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  • Design, synthesis and α-glucosidase inhibition study of novel embelin derivatives
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-22
    Xiaole Chen; Min Gao; Rongchao Jian; Weiqian David Hong; Xiaowen Tang; Yuling Li; Denggao Zhao; Kun Zhang; Wenhua Chen; Xi Zheng; Zhaojun Sheng; Panpan Wu

    Abstract Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC50 = 4.2 μM) against α-glucosidase in this study. Then, four series of novel embelin derivatives were designed, prepared and evaluated in α-glucosidase inhibition assays. The results show that most of the embelin derivatives synthesised are effective α-glucosidase inhibitors, with IC50 values at the micromolar level, especially 10d, 12d, and 15d, the IC50 values of which are 1.8, 3.3, and 3.6 μM, respectively. Structure–activity relationship (SAR) studies suggest that hydroxyl groups in the 2/5-position of para-benzoquinone are very important, and long-chain substituents in the 3-position are highly preferred. Moreover, the inhibition mechanism and kinetics studies reveal that all of 10d, 12d, 15d, and embelin are reversible and mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between 10d and 15d with α-glucosidase.

    更新日期:2020-01-23
  • A class of carbonic anhydrase IX/XII – selective carboxylate inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-22
    Rakia Abd Alhameed; Emanuela Berrino; Zainab Almarhoon; Ayman El-Faham; Claudiu T. Supuran

    Abstract A small series of 2,4-dioxothiazolidinyl acetic acids was prepared from thiourea, chloroacetic acid, aromatic aldehydes, and ethyl-2-bromoacetate. They were assayed for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, the cytosolic hCA I and II, and the transmembrane hCA IX and XII, involved among others in tumorigenesis (hCA IX and XII) and glaucoma (hCA II and XII). The two cytosolic isoforms were not inhibited by these carboxylates, which were also rather ineffective as hCA IX inhibitors. On the other hand, they showed submicromolar hCA XII inhibition, with KIs in the range of 0.30–0.93 µM, making them highly CA XII-selective inhibitors.

    更新日期:2020-01-23
  • Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-22
    Yi Le; Yiyuan Gan; Yihong Fu; Jiamin Liu; Wen Li; Xue Zou; Zhixu Zhou; Zhenchao Wang; Guiping Ouyang; Longjia Yan

    Abstract In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.

    更新日期:2020-01-23
  • Coumarins from Magydaris pastinacea as inhibitors of the tumour-associated carbonic anhydrases IX and XII: isolation, biological studies and in silico evaluation
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-17
    Benedetta Fois; Simona Distinto; Rita Meleddu; Serenella Deplano; Elias Maccioni; Costantino Floris; Antonella Rosa; Mariella Nieddu; Pierluigi Caboni; Claudia Sissi; Andrea Angeli; Claudiu T. Supuran; Filippo Cottiglia

    Abstract In an in vitro screening for human carbonic anhydrase (hCA) inhibiting agents from higher plants, the petroleum ether and ethyl acetate extracts of Magydaris pastinacea seeds selectively inhibited hCA IX and hCA XII isoforms. The phytochemical investigation of the extracts led to the isolation of ten linear furocoumarins (1–10), four simple coumarins (12–15) and a new angular dihydrofurocoumarin (11). The structures of the isolated compounds were elucidated based on 1 D and 2 D NMR, MS, and ECD data analysis. All isolated compounds were inactive towards the ubiquitous cytosolic isoform hCA I and II (Ki > 10,000 nM) while they were significantly active against the tumour-associated isoforms hCA IX and XII. Umbelliprenin was the most potent coumarin inhibiting hCA XII isoform with a Ki of 5.7 nM. The cytotoxicity of the most interesting compounds on HeLa cancer cells was also investigated.

    更新日期:2020-01-17
  • Deciphering the enzymatic target of a new family of antischistosomal agents bearing a quinazoline scaffold using complementary computational tools
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-15
    Victor Sebastian-Perez; Alfonso García-Rubia; Sayed H. Seif el-Din; Abdel-Nasser A. Sabra; Naglaa M. El-Lakkany; Samia William; Tom L. Blundell; Louis Maes; Ana Martinez; Nuria E. Campillo; Sanaa S. Botros; Carmen Gil

    Abstract A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed.

    更新日期:2020-01-15
  • Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-15
    Aurélie Hurtevent; Morgan Le Naour; Veronique Leclerc; Pascal Carato; Patricia Melnyk; Nathalie Hennuyer; Bart Staels; Monique Beucher-Gaudin; Daniel-Henri Caignard; Catherine Dacquet; Nicolas Lebegue

    Abstract A series of nitrogen heterocycles containing α–ethoxyphenylpropionic acid derivatives were designed as dual PPARα/γ agonist ligands for the treatment of type 2 diabetes (T2D) and its complications. 6-Benzoyl-benzothiazol-2-one was the most tolerant of the tested heterocycles in which incorporation of O-methyl oxime ether and trifluoroethoxy group followed by enantiomeric resolution led to the (S)-stereoisomer 44 b displaying the best in vitro pharmacological profile. Compound 44 b acted as a very potent full PPARγ agonist and a weak partial agonist on the PPARα receptor subtype. Compound 44 b showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain and could be considered as a selective PPARγ modulator (SPPARγM).

    更新日期:2020-01-15
  • Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII and of human thioredoxin reductase
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-13
    Mikhail Krasavin; Raivis Žalubovskis; Aiga Grandāne; Ilona Domračeva; Petr Zhmurov; Claudiu T. Supuran

    Abstract The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and – hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.

    更新日期:2020-01-13
  • Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-08
    Stane Pajk; Damijan Knez; Urban Košak; Maja Zorović; Xavier Brazzolotto; Nicolas Coquelle; Florian Nachon; Jacques-Philippe Colletier; Marko Živin; Jure Stojan; Stanislav Gobec

    Abstract Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer’s disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.

    更新日期:2020-01-09
  • Synthesis and human carbonic anhydrase I, II, VA, and XII inhibition with novel amino acid–sulphonamide conjugates
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-08
    Hasan Küçükbay; Nesrin Buğday; F. Zehra Küçükbay; Andrea Ageli; Gianluca Bartolucci; Claudiu T. Supuran

    Abstract A series of amino acid–sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid–sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.

    更新日期:2020-01-09
  • Synthesis, in vitro screening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-07
    David Malinak; Rafael Dolezal; Vendula Hepnarova; Miroslava Hozova; Rudolf Andrys; Petr Bzonek; Veronika Racakova; Jan Korabecny; Lukas Gorecki; Eva Mezeiova; Miroslav Psotka; Daniel Jun; Kamil Kuca; Kamil Musilek

    Abstract The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.

    更新日期:2020-01-08
  • Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-06
    Jing-wei Liang; Shi-long Li; Shan Wang; Wan-qiu Li; Fan-hao Meng

    Abstract C-Met plays a crucial role in the development and progression of neoplastic disease. Type II c-Met inhibitors recognise the inactive DFG-out conformation of the kinase, result in better anti-tumour effects due to synergistic effect against the other kinases. According to our previous works, an (E)-N'-benzylidene group was selected as the initial fragment. Two series of (E)-N'-benzylidene hydrazides were designed by fragment growth method. The inhibitory activities were in vitro investigated against c-Met and VEGFR-2. Compound 10b exhibited the most potent inhibitory activity against the c-Met inhibitor (IC50 = 0.37 nM). Compound 11b exhibited multi-target c-Met kinase inhibitory activity as a potential type II c-Met inhibitor (IC50 = 3.41 nM against c-Met; 25.34 nM against VEGFR-2). The two compounds also demonstrate the feasibility of fragment-based virtual screening method for drug discovery.

    更新日期:2020-01-06
  • Novel CDKs inhibitors for the treatment of solid tumour by simultaneously regulating the cell cycle and transcription control
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-03
    Xin Wang; Kaiyuan Deng; Cheng Wang; Yao Li; Tianqi Wang; Zhi Huang; Yakun Ma; Peiqing Sun; Yi Shi; Shengyong Yang; Yan Fan; Rong Xiang

    A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.

    更新日期:2020-01-04
  • Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-03
    Fabrice Pagniez; Nicolas Lebouvier; Young Min Na; Isabelle Ourliac-Garnier; Carine Picot; Marc Le Borgne; Patrice Le Pape

    (2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC90 = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8 g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.

    更新日期:2020-01-04
  • Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-03
    Jean Guillon; Anita Cohen; Clotilde Boudot; Alessandra Valle; Vittoria Milano; Rabindra Nath Das; Aurore Guédin; Stéphane Moreau; Luisa Ronga; Solène Savrimoutou; Maxime Demourgues; Elodie Reviriego; Sandra Rubio; Sandie Ferriez; Patrice Agnamey; Cécile Pauc; Serge Moukha; Pascale Dozolme; Sophie Da Nascimento; Pierre Laumaillé; Anne Bouchut; Nadine Azas; Jean-Louis Mergny; Catherine Mullié; Pascal Sonnet; Bertrand Courtioux

    A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.

    更新日期:2020-01-04
  • Sulphonamides incorporating 1,3,5-triazine structural motifs show antioxidant, acetylcholinesterase, butyrylcholinesterase, and tyrosinase inhibitory profile
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-03
    Nabih Lolak; Mehmet Boga; Muhammed Tuneg; Gulcin Karakoc; Suleyman Akocak; Claudiu T. Supuran

    A series of 16 novel benzenesulfonamides incorporating 1,3,5-triazine moieties substituted with aromatic amines, dimethylamine, morpholine and piperidine were investigated. These compounds were assayed for antioxidant properties by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, 2,2`-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical decolarisation assay and metal chelating methods. They were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase, which are associated with several diseases such as Alzheimer, Parkinson and pigmentation disorders. These benzenesulfonamides showed moderate DPPH radical scavenging and metal chelating activity, and low ABTS cation radical scavenging activity. Compounds 2 b, 3d and 3 h showed inhibitory potency against AChE with % inhibition values of >90. BChE was also effectively inhibited by most of the synthesised compounds with >90% inhibition potency. Tyrosinase was less inhibited by these compounds.

    更新日期:2020-01-04
  • Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2020-01-03
    Ivana Šagud; Nikolina Maček Hrvat; Ana Grgičević; Tena Čadež; Josipa Hodak; Milena Dragojević; Kornelija Lasić; Zrinka Kovarik; Irena Škorić

    The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors. HIGHLIGHTS Series of oxazole benzylamines were designed and synthesised The tested compounds showed binding selectivity for BChE Naphthoxazoles were more potent AChE inhibitors

    更新日期:2020-01-04
  • N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-27
    Wei-Yi Li; Wei-Wei Ni; Ya-Xi Ye; Hai-Lian Fang; Xing-Ming Pan; Jie-Ling He; Tian-Li Zhou; Juan Yi; Shan-Shan Liu; Mi Zhou; Zhu-Ping Xiao; Hai-Liang Zhu

    Abstract A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10−3 s−1) from the catalytic domain.

    更新日期:2019-12-27
  • Design, synthesis and biological evaluation of carbohydrate-based sulphonamide derivatives as topical antiglaucoma agents through selective inhibition of carbonic anhydrase II
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-22
    Zhuang Hou; Chuanchao Li; Yichuang Liu; Miao Zhang; Yitong Wang; Zhanfang Fan; Chun Guo; Bin Lin; Yang Liu

    Abstract A series of new carbohydrate-based sulphonamide derivatives were designed, synthesised by employing the so-call ‘sugar-tail’ approach. The compounds were evaluated in vitro against a panel of CAs. Compared to their parent compound p-sulfamoylbenzoic acid, these compounds showed nearly 100-fold improvement in their binding affinities against hCA II in vitro. All of compounds showed great water solubility and the pH value of their water solutions of compounds is 7.0. Such properties are advantageous to make them much less irritating to the eye when applied topical glaucomatous drugs, compared to the relatively highly acidic dorzolamide preparations (pH 5.5). Notably, compounds 7d, 7 g, 7 h demonstrated to topically lower intraocular pressure (IOP) in glaucomatous animals better than brinzolamide when applied as a 1% solution directly into the eye. Low cytotoxicity on human cornea epithelial cell was observed in the tested concentrations by the MTT assay.

    更新日期:2019-12-23
  • A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-22
    Jessica Ruzzolini; Anna Laurenzana; Elena Andreucci; Silvia Peppicelli; Francesca Bianchini; Fabrizio Carta; Claudiu T. Supuran; Maria Novella Romanelli; Chiara Nediani; Lido Calorini

    Abstract The emergence of tumour recurrence and resistance limits the survival rate for most tumour-bearing patients. Only, combination therapies targeting pathways involved in the induction and in the maintenance of cancer growth and progression might potentially result in an enhanced therapeutic efficacy. Herein, we provided a prospective combination treatment that includes suberoylanilide hydroxamic acid (SAHA), a well-known inhibitor of histone deacetylases (HDACs), and SLC-0111, a novel inhibitor of carbonic anhydrase (CA) IX. We proved that HDAC inhibition with SAHA in combination with SLC-0111 affects cell viability and colony forming capability to greater extent than either treatment alone of breast, colorectal and melanoma cancer cells. At the molecular level, this therapeutic regimen resulted in a synergistically increase of histone H4 and p53 acetylation in all tested cell lines. Overall, our findings showed that SAHA and SLC-0111 can be regarded as very attractive combination providing a potential therapeutic strategy against different cancer models.

    更新日期:2019-12-23
  • Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer’s disease
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-20
    Jun Mo; Tingkai Chen; Hongyu Yang; Yan Guo; Qi Li; Yuting Qiao; Hongzhi Lin; Feng Feng; Wenyuan Liu; Yao Chen; Zongliang Liu; Haopeng Sun

    Abstract Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer’s disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 µM; 15j, eqBChE IC50 = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.

    更新日期:2019-12-20
  • Discovery of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives as a novel selective inhibitor scaffold of JNK3
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-19
    Youri Oh; Miyoung Jang; Hyunwook Cho; Songyi Yang; Daseul Im; Hyungwoo Moon; Jung-Mi Hah

    Abstract 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives were designed and synthesised as selective inhibitors of JNK3, a target for the treatment of neurodegenerative diseases. Following previous studies, we have designed JNK3 inhibitors to reduce the molecular weight and successfully identified a lead compound that exhibits equipotent activity towards JNK3. Kinase profiling results also showed high selectivity for JNK3 among 38 kinases. Among the derivatives, the IC50 value of 8a, (R)-2-(1-(2-((1-(cyclopropanecarbonyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)-5-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)acetonitrile exhibited 227 nM, showing the highest inhibitory activity against JNK3.

    更新日期:2019-12-20
  • Inhibition survey with phenolic compounds against the δ- and η-class carbonic anhydrases from the marine diatom thalassiosira weissflogii and protozoan Plasmodium falciparum
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-19
    Siham A. Alissa; Hanan A. Alghulikah; Zeid A. ALOthman; Sameh M. Osman; Sonia Del Prete; Clemente Capasso; Alessio Nocentini; Claudiu T. Supuran

    Abstract The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum, have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (KIs 0.81–65.4 µM) and PfCA (KIs 0.62–78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA, which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria.

    更新日期:2019-12-20
  • Development of a cheminformatics platform for selectivity analyses of carbonic anhydrase inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-19
    Giulio Poli; Salvatore Galati; Adriano Martinelli; Claudiu T. Supuran; Tiziano Tuccinardi

    Abstract The selectivity for a specific human Carbonic Anhydrase (hCA) isoform is an important property a hCA inhibitor (CAI) should be endowed with, in order to constitute a valuable therapeutic tool for the treatment of a desired pathology. In this context, we developed a chemoinformatic platform that allows the analysis of the structure and selectivity profile of known CAIs reported in literature, with the aim of identifying structural motifs connected to ligand selectivity, thus providing useful guidelines for the design of novel ligands selective for the desired hCA isoform. The platform is able to perform ultrafast structure and selectivity analyses through ligand fingerprint similarity, with no need of structural information about the target receptor and ligands’ binding mode. It is easily accessible to the non-expert user through the implementation of a KNIME Analytic Platform workflow and could be extended to analyze the selectivity profile of known ligands of different target proteins.

    更新日期:2019-12-19
  • Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-18
    Yuan Zhang; Xin Meng; Haikang Tang; Minghui Cheng; Fujun Yang; Wenqing Xu

    Abstract Mutation of the proto-oncogene K-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Many drugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations, corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In this study, on the basis of the crystal structure of K-Ras, 21 analogues (TKR01–TKR21) containing urea or thiourea were rationally designed, which can effectively inhibit the lung cancer cell A549 growth. The designing of these compounds was based on the structure of K-Ras protein, and the related groups were replaced by bioisosteres to improve the affinity and selectivity. Biological testing revealed that compound TKR15 could significantly inhibit the proliferation of A549 cell with IC50 of 0.21 µM. Docking analysis showed that the TKR15 can effectively bind to the hydrophobic cavity and form a hydrogen bond with the Glu37. In addition, through flow apoptosis assay and immunofluorescence staining assay, it confirmed that this compound can inhibit A549 cell proliferation with the mechanism of blocking K-RasG12V protein and effector proteins interactions through the apoptotic pathway. In conclusion, our studies in finding novel potent compound (TKR15) with confirmed mechanism showed great potential for further optimisation and other medicinal chemistry relevant studies.

    更新日期:2019-12-19
  • Synthesis, antibacterial and anticancer activity, and docking study of aminoguanidines containing an alkynyl moiety
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-18
    Xianqing Deng; Mingxia Song

    Abstract Two series of aminoguanidines containing an alkynyl moiety were designed, synthesised, and screened for antibacterial and anticancer activities. Generally, the series 3a–3j with a 1,2-diphenylethyne exhibited better antibacterial activity than the other series (6a–6k) holding 1,4-diphenylbuta-1,3-diyne moiety antibacterial activity. Most compounds in series 3a–3j showed potent growth inhibition against the tested bacterial strains, with minimum inhibitory concentration (MIC) values in the range 0.25–8 µg/mL. Compound 3g demonstrated rapid and persistent bactericidal activity at 2 × MIC. The resistance study revealed that resistance of the tested bacteria towards 3g is not easily developed. Molecular docking studies revealed that compounds 3g and 6e bind strongly to the LpxC and FabH enzymes. Moreover, excellent activity of selected compounds against the growth of cancer cell lines A549 and SGC7901 was also observed, with IC50 values in the range 0.30–4.57 µg/mL. These findings indicate that compounds containing the aminoguanidine moiety are promising candidates for the development of new antibacterial and anticancer agents.

    更新日期:2019-12-19
  • Novel sulphonamides incorporating triazene moieties show powerful carbonic anhydrase I and II inhibitory properties
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-09
    Sinan Bilginer; Baris Gonder; Halise Inci Gul; Ruya Kaya; Ilhami Gulcin; Baris Anil; Claudiu T. Supuran

    Abstract A series of compounds incorporating 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl) benzenesulfonamide moieties were synthesised and their chemical structure was confirmed by physico-chemical methods. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were evaluated against human isoforms hCA I and II. KI values of these sulphonamides were in the range of 21 ± 4–72 ± 2 nM towards hCA I and in the range of 16 ± 6–40 ± 2 nM against hCA II. The 4-fluoro substituted derivative might be considered as an interesting lead due to its effective inhibitory action against both hCA I and hCA II (KIs of 21 nM), a profile rarely seen among other sulphonamide CA inhibitors, making it of interest in systems where the activity of the two cytosolic isoforms is dysregulated.

    更新日期:2019-12-19
  • Novel benzofuran-based sulphonamides as selective carbonic anhydrases IX and XII inhibitors: synthesis and in vitro biological evaluation
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-06
    Mohamed A. Abdelrahman; Wagdy M. Eldehna; Alessio Nocentini; Hany S. Ibrahim; Hadia Almahli; Hatem A. Abdel-Aziz; Sahar M. Abou-Seri; Claudiu T. Supuran

    Abstract Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (4a,b, 5a,b, 9a–c, and 10a–d), featuring the zinc anchoring benzenesulfonamide moiety linked to a benzofuran tail via a hydrazine or hydrazide linker. All the target benzofurans were examined for their inhibitory activities toward isoforms hCA I, II, IX, and XII. The target tumour-associated hCA IX and XII isoforms were efficiently inhibited with KIs spanning in ranges 10.0–97.5 and 10.1–71.8 nM, respectively. Interestingly, arylsulfonehydrazones 9 displayed the best selectivity toward hCA IX and XII over hCA I (SIs: 39.4–250.3 and 26.0–149.9, respectively), and over hCA II (SIs: 19.6–57.1 and 13.0–34.2, respectively). Furthermore, the target benzofurans were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Only benzofurans 5b and 10b possessed selective and moderate growth inhibitory activity toward certain cancer cell lines.

    更新日期:2019-12-19
  • Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-06
    Ahmed K. Farag; Ahmed H. E. Hassan; Byung Sun Ahn; Ki Duk Park; Eun Joo Roh

    Abstract Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC50 value of 1.97 µM against M-NFS-60 cells and good GIT absorption with Pe value of 19.0 ± 1.1 × 10−6 cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.

    更新日期:2019-12-19
  • Design, synthesis and molecular modelling studies of some pyrazole derivatives as carbonic anhydrase inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-04
    Yazgı Dizdaroglu; Canan Albay; Tayfun Arslan; Abdulilah Ece; Emir A. Turkoglu; Asiye Efe; Murat Senturk; Claudiu T. Supuran; Deniz Ekinci

    Abstract In this study, newly synthesised compounds 6, 8, 10 and other compounds (1–5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1–10 showed effective inhibition profiles with KI values in the range of 5.13–16.9 nM for hCA I and of 11.77–67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.

    更新日期:2019-12-19
  • Screening of benzenesulfonamide in combination with chemically diverse fragments against carbonic anhydrase by differential scanning fluorimetry
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-04
    Mikhail Krasavin; Stanislav Kalinin; Sergey Zozulya; Anastasiia Gryniukova; Petro Borysko; Andrea Angeli; Claudiu T. Supuran

    Abstract The differential scanning fluorimetry (DSF) screening of 5.692 fragments in combination with benzenesulfonamide (BSA) against bovine carbonic anhydrase (bCA) delivered >100 hits that either caused, on their own, a significant thermal shift (ΔTm, °C) in the protein melting temperature or significantly influenced the thermal shift observed for BSA alone. Three hits based on 1,2,3-triazole moiety represent the periphery of the recently reported potent inhibitors of hCA II, IX and XII which were efficacious in vivo. Such a re-discovery of suitable BSA periphery essentially validates the new fragment-based approach to the discovery of future CAIs. Structures of other validated fragment hits are reported.

    更新日期:2019-12-19
  • Evaluation of the paraoxonase-1 kinetic parameters of the lactonase activity by nonlinear fit of progress curves
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-02
    Marko Goličnik; Aljoša Bavec

    Abstract Although paraoxonase-1 (PON1) activity has been demonstrated to be a reliable biomarker of various diseases, clinical studies have been based only on relative comparison of specific enzyme activities, which capture differences mainly due to (usually unknown) PON1 concentration. Hence, the aim of this report is to present for the first time the simple evaluation method for determining autonomous kinetic parameter of PON1 that could be also associated with polymorphic forms and diseases; i.e. the Michaelis constant which is enzyme concentration independent quantity. This alternative approach significantly reduces the number of experiments needed, and it yields the results with great accuracy.

    更新日期:2019-12-19
  • Aryl derivatives of 3H-1,2-benzoxathiepine 2,2-dioxide as carbonic anhydrase inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-02
    Aleksandrs Pustenko; Alessio Nocentini; Anastasija Balašova; Ahmed Alafeefy; Mikhail Krasavin; Raivis Žalubovskis; Claudiu T. Supuran

    Abstract A new series of homosulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) possessing various substitution patterns and moieties in the 7, 8 or 9 position of the heterocylic ring were prepared by original procedures and investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. The 8-substituted homosulfocoumarins were the most effective hCA IX/XII inhibitors followed by the 7-substituted derivatives, whereas the substitution pattern in position 9 led to less effective binders for the transmembrane, tumour-associated isoforms IX/XII. The cytosolic isoforms hCA I and II were not inhibited by these compounds, similar to the sulfocoumarins/coumarins investigated earlier. As hCA IX and XII are validated anti-tumour targets, with one sulphonamide (SLC-0111) in Phase Ib/II clinical trials, finding derivatives with better selectivity for inhibiting the tumour-associated isoforms over the cytosolic ones, as the homosulfocoumarins reported here, is of crucial importance.

    更新日期:2019-12-19
  • Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-02
    Mariantonia Logozzi; Davide Mizzoni; Clemente Capasso; Sonia Del Prete; Rossella Di Raimo; Mario Falchi; Daniela F. Angelini; Alessandro Sciarra; Martina Maggi; Claudiu T. Supuran; Stefano Fais

    Abstract Acidity, hypoxia and increased release of exosomes are severe phenotypes of tumours. The regulation of pH in tumours involves the interaction of several proteins, including the carbonic anhydrases which catalyze the formation of bicarbonate and protons from carbon dioxide and water. Among CA isoforms, CA IX is over-expressed in a large number of solid tumours, conferring to cancer cells a survival advantage in hypoxic and acidic microenvironment, but there isn’t evidence that CA IX expression could have a real clinical impact. Therefore, in this study for the first time the expression and activity of CA IX have been investigated in the plasmatic exosomes obtained from patients with prostate carcinoma (PCa). For this purpose, the study was performed through different methodological approaches, such as NTA, western blot analysis, enzyme activity assay, Nanoscale flow cytometry, ELISA, confocal microscopy. The results showed that PCa exosomes significantly overexpressed CA IX levels and related activity as compared to healthy donors. Furthermore, CA IX expression and activity were correlated to the exosome intraluminal pH, demonstrating for the first time that PCa exosomes are acidic. Our data suggest the possible use of the exosomal CA IX expression and activity as a biomarker of cancer progression in PCa.

    更新日期:2019-12-19
  • Carbonic anhydrase IX as a novel candidate in liquid biopsy
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-02
    Ozen Ozensoy Guler; Claudiu. T. Supuran; Clemente Capasso

    Abstract Among the diagnostic techniques for the identification of tumour biomarkers, the liquid biopsy is considered one that offers future research on precision diagnosis and treatment of tumours in a non-invasive manner. The approach consists of isolating tumor-derived components, such as circulating tumour cells (CTC), tumour cell-free DNA (ctDNA), and extracellular vesicles (EVs), from the patient peripheral blood fluids. These elements constitute a source of genomic and proteomic information for cancer treatment. Within the tumour-derived components of the body fluids, the enzyme indicated with the acronym CA IX and belonging to the superfamily of carbonic anhydrases (CA, EC 4.2.1.1) is a promising aspirant for checking tumours. CA IX is a transmembrane-CA isoform that is strongly overexpressed in many cancers being not much diffused in healthy tissues except the gastrointestinal tract. Here, it is summarised the role of CA IX as tumour-associated protein and its putative relationship in liquid biopsyfor diagnosing and monitoring cancer progression.

    更新日期:2019-12-19
  • Benzothiazole derivatives as anticancer agents
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-02
    Ali Irfan; Fozia Batool; Syeda Andleeb Zahra Naqvi; Amjad Islam; Sameh M. Osman; Alessio Nocentini; Siham A. Alissa; Claudiu T. Supuran

    Abstract Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The BTA scaffolds showed a crucial role in the inhibition of the metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over the last decade discloses the role of BTA derivatives mainly as anticancer agents. Such compounds are effective against various types of cancer cell lines through a multitude of mechanisms, some of which are poorly studied or understood. The inhibition of tumour associated CAs by BTA derivatives is on the other hand better investigated and such compounds may serve as anticancer leads for the development of agents effective against hypoxic tumours.

    更新日期:2019-12-19
  • Novel tacrine–benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s Disease
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-25
    Gaia Fancellu; Karam Chand; Daniel Tomás; Elisabetta Orlandini; Luca Piemontese; Diana F. Silva; Sandra M. Cardoso; Sílvia Chaves; M. Amélia Santos

    Abstract Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.

    更新日期:2019-12-19
  • Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-25
    Jing-Wei Liang; Ming-Yang Wang; Shan Wang; Shi-Long Li; Wan-Qiu Li; Fan-Hao Meng

    Abstract Cyclin-dependent kinase 2 (CDK2) is the family of Ser/Thr protein kinases that has emerged as a highly selective with low toxic cancer therapy target. A multistage virtual screening method combined by SVM, protein-ligand interaction fingerprints (PLIF) pharmacophore and docking was utilised for screening the CDK2 inhibitors. The evaluation of the validation set indicated that this method can be used to screen large chemical databases because it has a high hit-rate and enrichment factor (80.1% and 332.83 respectively). Six compounds were screened out from NCI, Enamine and Pubchem database. After molecular dynamics and binding free energy calculation, two compounds had great potential as novel CDK2 inhibitors and they also showed selective inhibition against CDK2 in the kinase activity assay.

    更新日期:2019-12-19
  • Identifying novel sphingosine kinase 1 inhibitors as therapeutics against breast cancer
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-22
    Faez Iqbal Khan; Dakun Lai; Razique Anwer; Iffat Azim; Mohd Kalim Ahmad Khan

    Abstract Sphingosine kinase 1 (SphK1) is a promising therapeutic target against several diseases including mammary cancer. The aim of present work is to identify a potent lead compound against breast cancer using ligand-based virtual screening, molecular docking, MD simulations, and the MMPBSA calculations. The LBVS in molecular and virtual libraries yielded 20,800 hits, which were reduced to 621 by several parameters of drug-likeness, lead-likeness, and PAINS. Furthermore, 55 compounds were selected by ADMET descriptors carried forward for molecular interaction studies with SphK1. The binding energy (ΔG) of three screened compounds namely ZINC06823429 (–11.36 kcal/mol), ZINC95421501 (–11.29 kcal/mol), and ZINC95421070 (–11.26 kcal/mol) exhibited stronger than standard drug PF-543 (–9.9 kcal/mol). Finally, it was observed that the ZINC06823429 binds tightly to catalytic site of SphK1 and remain stable during MD simulations. This study provides a significant understanding of SphK1 inhibitors that can be used in the development of potential therapeutics against breast cancer.

    更新日期:2019-12-19
  • Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-22
    Dong Jin Hong; Seung Hyun Jung; Jisook Kim; Danbee Jung; Young Gil Ahn; Kwee Hyun Suh; Kyung Hoon Min

    Abstract A novel series of thieno[3,2-d]pyrimidine derivatives were synthesised and their inhibitory effects against diacylglycerol acyltransferase 1 (DGAT-1) were assessed. cis-Isomer 17a showed potent and selective inhibitory activity against DGAT-1 in SF9 cells. In addition, 17a had an acceptable pharmacokinetic profile and accumulated mainly in the small intestine and liver. Oral administration of 17a led to a significant reduction in plasma triacylglycerol level during an oral lipid tolerance test (OLTT) in murine and canine models. Taken together, 17a is a high-quality candidate that deserves further investigation.

    更新日期:2019-12-19
  • Further validation of strecker-type α-aminonitriles as a new class of potent human carbonic anhydrase II inhibitors: hit expansion within the public domain using differential scanning fluorimetry leads to chemotype refinement
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-22
    Mikhail Krasavin; Stanislav Kalinin; Sergey Zozulya; Anastasia Griniukova; Petro Borysko; Andrea Angeli; Claudiu T. Supuran

    Abstract Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase (bCA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency.

    更新日期:2019-12-19
  • Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-22
    Wandong Liu; Caiyun Hou; Jiaming Li; Xiaodong Ma; Yanchun Zhang; Mengqi Hu; Yuanzheng Huang

    Abstract Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95 µM) and COX-2 (IC50=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.

    更新日期:2019-12-19
  • Towards discovery of new leishmanicidal scaffolds able to inhibit Leishmania GSK-3
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-22
    Paula Martínez de Iturrate; Victor Sebastián-Pérez; Montserrat Nácher-Vázquez; Catherine S. Tremper; Despina Smirlis; Julio Martín; Ana Martínez; Nuria E. Campillo; Luis Rivas; Carmen Gil

    Abstract Previous reports have validated the glycogen synthase kinase-3 (GSK-3) as a druggable target against the human protozoan parasite Leishmania. This prompted us to search for new leishmanicidal scaffolds as inhibitors of this enzyme from our in-house library of human GSK-3β inhibitors, as well as from the Leishbox collection of leishmanicidal compounds developed by GlaxoSmithKline. As a result, new leishmanicidal inhibitors acting on Leishmania GSK-3 at micromolar concentrations were found. These inhibitors belong to six different chemical classes (thiadiazolidindione, halomethylketone, maleimide, benzoimidazole, N-phenylpyrimidine-2-amine and oxadiazole). In addition, the binding mode of the most active compounds into Leishmania GSK-3 was approached using computational tools. On the whole, we have uncovered new chemical scaffolds with an appealing prospective in the development and use of Leishmania GSK-3 inhibitors against this infectious protozoan.

    更新日期:2019-12-19
  • Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-19
    Lingling Yang; Feng Chen; Cheng Gao; Jiabao Chen; Junyan Li; Siyan Liu; Yuanyuan Zhang; Zhouyu Wang; Shan Qian

    Abstract Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide–streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.

    更新日期:2019-12-19
  • Synthesis, biological evaluation, and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-14
    Guangcheng Wang; Wenjing Liu; Zipeng Gong; Yong Huang; Yongjun Li; Zhiyun Peng

    Abstract A series of naphthalene-chalcone derivatives (3a–3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42 ± 0.15 µM, as compared to cisplatin (IC50 = 15.24 ± 1.27 µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4 µM, which was slightly more active than the reference compound colchicine (IC50 = 10.6 µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.

    更新日期:2019-12-19
  • Inhibition of SARS-CoV 3CL protease by flavonoids
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-14
    Seri Jo; Suwon Kim; Dong Hae Shin; Mi-Sun Kim

    Abstract There were severe panics caused by Severe Acute Respiratory Syndrome (SARS) and Middle-East Respiratory Syndrome-Coronavirus. Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, we applied a flavonoid library to systematically probe inhibitory compounds against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymatic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking analysis indicated that S1, S2 and S3′ sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a critical role in objecting false positive or overestimated inhibitory activity of flavonoids. With the systematic analysis, the three flavonoids are suggested to be templates to design functionally improved inhibitors.

    更新日期:2019-12-19
  • Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-amide derivatives as anti-inflammatory agents
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-11
    Qing-Kun Shen; Guo-Hua Gong; Gao- Li; Mei- Jin; Li-Hua Cao; Zhe-Shan Quan

    Abstract To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13 C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.

    更新日期:2019-12-19
  • Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-07
    Jie Fu; Fengqi Bao; Min Gu; Jing Liu; Zhipeng Zhang; Jiaoli Ding; Sai-Sai Xie; Jinsong Ding

    Abstract A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 μM for eeAChE; IC50 = 0.16 μM for hAChE), and it was also the best inhibitor to AChE-induced Aβ aggregation (29.02% at 100 μM) and an efficient inhibitor to self-induced Aβ aggregation (30.67% at 25 μM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).

    更新日期:2019-12-19
  • Statins interfere with the attachment of S. cerevisiae mtDNA to the inner mitochondrial membrane
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-07
    Angela Cirigliano; Antonia Amelina; Beatrice Biferali; Alberto Macone; Chiara Mozzetta; Michele Maria Bianchi; Mattia Mori; Bruno Botta; Elah Pick; Rodolfo Negri; Teresa Rinaldi

    Abstract The 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme of the mevalonate pathway for the synthesis of cholesterol in mammals (ergosterol in fungi), is inhibited by statins, a class of cholesterol lowering drugs. Indeed, statins are in a wide medical use, yet statins treatment could induce side effects as hepatotoxicity and myopathy in patients. We used Saccharomyces cerevisiae as a model to investigate the effects of statins on mitochondria. We demonstrate that statins are active in S.cerevisiae by lowering the ergosterol content in cells and interfering with the attachment of mitochondrial DNA to the inner mitochondrial membrane. Experiments on murine myoblasts confirmed these results in mammals. We propose that the instability of mitochondrial DNA is an early indirect target of statins.

    更新日期:2019-12-19
  • Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-05
    Suresh Velnati; Alberto Massarotti; Annamaria Antona; Maria Talmon; Luigia Grazia Fresu; Alessandra Silvia Galetto; Daniela Capello; Alessandra Bertoni; Valentina Mercalli; Andrea Graziani; Gian Cesare Tron; Gianluca Baldanzi

    Abstract A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.

    更新日期:2019-12-19
  • Design, synthesis, in vitro inhibition and toxicological evaluation of human carbonic anhydrases I, II and IX inhibitors in 5-nitroimidazole series
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-05
    Ashok Aspatwar; Nanda Kumar Parvathaneni; Harlan Barker; Emilie Anduran; Claudiu T. Supuran; Ludwig Dubois; Philippe Lambin; Seppo Parkkila; Jean-Yves Winum

    Abstract With the aim to obtain novel compounds possessing both strong affinity against human carbonic anhydrases and low toxicity, we synthesised novel thiourea and sulphonamide derivatives 3, 4 and 10, and studied their in vitro inhibitory properties against human CA I, CA II and CA IX. We also evaluated the toxicity of these compounds using zebrafish larvae. Among the three compounds, derivative 4 showed efficient inhibition against hCA II (KI = 58.6 nM). Compound 10 showed moderate inhibition against hCA II (KI = 199.2 nM) and hCA IX (KI = 147.3 nM), whereas it inhibited hCA I less weakly at micromolar concentrations (KI = 6428.4 nM). All other inhibition constants for these compounds were in the submicromolar range. The toxicity evaluation studies showed no adverse effects on the zebrafish larvae. Our study suggests that these compounds are suitable for further preclinical characterisation as potential inhibitors of hCA I, II and IX.

    更新日期:2019-12-19
  • Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-11-04
    Jian Liu; Yu Wen; Lina Gao; Liang Gao; Fengjun He; Jingxian Zhou; Junwei Wang; Rupeng Dai; Xiaojing Chen; Di Kang; Lihong Hu

    Abstract Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.

    更新日期:2019-12-19
  • Phosphonamidates are the first phosphorus-based zinc binding motif to show inhibition of β-class carbonic anhydrases from bacteria, fungi, and protozoa
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-10-30
    Siham A. Alissa; Hanan A. Alghulikah; Zeid A. Alothman; Sameh M. Osman; Sonia Del Prete; Clemente Capasso; Alessio Nocentini; Claudiu T. Supuran

    Abstract A primary strategy to combat antimicrobial resistance is the identification of novel therapeutic targets and anti-infectives with alternative mechanisms of action. The inhibition of the metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) from pathogens (bacteria, fungi, and protozoa) was shown to produce an impairment of the microorganism growth and virulence. As phosphonamidates have been recently validated as human α-CA inhibitors (CAIs) and no phosphorus-based zinc-binding group have been assessed to date against β-class CAs, herein we report an inhibition study with this class of compounds against β-CAs from pathogenic bacteria, fungi, and protozoa. Our data suggest that phosphonamidates are among the CAIs with the best selectivity for β-class over human isozymes, making them interesting leads for the development of new anti-infectives.

    更新日期:2019-12-19
  • In vitro inhibition of Mycobacterium tuberculosis β-carbonic anhydrase 3 with Mono- and dithiocarbamates and evaluation of their toxicity using zebrafish developing embryos
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-10-30
    Ashok Aspatwar; Milka Hammaren; Mataleena Parikka; Seppo Parkkila; Fabrizio Carta; Murat Bozdag; Daniela Vullo; Claudiu T. Supuran

    Abstract We investigated a panel of 14 compounds belonging to the monothiocarbamate (MTC) and dithiocarbamate (DTC) series against the β-carbonic anhydrase 3 (β-CA3) of Mycobacterium tuberculosis (Mtb). We also evaluated all compounds for toxicity using 1–5-day post fertilisation zebrafish embryos. 11 out of the 14 investigated derivatives showed effective nanomolar or submicromolar in vitro inhibition against the β-CA3 (KIs 2.4–812.0 nM), and among them four DTCs of the series (8–10 and 12) showed very significant inhibition potencies with KIs between 2.4 and 43 nM. Out of 14 compounds screened for toxicity and safety 9 compounds showed no adverse phenotypic effects on the developing zebrafish larvae at five days of exposure. The results of in vitro inhibition and the toxicological evaluation of our study suggest that 5 compounds are suitable for further in vivo preclinical characterisation in zebrafish model.

    更新日期:2019-12-19
  • Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-10-28
    Yuanying Fang; Shaokun Zhang; Min Li; Lijuan Xiong; Liangxing Tu; Saisai Xie; Yi Jin; Yanhua Liu; Zunhua Yang; Ronghua Liu

    Abstract GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0–2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).

    更新日期:2019-12-19
  • Enzyme-assisted modification of flavonoids from Matricaria chamomilla: antioxidant activity and inhibitory effect on digestive enzymes
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-10-28
    Elida Paula Dini de Franco; Fabiano Jares Contesini; Bianca Lima da Silva; Anna Maria Alves de Piloto Fernandes; Camila Wielewski Leme; João Pedro Gonçalves Cirino; Paula Renata Bueno Campos; Patrícia de Oliveira Carvalho

    Abstract Matricaria chamomilla L. contains antioxidant flavonoids that can have their bioactivity enhanced by enzymatic hydrolysis of specific glycosyl groups. This study implements an untargeted metabolomics approach based on ultra-performance liquid chromatography coupled with electrospray ionisation quadrupole time-of-flight mass spectrometry technique operating in MSE mode (UPLC-QTOF-MSE) and spectrophotometric analysis of chamomile aqueous infusions, before and after hydrolysis by hesperidinase and β-galactosidase. Several phenolic compounds were altered in the enzymatically treated infusion, with the majority being flavonoid derivatives of apigenin, esculetin, and quercetin. Although enzymatically modifying the infusion only led to a small increase in antioxidant activity (DPPH• method), its inhibitory effect on pancreatic lipase was of particular interest. The enzymatically treated infusion exhibited a greater inhibitory effect (EC50 of 35.6 µM) than unmodified infusion and kinetic analysis suggested mixed inhibition of pancreatic lipase. These results are of great relevance due to the potential of enzymatically treated functional foods in human health.

    更新日期:2019-12-19
  • Synthesis of thiazolidin-4-ones and thiazinan-4-ones from 1-(2-aminoethyl)pyrrolidine as acetylcholinesterase inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-10-23
    Adriana M. das Neves; Gabriele A. Berwaldt; Cinara T. Avila; Taís B. Goulart; Bruna C. Moreira; Taís P. Ferreira; Mayara S. P. Soares; Nathalia S. Pedra; Luiza Spohr; Anita A. A. dE Souza; Roselia M. Spanevello; Wilson Cunico

    Abstract The present study describes the synthesis of a novel series of thiazolidin-4-one and thiazinan-4-one using 1-(2-aminoethyl)pyrrolidine as amine precursor. All compounds were synthesised by one-pot three component cyclocondensation reaction from the amine, a substituted benzaldehyde and a mercaptocarboxylic acid. The compounds were obtained in moderate to good yields and were identified and characterised by 1H, 13 C, 2 D NMR and GC/MS techniques. The compounds also were screened for their in vitro acetylcholinesterase (AChE) activity in hippocampus and cerebral cortex on Wistar rats. The six most potent compounds have been investigated for their cytotoxicity by cell viability assay of astrocyte primary culture, an important cell of central nervous system. We highlighted two compounds (6a and 6k) that had the lowest IC50 in hippocampus (5.20 and 4.46 µM) and cerebral cortex (7.40 and 6.83 µM). These preliminary and important results could be considered a starting point for the development of new AChE inhibitory agents.

    更新日期:2019-12-19
  • Synthesis, activity and mechanism of alkoxy-, carbamato-, sulfonamido-, thioureido-, and ureido-derivatives of 2,4,5-trimethylpyridin-3-ol against inflammatory bowel disease
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-10-16
    Chhabi Lal Chaudhary; Pallavi Gurung; Seoul Jang; Suhrid Banskota; Tae-Gyu Nam; Jung-Ae Kim; Byeong-Seon Jeong

    Abstract Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10, and TGF-β), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.

    更新日期:2019-12-19
  • A structure-based approach towards the identification of novel antichagasic compounds: Trypanosoma cruzi carbonic anhydrase inhibitors
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-10-16
    Manuel A. Llanos; María L. Sbaraglini; María L. Villalba; María D. Ruiz; Carolina Carrillo; Catalina Alba Soto; Alan Talevi; Andrea Angeli; Seppo Parkkila; Claudiu T. Supuran; Luciana Gavernet

    Abstract Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.

    更新日期:2019-12-19
  • In vitro anticancer potentiality and molecular modelling study of novel amino acid derivatives based on N1,N3-bis-(1-hydrazinyl-1-oxopropan-2-yl) isophthalamide
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-07-09
    Asmaa F. Kassem; Gaber O. Moustafa; Eman S. Nossier; Hemat S. Khalaf; Marwa M. Mounier; Suliman A. Al-Yousef; Sabry Y. Mahmoud

    Abstract A series of N1,N3-bis (1-oxopropan-2-yl) isophthalamide-based derivatives 4–16 were prepared and their structures were confirmed by different spectral tools. The cytotoxic potentiality of novel compounds 4–16 was assessed by the MTT assay method on colon, lung and breast tumour cell lines. Compound 5 gave the most significant specificity anticancer activity with safety response on normal cell lines. In vitro enzyme assay and several apoptotic parameters were examined to elucidate the mode of action of compound 5. Molecular docking studies also were simulated to put insight and give better understanding to its structural features.

    更新日期:2019-12-19
  • 1-(Piperidin-3-yl)thymine amides as inhibitors of M. tuberculosis thymidylate kinase
    J. Enzyme Inhib. Med. Chem. (IF 4.027) Pub Date : 2019-12-11
    Yanlin Jian, Martijn D. P. Risseeuw, Mathy Froeyen, Lijun Song, Davie Cappoen, Paul Cos, Hélène Munier-Lehmann, Serge van Calenbergh

    Abstract A series of readily accessible 1-(piperidin-3-yl)thymine amides was designed, synthesised and evaluated as Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors. In line with the modelling results, most inhibitors showed reasonable MtbTMPK inhibitory activity. Compounds 4b and 4i were slightly more potent than the parent compound 3. Moreover, contrary to the latter, amide analogue 4g was active against the avirulent M. tuberculosis H37Ra strain (MIC50=35 µM). This finding opens avenues for future modifications.

    更新日期:2019-12-11
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