Archiv der Pharmazie

Identification of pyrazolopyridine derivatives as novel spleen tyrosine kinase inhibitors ()
Abstract Inhibition of spleen tyrosine kinase (Syk) is a promising strategy for the treatment of various allergic and autoimmune disorders such as asthma, rheumatoid arthritis, and allergic rhinitis. Previously, a Syk inhibitor with novel indazole scaffold was discovered by structure‐based virtual screening. Herein, the structure–activity relationship of the indazole Syk inhibitors was investigated. Several new inhibitors demonstrated potent activity against Syk. In particular, compound 18c showed good Syk inhibitory activity (IC50 = 1.2 µM), representing a good lead compound for further optimization.
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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 of three triterpene series and their activity against respiratory syncytial virus ()
Abstract The human respiratory syncytial virus (hRSV) is a leading cause of hospitalization due to acute lower respiratory infection especially in infants and young children, sometimes causing fatal cases. The monoclonal antibody palivizumab is one of the available options for preventing this virus, and at the moment there are several hRSV vaccine trials underway. Unfortunately, the only drug option to treat hRSV infection is ribavirin, which can be used in severe high‐risk cases. For this reason, new medicines are needed and, in this context, the triterpenes and their derivatives are promising alternatives, since many of them have shown important antiviral activity, such as bevirimat. Therefore, we report three series of triterpene (betulin (BE), betulinic acid (BA), and ursolic acid (UA)) derivatives tested against hRSV. The derivatives were synthesized by using commercial anhydrides in an easy and inexpensive step reaction. For the antiviral assay, A549 cells were infected by hRSV and after 96 h of compound or ribavirin (positive control) treatment, the cell viability was tested by MTT assay. DMSO, non‐infected cells and infected cells without treatment were used as negative control. The triterpene esterification at the hydroxyl group resulted in 17 derivatives. The 3,28‐di‐O‐acetylbetulin derivative (1a) showed the best results for cell viability, and real‐time PCR amplification was performed for 1a treatment. Remarkably, one new anti‐hRSV prototype was obtained through an easy synthesis of BE, which shall represent an alternative for a new lead compound for anti‐hRSV therapy.
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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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Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p‐propoxyphenylsubstituted‐1H‐benzimidazole derivatives ()
Abstract This study indicates the synthesis, cholinesterase (ChE) inhibitory activity, and molecular modeling studies of 48 compounds as o‐ and p‐(3‐substitutedethoxyphenyl)‐1H‐benzimidazole derivatives. According to the ChE inhibitor activity results, generally, para series are more active against acetylcholinesterase (AChE) whereas ortho series are more active against butyrylcholinesterase (BuChE). The most active compounds against AChE and BuChE are compounds A12 and B14 with IC50 values of 0.14 and 0.22 μM, respectively. Additionally, the most active 16 compounds against AChE/BuChE were chosen to investigate the neuroprotective effects, and the results indicated that most of the compounds have free radical scavenging properties and show their effects by reducing free radical production; moreover, some of the compounds significantly increased the viability of SH‐SY5Y cells exposed to H2O2. Overall, compounds A12 and B14 with potential AChE and BuChE inhibitory activities, high neuroprotection against H2O2‐induced toxicity, free radical scavenging properties, and metal chelating abilities may be considered as lead molecules for the development of multi‐target‐directed ligands against Alzheimer's disease.
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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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Synthesis and biological evaluation of some new tricyclic pyrrolo[3,2‐e]tetrazolo[1,5‐c]pyrimidine derivatives as potential antitubercular agents ()
Abstract A series of new tricyclic pyrrolo[3,2‐e]tetrazolo[1,5‐c]pyrimidines 8a–l were synthesized and characterized by IR, NMR (1H and 13C), and mass spectral analysis. The newly synthesized compounds 8a–l were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37Ra using an established XTT reduction menadione assay (XRMA). The title compounds exhibited minimum inhibitory concentrations (MIC90) ranging from 0.09 to >30 μg/mL. Five compounds (8c, 8i–l) were further confirmed for their dose‐dependent effect against MTB. These compounds were evaluated in the THP‐1 infection model, where 8i (MIC90 = 0.35 μg/mL), 8j (MIC90 = 1.17 μg/mL), 8k (MIC90 = 2.38 μg/mL), and 8l (MIC90 = 1.17 μg/mL) demonstrated significant antitubercular activity. All the ex vivo active compounds showed insignificant cytotoxicity against the human cancer cell lines, HeLa, MCF‐7, and THP‐1. Inactivity of all these compounds against Gram positive and Gram negative bacteria indicates their specificity. Molecular docking studies in the active site of the sterol 14alpha‐demethylase (CYP51) enzyme revealed a similar binding mode to the native ligand in the crystal structure, thereby helping to understand the ligand–protein interactions and to establish a structural basis for inhibition of MTB. The results suggest novel pharmacophores as selective and specific inhibitors against MTB that can be explored further to synthesize lead compounds against tuberculosis. In summary, the results clearly indicate the identification of some novel, selective, and specific inhibitors against MTB that can be explored further for potential antitubercular drugs.
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Editorial Board: Arch. Pharm. Chem. Life Sci. (8/2018) ()
Archiv der Pharmazie, Volume 351, Issue 8, August 2018.
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Cover Picture: Arch. Pharm. Chem. Life Sci. (8/2018) ()
Archiv der Pharmazie, Volume 351, Issue 8, August 2018.
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Schiff bases and their amines: Synthesis and discovery of carbonic anhydrase and acetylcholinesterase enzymes inhibitors ()
Abstract Three series of symmetrical Schiff bases were synthesized from 1,2‐diaminoethane, 1,3‐diaminopropane and 1,4‐diaminobutane and substituted benzaldehydes, and reduced by sodium borohydride to the corresponding benzylic diamines 4–6. All of the compounds obtained were characterized using elemental analysis, FT‐IR, 1H NMR, and 13C NMR spectroscopy. The enzyme inhibitory properties of these compounds were tested and the influence of the alkane chain length and the substituents on the phenyl group on the enzyme inhibition activity were examined. The novel Schiff bases and their amine derivatives (1a–d, 2a–d, 3b–d, 4a–c, 5a–c, 6a, 6c, 6d) were effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) with Ki values in the range of 159.43 ± 30.03 to 563.73 ± 115.30 nM for hCA I, 104.88 ± 18.44 to 524.32 ± 95.03 nM for hCA II, and 3.95 ± 0.74 to 30.83 ± 6.81 nM for AChE.
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Synthesis and antitumor evaluation of novel 4‐anilino‐7,8‐dihydropyrido[4,3‐d]pyrimidine‐6(5H)‐carboxylate derivatives as potential EGFR inhibitors ()
Abstract Novel series of 4‐anilino‐7,8‐dihydropyrido[4,3‐d]pyrimidine‐6(5H)‐carboxylates (5a–p, 7, and 8a–e) were synthesized and evaluated for their antiproliferative activity against the A549, HT29, H460, and H1975 cancer cell lines in vitro. Nine compounds (5a–c, 5i, 5j, 7, 8a, 8b, 8i) demonstrated moderate to significant cytotoxic activity with IC50 values below 18 µM on A549 cells, which were comparable to that of the reference gefitinib (IC50 = 18.44 µM). Especially, the further enzymatic analysis on epidermal growth factor receptor (EGFR), HER2, and VEGFR identified compound 5a as a promising hit that exhibited considerable potency both in cellular (IC50 = 5.67, 17.04, 11.29, and 12.65 µM, respectively) and EGFR enzymatic assays (IC50 = 14.8 nM). Compound 5a was capable of down‐regulating the expression of EGFR and inhibited EGFR phosphorylation in a dose‐dependent manner, representing a potential EGFR candidate for further optimization.
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Synthesis and antibacterial activities of novel pleuromutilin derivatives ()
Abstract Pleuromutilin derivatives 4a–h, 5a–g, and 6a–d were synthesized and characterized by IR, 1H NMR, and 13C NMR. All synthetic compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus (ATCC 25923), methicillin‐resistant S. aureus (MRSA, ATCC 43300), Pasteurella multocida (CVCC 408), Escherichia coli (ATCC 25922), and Salmonella typhimurium (ATCC 14028). Most compounds with quaternary amine showed higher antibacterial activities against both Gram‐positive and Gram‐negative bacteria strains. Among the screened compounds, compound 5a bearing an N,N,N‐trimethyl group at the C‐14 side chain of pleuromutilin was found to be the most active agent. Furthermore, preliminary molecular docking was performed to predict the binding interaction of the compounds in the binding pocket.
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Azole‐based non‐peptidomimetic plasmepsin inhibitors ()
Abstract The spread of drug‐resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases – plasmepsins (Plms) – are differentially expressed in multiple stages of the Plasmodium parasite's lifecycle and are considered as attractive drug targets. We report the development of novel azole‐based non‐peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino‐piperazine inhibitors. The best triazole‐based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance‐free antimalarial drug targeting the non‐digestive Plm IX or X, which are essential for the malaria parasite life cycle.
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Synthesis of novel sulfamides incorporating phenethylamines and determination of their inhibition profiles against some metabolic enzymes ()
Abstract A series of sulfamides were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carbonic anhydrase inhibition properties. The synthesis of sulfamides was achieved by the reactions of phenethylamines with N,N‐dimethylsulfamoyl chloride in the presence of Et3N. The methoxylated sulfamides were converted into their phenolic derivatives with BBr3 for structure–activity relationships. The synthesized sulfamide/phenolic sulfamide derivatives were investigated as cholinesterase inhibitors and their relative role in AChE versus BChE inhibition was defined. Sulfamide/phenolic sulfamide derivatives are known as important carbonic anhydrase inhibitors; therefore, the synthesized compounds were investigated for inhibitory effects on both carbonic anhydrase isoenzymes. Additionally, we evaluated four different enzymes, which were inhibited in the low nanomolar range by these compounds. According to the present studies, for AChE, BChE, and carbonic anhydrase I and II, the ranges of results are recorded as 0.027–0.076 nM, 0.075–0.327 nM, 0.123–0.678 nM, and 0.024–0.688 nM, respectively.
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Design and evaluation of biological activities of 1,3‐oxazolidinone derivatives bearing amide, sulfonamide, and thiourea moieties ()
Abstract 1,3‐Oxazolidine‐2‐one is an important heterocyclic ring participating in the chemical structure of many drugs. In this research, 22 new amide/sulfonamide/thiourea derivatives (1–22) were obtained by the reaction of (S)‐4‐(4‐aminobenzyl)‐2(1H)‐1,3‐oxazolidinone with 4‐substituted benzoyl chlorides, 4‐substituted benzene sulfonyl chlorides, and 4‐substituted phenyl isothiocyanates. The structures of all synthesized compounds were clarified by FT‐IR, NMR, and mass spectroscopic and elemental analysis techniques. The synthesized compounds were screened for their antimicrobial activity. Antimicrobial susceptibility and cellular physiology were evaluated using the microbroth dilution assay and the flow cytometry method. As a result, it was determined that compound 16 displayed better antimicrobial activity than chloramphenicol against Gram‐positive bacteria, especially Staphylococcus aureus. In order to understand the mechanism of effect of the compounds on the cell membrane, fluorescence microscopy was used. Cell membrane damage of the Gram positive bacteria treated with compound 16 was observed as a result of intense staining with propidium iodide. In addition, genotoxicity, cytotoxicity, and absorption, distribution, metabolism, and excretion (ADME) parameters of compound 16 were examined and it was found as non‐mutagenic and non‐cytotoxic at the concentration at which it showed antimicrobial activity. According to the calculated ADME parameters and drug likeness scores, the compounds can be good drug candidates, especially compound 16.
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Synthesis, characterization, and SAR of arylated indenoquinoline‐based cholinesterase and carbonic anhydrase inhibitors ()
We report the synthesis of bromoindenoquinolines (15a–f) by Friedlander reactions in low yields (13–50%) and the conversion of the corresponding phenyl‐substituted indenoquinoline derivatives 16–21 in high yields (80–96%) by Suzuki coupling reactions. To explore the structure–activity relationship (SAR), their inhibition potentials to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase cyctosolic (hCA I and II) enzymes were determined. Monophenyl (16–18) indenoquinolines significantly inhibited the AChE and BChE enzymes in ranges of IC50 37–57 nM and 84–93 nM, respectively, compared with their starting materials 15a–c and reference compounds (galanthamine and tacrine). On the other hand, these novel arylated indenoquinoline‐based derivatives were effective inhibitors of the BChE, hCA I and II, BChE and AChE enzymes with Ki values in the range of 37 ± 2.04 to 88640 ± 1990 nM for AChE, 120.94 ± 37.06 to 1150.95 ± 304.48 nM for hCA I, 267.58 ± 98.05 to 1568.16 ± 438.67 nM for hCA II, and 84 ± 3.86 to 144120 ± 2910 nM for BChE. As a result, monophenyl indenoquinolines 16–18 may have promising anti‐Alzheimer drug potential and 3,8‐dibromoindenoquinoline amine (15f) can be novel hCA I and hCA II enzyme inhibitors.
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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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Recent updates of fluoroquinolones as antibacterial agents ()
Abstract Fluoroquinolones remain one of the most important kind of antibacterial agents used nowadays. The emergence of more virulent and resistant strains of bacteria by the development of either mutated DNA‐binding proteins or efflux pump mechanism for drugs is considered the main problem associated with the therapeutic use of these drugs. This situation participated in pushing researchers to design new fluoroquinolone derivatives, mainly with different substituents at C‐7 to withstand these resistant strains of bacteria and to obtain a wider spectrum of activity including activity against anaerobic organisms. Conjugation of fluoroquinolones with substitutions such as 1,2,4‐triazoles, alkyl oximes, flavonoids, aryl furans, benzofuroxans, metronidazoles or even other antibiotics such as neomycin‐B produced derivatives that have a superior and wider spectrum of activity and better resistance than the classical fluoroquinolone agents. Addition of a hydroxamic acid moiety to fluoroquinolones also increased the activity against Proteus mirabilis, which represents one of the most resistant strains of bacteria in urinary tract infections. This review aims to highlight the recent updates made for fluoroquinolones for broadening the spectrum of activity to become active not only against resistant strains of bacteria but also against anaerobic pathogens.
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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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