| 1. |
- Aneja, Babita, et al.
(author)
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Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis
- 2019
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 163, s. 840-852
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Journal article (peer-reviewed)abstract
- Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 mu M, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.
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| 2. |
- Belfrage, Anna Karin, 1977-, et al.
(author)
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Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
- 2018
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 148, s. 453-464
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Journal article (peer-reviewed)abstract
- Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).
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| 3. |
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| 4. |
- Caraballo, Remi, et al.
(author)
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Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo
- 2015
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 103, s. 191-209
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Journal article (peer-reviewed)abstract
- The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.
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| 5. |
- Chistov, Alexey A., et al.
(author)
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Compounds based on 5-(perylen-3-ylethynyl)uracil scaffold: High activity against tick-borne encephalitis virus and non-specific activity against enterovirus A
- 2019
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 171, s. 93-103
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Journal article (peer-reviewed)abstract
- Rigid amphipathic fusion inhibitors (RAFIs) are potent antivirals based on a perylene core linked with a nucleoside moiety. Sugar-free analogues of RAFIs, 5-(perylen-3-ylethynyl)uracil-1-acetic acid 1 and its amides 2, were synthesized using combined protection group strategy. Compounds 1 and 2 appeared to have low toxicity on porcine embryo kidney (PEK) or rhabdomiosarcoma (RD) cells together with remarkable activity against enveloped tick-borne encephalitis virus (TBEV): EC 50 values vary from 0.077 μM to subnanomolar range. Surprisingly, 3-pivaloyloxymethyl (Pom) protected precursors 7 and 8 showed even more pronounced activity. All the compounds showed no activity against several non-enveloped enteroviruses, except 4-hydroxybutylamides 2d,g, which inhibited the reproduction of enterovirus A71 with EC 50 50–100 μM, with a non-specific mode of action. The results suggest that the carbohydrate moiety of RAFI nucleosides does not play a crucial role in their antiviral action, and biological activity of the 5-(perylen-3-ylethynyl)uracil scaffold can be effectively modulated by substituents in positions 1 and 3. The high antiviral activity of these new compounds, coupled with low toxicity advocate their potential role in antiviral therapy.
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| 6. |
- Deplano, Alessandro, et al.
(author)
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Novel propanamides as fatty acid amide hydrolase inhibitors
- 2017
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 136, s. 523-542
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Journal article (peer-reviewed)abstract
- Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroary1)-2-(4(2-(trifluoromethyl)pyridin-4-y0amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or noncompetitive (TPA14) inhibition modes.
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| 7. |
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| 8. |
- Ekblad, Torun, et al.
(author)
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Towards small molecule inhibitors of mono-ADP-ribosyltransferases
- 2015
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 95, s. 546-551
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Journal article (peer-reviewed)abstract
- Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.
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| 9. |
- García-Gallego, Sandra, et al.
(author)
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HIV-1 antiviral behavior of anionic PPI metallo-dendrimers with EDA core
- 2015
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 98, s. 139-148
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Journal article (peer-reviewed)abstract
- The development of novel strategies to prevent HIV-1 infection is of outstanding relevance. Metal complexes of Cu2+, Ni2+, Co2+ and Zn2+ derived from sulfonated and carboxylated poly(propylene imine) dendrimers with ethylenediamine core were evaluated as tunable antiviral agents against HIV-1. After demonstrating their biocompatibility, specific trends in the antiviral properties were found, related to both the dendritic scaffold (peripheral group, generation) and the bound metal ions (sort, amount). In HEC-1A and VK-2 cell lines, as model of the first barrier against HIV-1 infection, a high preventive inhibitory action was found, which also avoided virus internalization inside cells and inhibited both CCR5 and CXCR4 HIV-1 strains. In peripheral blood mononuclear cells (PBMC), as model of the second barrier, a dual preventive and therapeutic behavior was observed. A rational design of such metallodendrimers opens new avenues for the production of versatile and efficient treatments against HIV-1 infection.
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| 10. |
- Keri, Rangappa S., et al.
(author)
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An overview of benzo[b]thiophene-based medicinal chemistry
- 2017
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In: European Journal of Medicinal Chemistry. - : Elsevier Masson SAS. - 0223-5234 .- 1768-3254. ; 138, s. 1002-1033
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Research review (peer-reviewed)abstract
- Among sulfur containing heterocycles, benzothiophene and its derivatives are at the focus as these candidates have structural similarities with active compounds to develop new potent lead molecules in drug design. Benzo[b]thiophene scaffold is one of the privileged structures in drug discovery as this core exhibits various biological activities allowing them to act as anti-microbial, anti-cancer, anti-inflammatory, anti-oxidant, anti-tubercular, anti-diabetic, anti-convulsant agents and many more. Further, numerous benzothiophene-based compounds as clinical drugs have been extensively used to treat various types of diseases with high therapeutic potency, which has led to their extensive developments. Due to the wide range of biological activities of benzothiophene, their structure activity relationships (SAR) have generated interest among medicinal chemists, and this has culminated in the discovery of several lead molecules against numerous diseases. The present review is endeavoring to highlight the progress in the various pharmacological activities of benzo[b]thiophene derivatives. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic benzothiophene-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes. Also, SAR studies that highlight the chemical groups responsible for evoking the potential activities of benzothiophene derivatives are studied and compared.
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