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Journal of Enzyme Inhibition and Medicinal Chemistry

Kira Mergemeier, Florian Galster, Matthias Lehr
Recently, we have described a method for evaluation of plasma amine oxidase (PAO) inhibitors, which monitors the formation of 6-(5-phenyl-2H-tetrazol-2-yl)hexanal from the corresponding amine substrate by HPLC with UV-detection using purified bovine PAO. We now investigated, whether crude bovine plasma can be used as enzyme source in this assay instead of the purified enzyme. With the aid of specific inhibitors, it was ensured that there was no detectable activity of other important amine oxidases in the plasma, namely monoamine oxidase (MAO) A and B and diamine oxidase (DAO)...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Cheng-Zhi Gao, Wei Dong, Zhi-Wen Cui, Qiong Yuan, Xia-Min Hu, Qing-Ming Wu, Xianlin Han, Yao Xu, Zhen-Li Min
A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 ± 1.25 nM) and MDA-MB-436 cancer cell (11.62 ± 2.15 μM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Qing-Wen Zhang, Zi-Dan Ye, Chang Shen, Hong-Xia Tie, Lei Wang, Lei Shi
HGF/c-Met signalling pathway plays an important role in the development of cancers. A series of 6,7-dimethoxy-4-anilinoquinolines possessing benzimidazole moiety were synthesised and identified as potent inhibitors of the tyrosine kinase c-Met. Their in vitro biological activities against three cancer cell lines (A549, MCF-7, and MKN-45) were also evaluated. Most of these compounds exhibited moderate to remarkable potency. Among them, compound 12n showed the most potent inhibitory activity against c-Met with IC50 value of 0...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Kanyani Sangpheak, Monika Mueller, Nitchakan Darai, Peter Wolschann, Chonticha Suwattanasophon, Ritbey Ruga, Warinthon Chavasiri, Supaporn Seetaha, Kiattawee Choowongkomon, Nawee Kungwan, Chompoonut Rungnim, Thanyada Rungrotmongkol
Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomerase II (hTopoII), which catalyzes the cleavage and rejoining of double-stranded DNA, is an important molecular target for the development of novel cancer therapeutics. In order to diversify the pharmacological activity of chalcones and to extend the scaffold of topoisomerase inhibitors, a series of chalcones was screened against hTopoIIα by computational techniques, and subsequently tested for their in vitro cytotoxicity...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Marcin Skoreński, Aleksandra Milewska, Krzysztof Pyrć, Marcin Sieńczyk, Józef Oleksyszyn
West Nile virus (WNV) is a member of the flavivirus genus belonging to the Flaviviridae family. The viral serine protease NS2B/NS3 has been considered an attractive target for the development of anti-WNV agents. Although several NS2B/NS3 protease inhibitors have been described so far, most of them are reversible inhibitors. Herein, we present a series of α-aminoalkylphosphonate diphenyl esters and their peptidyl derivatives as potent inhibitors of the NS2B/NS3 protease. The most potent inhibitor identified was Cbz-Lys-Arg-(4-GuPhe)P (OPh)2 displaying Ki and k2 /Ki values of 0...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Esma Kocaoğlu, Oktay Talaz, Hüseyin Çavdar, Murat Şentürk, Claudiu T Supuran, Deniz Ekinci
Glutathione reductase (GR) is a crucial antioxidant enzyme which is responsible for the maintenance of antioxidant GSH molecule. Antimalarial effects of some chemical molecules are attributed to their inhibition of GR, thus inhibitors of this enzyme are expected to be promising candidates for the treatment of malaria. In this work, GR inhibitory properties of N-Methylpyrrole derivatives are reported. It was found that all compounds have better inhibitory activity than the strong GR inhibitor N,N-bis(2-chloroethyl)-N-nitrosourea, especially three molecules, 8 m, 8 n, and 8 q, were determined to be the most powerful among them...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Dilek Canakci, Ismail Koyuncu, Nabih Lolak, Mustafa Durgun, Suleyman Akocak, Claudiu T Supuran
In this study, a series of 10 novel copper (II) and silver complexes of 1,3-diaryltriazene-substituted sulfonamides was synthesised. All the synthesised ligands and their metal complexes were assessed for in vitro cytotoxicity against human colorectal adenocarcinoma (DLD-1), cervix carcinoma (HeLa), breast adenocarcinoma (MDA-MB-231), colon adenocarcinoma (HT-29), endometrial adenocarcinoma (ECC-1), prostate cancer (DU-145 and PC-3), normal embryonic kidney (HEK-293), normal prostate epithelium (PNT-1A), and normal retinal pigment epithelium (ARPE-19) cells...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Ismail Koyuncu, Ataman Gonel, Mustafa Durgun, Abdurrahim Kocyigit, Ozgur Yuksekdag, Claudiu T Supuran
Carbonic anhydrase IX (CA IX) has recently been validated as an antitumor/antimetastatic drug target. In this study, we examined the underlying molecular mechanisms and the anticancer activity of sulfonamide CA IX inhibitors against cervical cancer cell lines. The effects of several sulfonamides on HeLa, MDA-MB-231, HT-29 cancer cell lines, and normal cell lines (HEK-293, PNT-1A) viability were determined. The compounds showed high cytotoxic and apoptotic activities, mainly against HeLa cells overexpressing CA IX...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Elena Andreucci, Jessica Ruzzolini, Silvia Peppicelli, Francesca Bianchini, Anna Laurenzana, Fabrizio Carta, Claudiu T Supuran, Lido Calorini
Drug combination represents one of the most accredited strategies of cancer therapy able to improve drug efficacy and possibly overcome drug resistance. Among the agents used to complement conventional chemotherapy, carbonic anhydrase IX (CAIX) inhibitors appear as one of the most suitable, as markers of hypoxic and acidic cancer cells which do not respond to chemo- and radiotherapy. We performed preclinical in vitro assays to evaluate whether the SLC-0111 CAIX inhibitor co-operates and potentiates the cytotoxic effects of conventional chemotherapeutic drugs in A375-M6 melanoma cells, MCF7 breast cancer cells, and HCT116 colorectal cancer cells...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Mohammed S Abdel-Maksoud, Mohammed I El-Gamal, Mahmoud M Gamal El-Din, Chang Hyun Oh
The present work describes the design and synthesis of a novel series of 1,3-diaryl-4-sulfonamidoarylpyrazole derivatives 1a-q and 2a-q and their in vitro biological activities. The target compounds were evaluated for antiproliferative activity against NCI-60 cell line panel. Compounds 1c, 1g, 1k-m, 1o, 2g, 2h, 2k-m, 2o, and 2q showed the highest mean inhibition percentages at 10 µM single-dose testing and were selected to be tested at 5-dose mode. The ICs50 of the most potent compounds were determined over the 60 cell lines...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Serena Massari, Angela Corona, Simona Distinto, Jenny Desantis, Alessia Caredda, Stefano Sabatini, Giuseppe Manfroni, Tommaso Felicetti, Violetta Cecchetti, Christophe Pannecouque, Elias Maccioni, Enzo Tramontano, Oriana Tabarrini
The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify oxazinone-based compounds as new anti-RNase H chemotypes. The presence of the catechol moiety at the C-2 position of the scaffold emerged as critical to achieve potent anti-RNase H activity, which also encompassed anti-RNA dependent DNA polymerase (RDDP) activity for the tricyclic derivatives...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
M Lourdes Sciú, Victor Sebastián-Pérez, Loreto Martinez-Gonzalez, Rocio Benitez, Daniel I Perez, Concepción Pérez, Nuria E Campillo, Ana Martinez, E Laura Moyano
Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer's disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1-3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Agostino Cilibrizzi, Giuseppe Floresta, Vincenzo Abbate, Maria Paola Giovannoni
This study reports the application of inverse virtual screening (iVS) methodologies to identify cellular proteins as suitable targets for a library of heterocyclic small-molecules, with potential pharmacological implications. Standard synthetic procedures allow facile generation of these ligands showing a high degree of core scaffold diversity. Specifically, we have computationally investigated the binding efficacy of the new series for target proteins which are involved in cancer pathogenesis. As a result, nine macromolecules demonstrated efficient binding interactions for the molecular dataset, in comparison to the co-crystallised ligand for each target...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Jonathan Elie, Johnny Vercouillie, Nicolas Arlicot, Lucas Lemaire, Rudy Bidault, Sylvie Bodard, Christel Hosselet, Jean-Bernard Deloye, Sylvie Chalon, Patrick Emond, Denis Guilloteau, Frédéric Buron, Sylvain Routier
A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C-H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC50 values of 0...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Joana Magalhães, Nina Franko, Giannamaria Annunziato, Marco Pieroni, Roberto Benoni, Anna Nikitjuka, Andrea Mozzarelli, Stefano Bettati, Anna Karawajczyk, Aigars Jirgensons, Barbara Campanini, Gabriele Costantino
The lack of efficacy of current antibacterials to treat multidrug resistant bacteria poses a life-threatening alarm. In order to develop enhancers of the antibacterial activity, we carried out a medicinal chemistry campaign aiming to develop inhibitors of enzymes that synthesise cysteine and belong to the reductive sulphur assimilation pathway, absent in mammals. Previous studies have provided a novel series of inhibitors for O-acetylsulfhydrylase - a key enzyme involved in cysteine biosynthesis. Despite displaying nanomolar affinity, the most active representative of the series was not able to interfere with bacterial growth, likely due to poor permeability...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Yuheng Hu, Bing Wang, Jie Yang, Teng Liu, Jie Sun, Xiaojing Wang
A variety of substituted 3-arylcoumarin derivatives were synthesised through microwave radiation heating. The method has characteristics of environmental friendliness, economy, simple separation, and purification process, less by-products and high reaction yield. Those 3-arylcoumarin derivatives were screened for antioxidant, α-glucosidase inhibitory and advanced glycation end-products (AGEs) formation inhibitory. Most compounds exhibited significant antioxidant and AGEs formation inhibitory activities. Anti-diabetic activity studies showed that compounds 11 and 17 were equipotent to the standard drug glibenclamide in vivo...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Suleyman Akocak, Nabih Lolak, Silvia Bua, Claudiu T Supuran
A series of new 1,3-diaryltriazene sulfonamides was synthesised by reaction of diazonium salt of metanilamide (3-aminobenzene sulfonamide) with substituted aromatic amines. The obtained new compounds were assayed as inhibitors of four physiologically and pharmacologically relevant human (h) isoforms of carbonic anhydrases (CA, EC, specifically, hCA I, hCA II, and hCA VII (cytosolic isoforms), as well as the tumour-associated membrane-bound isoform hCA IX. All isoforms investigated here were inhibited by the newly synthesised 1,3-diaryltriazene sulfonamide derivatives from the micromolar to the nanomolar range...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Jian Xin, Min Hu, Qian Liu, Tian Tai Zhang, Dong Mei Wang, Song Wu
Histamine H3 receptor (H3 R), a kind of G-protein coupled receptor (GPCR), is expressed mainly in the central nervous system (CNS) and plays a vital role in homoeostatic control. This study describes the design and synthesis of a series of novel H3 R antagonists based on the iso-flavone scaffold. The results of the bioactivity evaluation show that four compounds (1c, 2c, 2h, and 2o) possess significant H3 R inhibitory activities. Molecular docking indicates that a salt bridge, π-π T-shape interactions, and hydrophobic interaction all contribute to the interaction between compound 2h and H3 R...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Jang Hoon Kim, Nguyen Phuong Thao, Yoo Kyong Han, Young Suk Lee, Bui Thi Thuy Luyen, Ha Van Oanh, Young Ho Kim, Seo Young Yang
Cholinesterases (ChEs) are enzymes that break down neurotransmitters associated with cognitive function and memory. We isolated cinnamic acids (1 and 2), indolinones (3 and 4), and cycloartane triterpenoid derivatives (5-19) from the roots of Cimicifuga dahurica (Turcz.) Maxim. by chromatography. These compounds were evaluated for their inhibitory activity toward ChEs. Compound 1 was determined to have an IC50 value of 16.7 ± 1.9 μM, and to act as a competitive inhibitor of acetylcholinesterase (AChE)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Giannamaria Annunziato, Laura Giovati, Andrea Angeli, Marialaura Pavone, Sonia Del Prete, Marco Pieroni, Clemente Capasso, Agostino Bruno, Stefania Conti, Walter Magliani, Claudiu T Supuran, Gabriele Costantino
Infections caused by pathogens resistant to the available antimicrobial treatments represent nowadays a threat to global public health. Recently, it has been demonstrated that carbonic anhydrases (CAs) are essential for the growth of many pathogens and their inhibition leads to growth defects. Principal drawbacks in using CA inhibitors (CAIs) as antimicrobial agents are the side effects due to the lack of selectivity toward human CA isoforms. Herein we report a new class of CAIs, which preferentially interacts with microbial CA active sites over the human ones...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
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