当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays.

Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays.

Abstract：

:Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Parodi A,Righetti G,Pesce E,Salis A,Tasso B,Urbinati C,Tomati V,Damonte G,Rusnati M,Pedemonte N,Cichero E,Millo E

doi

10.1016/j.ejmech.2020.112833

subject

Has Abstract

pub_date

2020-12-15 00:00:00

pages

112833

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30805-9

journal_volume

208

pub_type

杂志文章

相关文献

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Conformational studies of chiral D-Lys-PNA and achiral PNA system in binding with DNA or RNA through a molecular dynamics approach.

    abstract：:The growing interest in peptide nucleic acid (PNA) oligomers has led to the development of a very wide variety of PNA derivatives. Among others, the introduction of charged chiral groups on a PNA oligomer has proven effective in improving DNA binding ability, complexation direction and cellular uptake. In particular, ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.08.015

    authors： Autiero I,Saviano M,Langella E

    更新日期：2015-02-16 00:00:00

  • Synthesis and biological screening of 2'-aryl/benzyl-2-aryl-4-methyl-4',5-bithiazolyls as possible anti-tubercular and antimicrobial agents.

    abstract：:A series of 2'-aryl/benzyl-2-aryl-4-methyl-4',5-bithiazolyl derivatives, 25-64 were synthesized and evaluated for inhibitory activity against Mycobacterium smegmatis MC(2) 155 strain and antimicrobial activities against four pathogenic bacteria Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Proteus vul...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.03.016

    authors： Abhale YK,Sasane AV,Chavan AP,Deshmukh KK,Kotapalli SS,Ummanni R,Sayyad SF,Mhaske PC

    更新日期：2015-04-13 00:00:00

  • Dimeric aryl-substituted imidazoles may inhibit ALT cancer by targeting the multimeric G-quadruplex in telomere.

    abstract：:In 10-15% of cancers, telomere maintenance is provided by a telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making telomerase inhibitors ineffective on these cancers. Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or d...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.111891

    authors： Hu MH,Lin XT,Liu B,Tan JH

    更新日期：2020-01-15 00:00:00

  • Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.

    abstract：:Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.05.046

    authors： Roselli M,Carocci A,Budriesi R,Micucci M,Toma M,Di Cesare Mannelli L,Lovece A,Catalano A,Cavalluzzi MM,Bruno C,De Palma A,Contino M,Perrone MG,Colabufo NA,Chiarini A,Franchini C,Ghelardini C,Habtemariam S,Lentini G

    更新日期：2016-10-04 00:00:00

  • Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols.

    abstract：:Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N-trans-cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N-acylation carried out in a two-phase system. The substances were tested i...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.10.051

    authors： Gunia-Krzyżak A,Żesławska E,Słoczyńska K,Koczurkiewicz P,Nitek W,Żelaszczyk D,Szkaradek N,Waszkielewicz AM,Pękala E,Marona H

    更新日期：2016-01-01 00:00:00

  • New imidazolidineiminothione derivatives: Synthesis, spectral characterization and evaluation of antitumor, antiviral, antibacterial and antifungal activities.

    abstract：:A series of new imidazolidineiminothione derivatives with various halogenated and alkylated aromatic substituents at N-(1) and at N-(3) was synthesized through the reaction of N-arylcyanothioformamides with arylisocyanate derivatives. Structure of imidazolidineiminothione derivatives were established based on spectros...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.06.051

    authors： Moussa Z,El-Sharief MAMS,Abbas SY

    更新日期：2016-10-21 00:00:00

  • Base promoted synthesis of novel indole-dithiocarbamate compounds as potential anti-inflammatory therapeutic agents for treatment of acute lung injury.

    abstract：:An efficient protocol for highly chemoselective introduction of dithiocarbamate groups to nitrogen position of indoles with bis(dialkylaminethiocarbonyl)disulfides was achieved by employing t-BuOK as a promoter. Based on this methodology, twenty nine novel indole-dithiocarbamate compounds were prepared in moderate to ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.03.022

    authors： Song Z,Zhou Y,Zhang W,Zhan L,Yu Y,Chen Y,Jia W,Liu Z,Qian J,Zhang Y,Li C,Liang G

    更新日期：2019-06-01 00:00:00

  • Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency.

    abstract：:The term varicose vein refers to the twisted and swollen vein visible under the skin surface which occurs most commonly in the leg. Epidemiological studies report a varying percentage of incidences from 2 to 56% in men and <1-60% in women. Venous insufficiency is most often caused by the damage to the valves and walls...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2019.04.075

    authors： Lichota A,Gwozdzinski L,Gwozdzinski K

    更新日期：2019-08-15 00:00:00

  • Synthesis of indazole motifs and their medicinal importance: an overview.

    abstract：:Indazoles is an important class of heterocyclic compounds having a wide range of biological and pharmaceutical applications. There is enormous potential in the synthesis of novel heterocyclic systems to be used as building blocks for the next generation of pharmaceuticals as anti-bacterial, anti-depressant and anti-in...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2014.11.029

    authors： Gaikwad DD,Chapolikar AD,Devkate CG,Warad KD,Tayade AP,Pawar RP,Domb AJ

    更新日期：2015-01-27 00:00:00

  • Fluorine-substituted tetracationic ABAB-phthalocyanines for efficient photodynamic inactivation of Gram-positive and Gram-negative bacteria.

    abstract：:Herein, we report the synthesis and characterization of new amphiphilic phthalocyanines (Pcs), the study of their singlet oxygen generation capabilities, and biological assays to determine their potential as photosensitizers for photodynamic inactivation of bacteria. In particular, Pcs with an ABAB geometry (where A a...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.111957

    authors： Revuelta-Maza MÁ,González-Jiménez P,Hally C,Agut M,Nonell S,de la Torre G,Torres T

    更新日期：2020-02-01 00:00:00

  • Design, synthesis and evaluation of diarylpiperazine derivatives as potent anti-tubercular agents.

    abstract：:Molecular hybridization is an emerging approach to design novel ligands by combination of two or more pharmacophoric subunits of known bioactive compounds. In the present study, we have designed a novel series of diarylpiperazine analogues, synthesized, characterized using FTIR, (1)H NMR, Mass, Elemental analysis and ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2015.10.024

    authors： Penta A,Franzblau S,Wan B,Murugesan S

    更新日期：2015-11-13 00:00:00

  • Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity.

    abstract：:In an attempt to develop effective and safe anticancer agents, we designed, synthesized and examined 23 novel quinacrine (QC) derivatives by combining the 9-aminoacridine scaffold and the [1,3]thiazinan-4-ones group. Most of these hybrids showed strong anticancer activities, among which 3-(3-(6-chloro-2-methoxyacridin...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2017.11.097

    authors： Solomon VR,Pundir S,Le HT,Lee H

    更新日期：2018-01-01 00:00:00

  • InCl3 mediated heteroarylation of indoles and their derivatization via CH activation strategy: Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis.

    abstract：:A new class of PDE4 inhibitors were designed and synthesized via the InCl3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.04.020

    authors： Sunke R,Bankala R,Thirupataiah B,Ramarao EVVS,Kumar JS,Doss HM,Medishetti R,Kulkarni P,Kapavarapu RK,Rasool M,Mudgal J,Mathew JE,Shenoy GG,Parsa KVL,Pal M

    更新日期：2019-07-15 00:00:00

  • Preparation of 4-azaindole and 7-azaindole dimers with a bisalkoxyalkyl spacer in order to preferentially target melatonin MT1 receptors over melatonin MT2 receptors.

    abstract：:Several 4-azaindole and 7-azaindole dimer analogues of melatonin with a bisalkoxyalkyl spacer between the position 5 of each heterocycle were synthetized. Our aim was to investigate the influence of the spacers length on the selectivity of such compounds for the MT(1) receptors over the MT(2) receptors. Our results su...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2004.03.005

    authors： Larraya C,Guillard J,Renard P,Audinot V,Boutin JA,Delagrange P,Bennejean C,Viaud-Massuard MC

    更新日期：2004-06-01 00:00:00

  • Alkoxyphenylthiazoles with broad-spectrum activity against multidrug-resistant gram-positive bacterial pathogens.

    abstract：:With the continued rise of antibiotic resistance and reduced susceptibility to almost all front-line antibiotics, multidrug-resistant Gram-positive bacterial infections represent an incessant threat to healthcare providers. This study presents a new series of phenylthiazole compounds where two active moieties were com...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2018.04.049

    authors： ElAwamy M,Mohammad H,Hussien A,Abutaleb NS,Hagras M,Serya RAT,Taher AT,Abouzid KA,Seleem MN,Mayhoub AS

    更新日期：2018-05-25 00:00:00

  • Synthesis and biological evaluation of novel 3,4-diaryl-1,2,5-selenadiazol analogues of combretastatin A-4.

    abstract：:A set of novel selenium-containing heterocyclic analogues of combretastatin A-4 (CA-4) have been designed and synthesised using a rigid 1,2,5-selenadiazole as a linker to fix the cis-orientation of ring-A and ring-B. All of the target compounds were evaluated for their in vitro anti-proliferative activities. Among the...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.09.046

    authors： Guan Q,Yang F,Guo D,Xu J,Jiang M,Liu C,Bao K,Wu Y,Zhang W

    更新日期：2014-11-24 00:00:00

  • Antimycobacterial activity of natural products and synthetic agents: pyrrolodiquinolines and vermelhotin as anti-tubercular leads against clinical multidrug resistant isolates of Mycobacterium tuberculosis.

    abstract：:Various classes of natural products and synthetic compounds were tested against reference strains and clinical multidrug resistant isolates of Mycobacterium tuberculosis. Vermelhotin (19), a natural tetramic acid from fungi, was the most active toward clinical MDR TB isolates (MIC 1.5-12.5 μg/mL). Synthetic compounds ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.10.026

    authors： Ganihigama DU,Sureram S,Sangher S,Hongmanee P,Aree T,Mahidol C,Ruchirawat S,Kittakoop P

    更新日期：2015-01-07 00:00:00

  • A "natural" approach: synthesis and cytoxicity of monodesmosidic glycyrrhetinic acid glycosides.

    abstract：:Several pentacyclic triterpenoic acids have shown noteworthy antitumor activity, among them betulinic acid as well as oleanolic acid and derivatives thereof. Glycyrrhetinic acid (GA) exhibits some cytotoxic activity albeit this compound is not as active as betulinic acid, but GA came in the focus of scientific interes...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2013.11.024

    authors： Schwarz S,Siewert B,Xavier NM,Jesus AR,Rauter AP,Csuk R

    更新日期：2014-01-24 00:00:00

  • The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: a concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives.

    abstract：:A convenient and facile synthesis, in silico docking studies and in vitro biological evaluation of N-substituted 5-butylimidazole derivatives as potent Angiotensin II (ANG II) receptor type 1 (AT1) blockers (ARBs) has been reported in the current study. Our efforts have been directed towards the development of an effi...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2012.07.040

    authors： Agelis G,Resvani A,Durdagi S,Spyridaki K,Tůmová T,Slaninová J,Giannopoulos P,Vlahakos D,Liapakis G,Mavromoustakos T,Matsoukas J

    更新日期：2012-09-01 00:00:00

  • Current research on hyaluronic acid-drug bioconjugates.

    abstract：:Hyaluronic acid (HA) is a mucopolysaccharide acid composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. Based on numerous characteristics such as viscoelastic properties, water-binding ability, biocompatibility and non-immunogenicity, HA has been approved by FDA for biological and m...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2014.08.067

    authors： Zhang H,Huang S,Yang X,Zhai G

    更新日期：2014-10-30 00:00:00

  • Mannich bases in medicinal chemistry and drug design.

    abstract：:The biological activity of Mannich bases, a structurally heterogeneous class of chemical compounds that are generated from various substrates through the introduction of an aminomethyl function by means of the Mannich reaction, is surveyed, with emphasis on the relationship between structure and biological activity. T...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.ejmech.2014.10.076

    authors： Roman G

    更新日期：2015-01-07 00:00:00

  • Quinolone antibiotic derivatives as new selective Axl kinase inhibitors.

    abstract：:Axl is a new promising molecular target for antineoplastic therapies. A series of quinolone antibiotic derivatives were designed and synthesized as new selective Axl inhibitors. One of the most promising compound 8i bound tightly to Axl with a Kd value of 1.1 nM, and inhibited its kinase activity with an IC50 value of...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.01.065

    authors： Tan L,Zhang Z,Gao D,Chan S,Luo J,Tu ZC,Zhang ZM,Ding K,Ren X,Lu X

    更新日期：2019-03-15 00:00:00

  • Novel pentacyclic triterpenes exhibiting strong neuroprotective activity in SH-SY5Y cells in salsolinol- and glutamate-induced neurodegeneration models.

    abstract：:Novel triterpene derivatives were prepared and evaluated in salsolinol (SAL)- and glutamate (Glu)-induced models of neurodegeneration in neuron-like SH-SY5Y cells. Among the tested compounds, betulin triazole 4 bearing a tetraacetyl-β-d-glucose substituent showed a highly potent neuroprotective effect. Further studies...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2021.113168

    authors： Gonzalez G,Hodoň J,Kazakova A,D'Acunto CW,Kaňovský P,Urban M,Strnad M

    更新日期：2021-01-16 00:00:00

  • Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors.

    abstract：:PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2019.06.021

    authors： Yan G,Pu C,Lan S,Zhong X,Zhou M,Hou X,Yang J,Shan H,Zhao L,Li R

    更新日期：2019-09-15 00:00:00

  • 6-Amino-2,4,5-trimethylpyridin-3-ols: a new general synthetic route and antiangiogenic activity.

    abstract：:A new synthetic strategy for preparation of a wide range of 6-amino-2,4,5-trimethylpyridin-3-ols from pyridoxine·HCl via a six-step sequence has been developed. This approach features an introduction of various amino groups to C(6)-position of 3-benzyloxy-6-bromo-2,4,5-trimethylpyridine (13), a key intermediate, by a ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.03.045

    authors： Kim DG,Kang Y,Lee H,Lee EK,Nam TG,Kim JA,Jeong BS

    更新日期：2014-05-06 00:00:00

  • 2-Azetidinone derivatives: design, synthesis and evaluation of cholesterol absorption inhibitors.

    abstract：:Fourteen new derivatives of the 2-azetidinone cholesterol absorption inhibitors have been synthesized, and three of them were enantiomerically pure. All the new compounds were evaluated for their activity to inhibit cholesterol absorption in rats, and most of them showed comparable effects in lowering the levels of to...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2008.09.033

    authors： Wang Y,Zhang H,Huang W,Kong J,Zhou J,Zhang B

    更新日期：2009-04-01 00:00:00

  • The enhancement of neutron irradiation of HeLa-S cervix carcinoma cells by cell-nucleus-addressed deca-p-boronophenylalanine.

    abstract：:Boron neutron capture therapy (BNCT) is an experimental treatment modality which depends on a sufficient cellular uptake of Boron ((10)B) followed by an exposure to a thermal neutron beam from a nuclear reactor. High energetic particles (4He and 7Li) are created during the neutron capture reaction and produce DNA dama...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0223-5234(03)00088-6

    authors： Braun K,Wolber G,Waldeck W,Pipkorn R,Jenne J,Rastert R,Ehemann V,Eisenmenger A,Corban-Wilhelm H,Braun I,Heckl S,Debus J

    更新日期：2003-06-01 00:00:00

  • Development of antimycobacterial tetrahydrothieno[2,3-c]pyridine-3-carboxamides and hexahydrocycloocta[b]thiophene-3-carboxamides: Molecular modification from known antimycobacterial lead.

    abstract：:Twenty derivatives of 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide and ten of 2-substituted 4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-3-carboxamide were synthesized by molecular modification of a known antimycobacterial molecule. Compounds were evaluated in vitro against Mycobacterium tuber...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2014.02.028

    authors： Nallangi R,Samala G,Sridevi JP,Yogeeswari P,Sriram D

    更新日期：2014-04-09 00:00:00

  • Structural variations of piritrexim, a lipophilic inhibitor of human dihydrofolate reductase: synthesis, antitumor activity and molecular modeling investigations.

    abstract：:Piritrexim (PTX) (1), a lipophilic inhibitor of the human dihydrofolate reductase, has been evaluated as an anticancer agent. The synthesis of four structural variations (2-5) of PTX is reported. The PTX analogues 2-5 were obtained by reaction of suitable C3-building blocks with pyrimidine-2,4,6-triamine (14) or with ...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2004.09.001

    authors： Zink M,Lanig H,Troschütz R

    更新日期：2004-12-01 00:00:00

  • The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors.

    abstract：:A novel series of HIV-1 integrase strand transfer inhibitors were designed using the venerable two-metal binding pharmacophore model and incorporating structural elements from two different literature scaffolds. This manuscript describes a number of 8-hydroxyquinoline tetracyclic lactams with exceptional antiviral act...

    journal_title：European journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.ejmech.2016.03.038

    authors： Velthuisen EJ,Johns BA,Temelkoff DP,Brown KW,Danehower SC

    更新日期：2016-07-19 00:00:00