicana was more sensitive to the action of the compounds than L.(V)braziliensis, either in the promastigote or in the amastigote form. Five compounds exhibited moderate efficacy against L.(L)mexicana promastigotes, with IC50 values ranging from 9.65 to 14.76 µM. From the mentioned molecules, three compounds, 1e, 1f, and 1h, showed a discrete response against axenic and intracellular amastigotes, with LD50 values between 19 and 24 µM. Moreover, an in vitro evaluation was performed on an antimony‐resistant amastigote strain and a human isolate amastigote strain. These three compounds showed discrete toxicity on peritoneal macrophages; however, their relatively good antiamastigote response compared to the drug glucantime promoted our trifluoromethyl‐substituted benzo[b][1,8]naphthyridin‐4(1H)‐ones as a potential platform to design potent antileishmanial agents.
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Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors ()
Abstract In an effort to develop potent monoamine oxidase (MAO) inhibitors, new pyrrole derivatives were obtained via the selective reduction of the CC bonds of 1‐(1‐methyl‐1H‐pyrrol‐2‐yl)‐3‐[5‐(aryl)furan‐2‐yl]prop‐2‐en‐1‐ones through palladium catalyzed hydrogenation in ethanol. The synthesized compounds were screened for their inhibitory effects on MAO‐A and MAO‐B by an in vitro fluorometric method. The selectivity index (SI) value was given as the ratio of IC50 (MAO‐A)/IC50 (MAO‐B) for each compound. 3‐(5‐(4‐Chlorophenyl)furan‐2‐yl)‐1‐(1‐methyl‐1H‐pyrrol‐2‐yl)propan‐1‐one (6) was identified as the most selective MAO‐A inhibitor in this series, with an IC50 value of 0.162 µM and a SI value of 0.002. Kinetic studies were also carried out to assess the nature of MAO‐A inhibition by compound 6. According to Lineweaver–Burk plots, compound 6 was found to be a competitive MAO‐A inhibitor and the Ki value of compound 6 was determined as 0.1221 μM. Docking studies were performed for compound 6 and clorgyline using the human MAO‐A crystal structure (PDB ID: 2Z5Y). The docking results showed that compound 6 presented similar interactions as clorgyline in the active center cavity of the enzyme. Molinspiration software was used to determine the physicochemical parameters of all compounds for an evaluation of their compliance to Lipinski's rule of five. Compound 6 did not violate Lipinski's rule, making it a potential orally bioavailable therapeutic agent.
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meta‐Cyanobenzyl substituted benzimidazolium salts: Synthesis, characterization, crystal structure and carbonic anhydrase, α‐glycosidase, butyrylcholinesterase, and acetylcholinesterase inhibitory properties ()
Abstract meta‐Cyanobenzyl‐substituted N‐heterocyclic carbene (NHC) precursors were synthesized by the reaction of a series of N‐(alkyl)benzimidazolium with 3‐bromomethyl‐benzonitrile. These benzimidazolium salts were characterized by using 1H NMR, 13C NMR, FTIR spectroscopy, and elemental analysis techniques. The molecular and crystal structures of 2f and 2g complexes were obtained by using the single‐crystal X‐ray diffraction method. The derivatives of these novel NHC precursors were effective inhibitors of α‐glycosidase (AG), the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with Ki values in the range of 1.01–2.12 nM for AG, 189.56–402.44 nM for hCA I, 112.50–277.37 nM for hCA II, 95.45–352.58 nM for AChE, and 132.91–571.18 nM for BChE. In the last years, inhibition of the CA enzyme has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances such as obesity, glaucoma, cancer, and epilepsy.
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Emergence of promising novel DPP‐4 inhibitory heterocycles as anti‐diabetic agents: A review ()
Abstract Diabetes has turned out to be an epidemic in the recent years all over the world, and today it has become a burden on the healthcare system. Over the years, with technological advancements, different classes of antidiabetic medications have emerged, like sulfonylureas, biguanides, alpha‐glucosidase inhibitors, and thiazolidinediones, but these are often loaded with serious aftermaths like hypoglycemia, weight gain, cardiovascular and renal issues. Dipeptidyl peptidase‐4 (DPP‐4) inhibition is an exciting and new approach in the treatment of type‐2 diabetes. DPP‐4 inhibitors or “gliptins” are weight neutral, pose lesser risk of hypoglycemia, and provide a long‐term post‐meal glycemic control. In this review, an attempt has been made to investigate novel potential compounds that can be added to the existing list of anti‐diabetic drugs.
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