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Journal of Enzyme Inhibition and Medicinal Chemistry

Qin Li, Juping Zhang, Liu Zeng Chen, Jie Quan Wang, Hai Ping Zhou, Wen Jian Tang, Wei Xue, Xin Hua Liu
To develop novel anti-inflammatory agents, a series of new pentadienone oxime ester compounds were designed and synthesized. The structures were determined by IR, 1H NMR, 13 C NMR, and HRMS. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition against LPS-induced nitric oxide (NO) release in RAW 264.7 cell. Among them, compound 5j was found to be one of the most potent compounds in inhibiting NO and IL-6 (IC50 values were 6.66 µM and 5.07 µM, respectively)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Vincenzo Alterio, Davide Esposito, Simona Maria Monti, Claudiu T Supuran, Giuseppina De Simone
Pyridinium containing sulfonamides have been largely investigated as carbonic anhydrase inhibitors (CAIs), showing interesting selectivity features. Nevertheless, only few structural studies are so far available on adducts that these compounds form with diverse CA isoforms. In this paper, we report the structural characterization of the adduct that a triphenylpyridinium derivative forms with hCA II, showing that the substitution of the pyridinium ring plays a key role in determining the conformation of the inhibitor in the active site and consequently the binding affinity to the enzyme...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Abdul-Malek S Altamimi, Ahmed M Alafeefy, Agnese Balode, Igor Vozny, Aleksandrs Pustenko, Mohey Eldin El Shikh, Fatmah A S Alasmary, Sherif A Abdel-Gawad, Raivis Žalubovskis
A series of symmetric molecules incorporating aryl or pyridyl moieties as central core and 1,4-substituted triazoles as a side bridge was synthesised. The new compounds were investigated as lactate dehydro-genase (LDH, EC inhibitors. The cancer associated LDHA isoform was inhibited with IC50 = 117-174 µM. Seven compounds exhibited better LDHA inhibition (IC50 117-136 µM) compared to known LDH inhibitor - galloflavin (IC50 157 µM).
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Alane Beatriz Vermelho, Verônica da Silva Cardoso, Eduardo Ricci Junior, Elisabete Pereira Dos Santos, Claudiu T Supuran
Sulfonamide carbonic anhydrase (CA, EC inhibitors targeting the α-class enzyme from the protozoan pathogen Trypanosoma cruzi, responsible of Chagas disease, were recently reported. Although many such derivatives showed low nanomolar activity in vitro, they were inefficient anti-T. cruzi agents in vivo. Here, we show that by formulating such sulfonamides as nanoemulsions in clove (Eugenia caryophyllus) oil, highly efficient anti-protozoan effects are observed against two different strains of T. cruzi...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Xianling Ning, Hailong Qi, Ridong Li, Yan Jin, Michael A McNutt, Yuxin Yin
The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50 = 1.05 ± 0.17 µM) and 3h (IC50 = 0.96 ± 0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50 = 2.95 ± 0.53 µM) and the known PKM2 inhibitor shikonin (IC50 = 8...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Juan Hu, Wen-Sheng Pang, Jing Han, Kuan Zhang, Ji-Zhou Zhang, Li-Dian Chen
Stroke is a disease of the leading causes of mortality and disability across the world, but the benefits of drugs curative effects look less compelling, intracellular calcium overload is considered to be a key pathologic factor for ischemic stroke. Gualou Guizhi decoction (GLGZD), a classical Chinese medicine compound prescription, it has been used to human clinical therapy of sequela of cerebral ischemia stroke for 10 years. This work investigated the GLGZD improved prescription against intracellular calcium overload could decreased the concentration of [Ca2+]i in cortex and striatum neurone of MCAO rats...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Xiao-Hui Gao, Lin-Bo Liu, Hao-Ran Liu, Jing-Jing Tang, Lu Kang, Hongnian Wu, Peiwu Cui, Jianye Yan
A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a-4c and 7a-7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure-activity relationship investigation revealed that the substituted position of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and BChE. In addition, it seemed that the bioactivity of picolinamide amide derivatives was stronger than that of benzamide derivatives...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Hala B El-Nassan, Bassem H Naguib, Engy A Beshay
Three series of 2-arylpyridothieno[3,2-d]pyrimidin-4-ones 3a-j, pyridothienotriazolopyrimidines 6-8 and 4-imino-pyridothieno[3,2-d]pyrimidines 9a,b were prepared to improve the pim-1 inhibitory activity of the previously reported 2-arylpyridothieno[3,2-d]pyrimidin-4-ones. All the test compounds showed highly potent pim-1 inhibition with IC50 in the range of 0.06-1.76 µM. No significant difference was detected between the pim-1 inhibitory activity of the 4-pyrimidinone and the 4-imino (=NH) or the cyclised triazolopyrimidine derivatives...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Xianrui Xie, Wei Cong, Feng Zhao, Hongjuan Li, Wenyu Xin, Guige Hou, Chunhua Wang
Twenty-four novel 5-phenyl-1,3,4-oxadiazole-2-thiol (POT) analogues, benzo[d]oxazole-2-thiol, benzo[d]thiazole-2-thiol and 5-methyl-1,3,4-thiadiazole-2-thiol-substituted N,N-bis(2-hydroxyethyl) quaternary ammonium salts (QAS) (5a-d, 6a-d, 7a-d, 10a-d, 13a-d, 16a-d) were prepared and characterised by FTIR, NMR and elemental analysis. Part of target compounds (5d, 6d, 7d, 10d, 13d, 16d) displayed potent antimicrobial effect against ten common pathogens (S. aureus, α-H-tococcus, β-H-tococcus, E. coli, P. aeruginosa, Proteus vulgaris, Canidia Albicans, Cytospora mandshurica, Physalospora piricola, Aspergillus niger) and had relatively low cytotoxity against two human cell lines (HaCat and LO2)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Eisuke Kato, Kazuhiro Kawakami, Jun Kawabata
Dipeptidyl peptidase 4 (DPP-4) inhibitors are used for the treatment of type-2 diabetes mellitus. Various synthetic inhibitors have been developed to date, and plants containing natural DPP-4 inhibitors have also been identified. Here, 13 plant samples were tested for their DPP-4 inhibitory activity. Macrocarpals A-C were isolated from Eucalyptus globulus through activity-guided fractionation and shown to be DPP-4 inhibitors. Of these, macrocarpal C showed the highest inhibitory activity, demonstrating an inhibition curve characterised by a pronounced increase in activity within a narrow concentration range...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Marco T C Pessôa, Silmara L G Alves, Alex G Taranto, José A F P Villar, Gustavo Blanco, Leandro A Barbosa
Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (γ-Benzylidene digoxin derivatives) with substitutions in the lactone ring (including non-oxygen and ether groups), to obtain CTS with better NKA isoform specificity. Some of these derivatives show some NKA isoform selective effects, with BD-3, BD-8, and BD-13 increasing NKA α2 activity, BD-5 inhibiting NKA α1 and NKA α3, BD-10 reducing NKA α1, but stimulating NKA α2 and α3; and BD-14, BD-15, and BD-16 enhancing NKA α3 activity...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Sonali Kurup, Bradley McAllister, Pavlina Liskova, Trusha Mistry, Anthony Fanizza, Dan Stanford, Jolanta Slawska, Ulrich Keller, Alexander Hoellein
Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1-18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1-18 allow for a structure-activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Daniela Vullo, R Siva Sai Kumar, Andrea Scozzafava, James G Ferry, Claudiu T Supuran
The β-carbonic anhydrases (CAs, EC from the pathogenic bacterium Clostridium perfringens (CpeCA) was recently characterised kinetically and for its anion inhibition profile. In the search of effective CpeCA inhibitors, possibly useful to inhibit the growth/pathogenicity of this bacterium, we report here an inhibition study of this enzyme with a panel of aromatic, heterocyclic and sugar sulphonamides/sulphamates. Some sulphonamides, such as acetazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, sulthiame and 4-(2-hydroxymethyl-4-nitrophenyl-sulphonamido)ethylbenzenesulphonamide were effective CpeCA inhibitors, with KIs in the range of 37...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Mostafa M Ghorab, Mansour S Alsaid, Aiten M Soliman, Abdullah A Al-Mishari
Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5-19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5-19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Rati K P Tripathi, Vishnu M Sasi, Sukesh K Gupta, Sairam Krishnamurthy, Senthil R Ayyannan
A series of 2-amino-5-nitrothiazole derived semicarbazones were designed, synthesised and investigated for MAO and ChE inhibition properties. Most of the compounds showed preferential inhibition towards MAO-B. Compound 4, (1-(1-(4-Bromophenyl)ethylidene)-4-(5-nitrothiazol-2-yl)semicarbazide) emerged as lead candidate (IC50 = 0.212 µM, SI = 331.04) against MAO-B; whereas compounds 21 1-(5-Bromo-2-oxoindolin-3-ylidene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0.264 µM) and 17 1-((4-Chlorophenyl) (phenyl)methylene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Nazar Trotsko, Agata Przekora, Justyna Zalewska, Grażyna Ginalska, Agata Paneth, Monika Wujec
In our present research, we synthesised new thiazolidine-2,4-diones (12-28). All the newly synthesised compounds were evaluated for antiproliferative and antibacterial activity. Antiproliferative evaluation was carried out using normal human skin fibroblasts and tumour cell lines: A549, HepG2, and MCF-7. The IC50 values were determined for tested compounds revealing antiproliferative activity. Moreover, safety index (SI) was calculated. Among all tested derivatives, the compound 18 revealed the highest antiproliferative activity against human lung, breast, and liver cancer cells...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Daniela Vullo, Sonia Del Prete, Sameh M Osman, Fatmah A S Alasmary, Zeid AlOthman, William A Donald, Clemente Capasso, Claudiu T Supuran
The β-class carbonic anhydrase (CA, EC from the pathogenic bacterium Burkholderia pseudomallei, BpsCAβ, that is responsible for the tropical disease melioidosis was investigated for its activation with natural and non-natural amino acids and amines. Previously, the γ-CA from this bacterium has been investigated with the same library of 19 amines/amino acids, which show very potent activating effects on both enzymes. The most effective BpsCAβ activators were L- and D-DOPA, L- and D-Trp, L-Tyr, 4-amino-L-Phe, histamine, dopamine, serotonin, 2-pyridyl-methylamine, 1-(2-aminoethyl)-piperazine and L-adrenaline with KAs of 0...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Tomasz Frączek, Rafał Kamiński, Agnieszka Krakowiak, Evelien Naessens, Bruno Verhasselt, Piotr Paneth
In search of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved solubility, two series of novel diaryl ethers with phenacyl moiety were designed and evaluated for their HIV-1 reverse transcriptase inhibition potentials. All compounds exhibited good to excellent results with IC50 at low micromolar to submicromolar concentrations. Two most active compounds (7e and 7 g) exhibit inhibitory potency comparable or even better than that of nevirapine and rilpivirine. Furthermore, SupT1 and CD4(+) cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Tim Fischer, Karim Najjar, Frank Totzke, Christoph Schächtele, Wolfgang Sippl, Christoph Ritter, Andreas Hilgeroth
With ongoing resistance problems against the marketed EGFR inhibitors having a quinazoline core scaffold there is a need for the development of novel inhibitors having a modified scaffold and, thus, expected lower EGFR resistance problems. An additional problem concerning EGFR inhibitor resistance is an observed heterodimerization of EGFR with PDGFR-β that neutralises the sole inhibitor activity towards EGFR. We developed novel pyrimido[4,5-b]indoles with varied substitution patterns at the 4-anilino residue to evaluate their EGFR and PDGFR-β inhibiting properties...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Kamila Czarnecka, Małgorzata Girek, Karolina Maciejewska, Robert Skibiński, Jakub Jończyk, Marek Bajda, Jacek Kabziński, Przemysław Sołowiej, Ireneusz Majsterek, Paweł Szymański
Alzheimer's disease (AD) is the most common progressive form of brain neurodegeneration and the most prevailing cause of dementia. Unfortunately, the aetiology of AD is not completely studied but different factors are associated with the development of AD such as among others low level of acetylcholine, aggregation of β-amyloid (Aβ), hyperphosphorylated tau protein, oxidative stress, and inflammation. The study encompass organic syntheses of 2,3-dihydro-1H-cyclopenta[b]quinoline with 5,6-dichloronicotinic acid and suitable linkers derivatives as multifunctional agents for AD treatment...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
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