5321-49-3Relevant articles and documents
Rational modifications, synthesis and biological evaluation of new potential antivirals for RSV designed to target the M2-1 protein
Bassetto, Marcella,Benato, Sara,Brancale, Andrea,Ferla, Salvatore,Jochmans, Dirk,Manganaro, Roberto,Neyts, Johan,Paulissen, Jasmine
supporting information, (2020/03/13)
Respiratory syncytial virus (RSV) is the main cause of lower respiratory tract diseases in infants and young children, with potentially serious and fatal consequences associated with severe infections. Despite extensive research efforts invested in the identification of therapeutic measures, no vaccine is currently available, while treatment options are limited to ribavirin and palivizumab, which both present significant limitations. While clinical and pre-clinical candidates mainly target the viral fusion protein, the nucleocapsid protein or the viral polymerase, our focus has been the identification of new antiviral compounds targeting the viral M2-1 protein, thanks to the presence of a zinc-ejecting group in their chemical structure. Starting from an anti-RSV hit we had previously identified with an in silico structure-based approach, we have designed, synthesised and evaluated a new series of dithiocarbamate analogues, with which we have explored the antiviral activity of this scaffold. The findings presented in this work may provide the basis for the identification of a new antiviral lead to treat RSV infections.
Development of 2-amino-4-phenylthiazole analogues to disrupt myeloid differentiation factor 88 and prevent inflammatory responses in acute lung injury
Chen, Lingfeng,Chen, Hongjin,Chen, Pengqin,Zhang, Wenxin,Wu, Chao,Sun, Chuchu,Luo, Wu,Zheng, Lulu,Liu, Zhiguo,Liang, Guang
, p. 22 - 38 (2018/10/23)
Myeloid differentiation primary response protein 88 (MyD88), an essential adapter protein used by toll-like receptors (TLR), is a promising target molecule for the treatment of respiratory inflammatory diseases. Previous studies explored the activities of novel 2-amino-4-phenylthiazole analogue (6) in inflammation-induced cancer, and identified the analogue as an inhibitor of MyD88 toll/interleukin-1 receptor (TIR) homology domain dimerization. Here, we describe the synthesis of 47 new analogues by modifying different sites on this lead compound and assessed their anti-inflammatory activities in lipopolysaccharide-induced mouse primary peritoneal macrophages (MPMs). The most promising compound, 15d, was found to effectively interact with MyD88 protein and prevented formation of the MyD88 homodimeric complex. Furthermore, 15d showed in vivo anti-inflammatory activity in LPS-caused model of acute lung injury. This work provides new candidates as MyD88 inhibitors to combat inflammation diseases.
Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors
Paudel, Suresh,Acharya, Srijan,Yoon, Goo,Kim, Kyeong-Man,Cheon, Seung Hoon
, p. 2266 - 2276 (2017/03/23)
Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50?=?158.7?nM for 5-HT, 99?nM for NE and 97.5?nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.
Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation
Panek, Dawid,Wi?ckowska, Anna,Wichur, Tomasz,Bajda, Marek,Godyń, Justyna,Jończyk, Jakub,Mika, Kamil,Janockova, Jana,Soukup, Ondrej,Knez, Damijan,Korabecny, Jan,Gobec, Stanislav,Malawska, Barbara
, p. 676 - 695 (2016/10/13)
The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In?vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50values ranging from 0.83?μM to 19.18?μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50?μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50?=?0.83?μM) and inhibitory activity against hBACE1 (33.61% at 50?μM). Compound 52 is a selective AChE inhibitor (IC50 AChE?=?6.47?μM) with BACE1 inhibitory activity (26.3% at 50?μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10?μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2
Hankosky, Emily R.,Joolakanti, Shyam R.,Nickell, Justin R.,Janganati, Venumadhav,Dwoskin, Linda P.,Crooks, Peter A.
, p. 5467 - 5472 (2017/11/21)
A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [3H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [3H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [3H]DA uptake at VMAT2, Ki changes in the nanomolar range (Ki = 0.014–0.073 μM). Compound 15d exhibited the highest affinity (Ki = 0.014 μM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (Ki = 0.073 μM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2.
Flavonoid derivatives as selective ABCC1 modulators: Synthesis and functional characterization
Obreque-Balboa, José Esteban,Sun, Qiu,Bernhardt, Günther,K?nig, Burkhard,Buschauer, Armin
supporting information, p. 124 - 133 (2016/01/20)
A series of chromones, bearing substituted amino groups or N-substituted carboxamide moieties in position 2, was synthesized and characterized in cellular assays for modulation of the ABC transporters ABCC1 (MDCKII-MRP1 cells), ABCB1 (Kb-V1 cells) and ABCG2 (MCF-7/Topo cells). The most potent ABCC1 modulators identified among these flavonoid-type compounds were comparable to the reference compound reversan regarding potency, but superior in terms of selectivity concerning ABCB1 and ABCG2 (2-[4-(Benzo[c][1,2,5]oxadiazol-5-ylmethyl)piperazin-1-yl]-5,7-dimethoxy-4H-chromen-4-one (51): ABCC1, IC50 11.3-1/4M; inactive at ABCB1 and ABCG2). Compound 51 was as effective as reversan in reverting ABCC1-mediated resistance to cytostatics in MDCKII-MRP1 cells and proved to be stable in mouse plasma and cell culture medium. Modulators, such as compound 51, are of potential value as pharmacological tools for the investigation of the (patho)physiological role of ABCC1.
Geometric control of nuclearity in copper(I)/dioxygen chemistry
Abe, Tsukasa,Morimoto, Yuma,Tano, Tetsuro,Mieda, Kaoru,Sugimoto, Hideki,Fujieda, Nobutaka,Ogura, Takashi,Itoh, Shinobu
, p. 8786 - 8794 (2014/10/16)
Copper(I) complexes supported by a series of N3-tridentate ligands bearing a rigid cyclic diamine framework such as 1,5-diazacyclooctane (L8, eight-membered ring), 1,4-diazacycloheptane (L7, seven-membered ring), or 1,4-diazacyclohexane (L6, six-membered ring) with a common 2-(2-pyridyl)ethyl side arm were synthesized and their reactivity toward O2 were compared. The copper(I) complex of L8 preferentially provided a mononuclear copper(II) end-on superoxide complex S as reported previously [Itoh, S., et al. J. Am. Chem. Soc. 2009, 131, 2788-2789], whereas a copper(I) complex of L7 gave a bis(μ-oxido)dicopper(III) complex O at a low temperature (-85 °C) in acetone. On the other hand, no such active-oxygen complex was detected in the oxygenation reaction of the copper(I) complex of L6 under the same conditions. In addition, O2-reactivity of the copper(I) complex supported by an acyclic version of the tridentate ligand (LA, PyCH2CH 2N(CH3)CH2CH2CH2N(CH 3)2; Py = 2-pyridyl) was examined to obtain a mixture of a (μ- η2:η2-peroxido)dicopper(II) complex SP and a bis(μ-oxido)dicopper(III) complex O. Careful inspection of the crystal structures of copper(I) and copper(II) complexes and the redox potentials of copper(I) complexes has revealed important geometric effects of the supporting ligands on controlling nuclearity of the generated copper active-oxygen complexes.
Discovery and biological evaluation of adamantyl amide 11β-HSD1 inhibitors
Webster, Scott P.,Ward, Peter,Binnie, Margaret,Craigie, Eilidh,McConnell, Kirsty M.M.,Sooy, Karen,Vinter, Andy,Seckl, Jonathan R.,Walker, Brian R.
, p. 2838 - 2843 (2008/02/05)
A series of adamantyl amide 11β-HSD1 inhibitors has been discovered and chemically modified. Selected compounds are selective for 11β-HSD1 over 11β-HSD2 and possess excellent cellular potency in human and murine 11β-HSD1 assays. Good pharmacodynamic characteristics are observed in ex vivo assays.
Biologically Active Compounds through Catalysis: Efficient Synthesis of N-(Heteroarylcarbonyl)-N′-(arylalkyl)piperazines
Kumar, Kamal,Michalik, Dirk,Castro, Ivette Garcia,Tillack, Annegret,Zapf, Alexander,Arlt, Michael,Heinrich, Timo,Boettcher, Henning,Beller, Matthias
, p. 746 - 757 (2007/10/03)
A practical route for the synthesis of new biologically active 5-HT 2A receptor antagonists has been developed. In only three catalytic steps, this class of central nervous system (CNS) active compounds can be synthesized efficiently with high diversity. As the initial step, an anti-Markovnikov addition of amines to styrenes provides an easy route to N-(arylalkyl)piperazines, which constitute the core structure of the active molecules. Here, base-catalyzed hydroamination reactions of styrenes with benzylated piperazine proceeded in high yield even at room temperature. After catalytic debenzylation, the free amines were successfully carbonylated with different aromatic and heteroaromatic halides and carbon monoxide to yield the desired compounds in good to excellent yields. The two key reactions, base-catalyzed hydroamination of styrenes and palladium-catalyzed aminocarbonylation of haloarenes/heterocycles, showed tolerance towards various functional groups, thereby demonstrating the potential to synthesize a wide variety of new derivatives of this promising class of pharmaceuticals.
Synthesis and preliminary pharmacological evaluation of 4′-arylalkyl analogues of clozapine. II. Effect of the nature and length of the linker
Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Podloucka, Anna,Taylor, David A.
, p. 875 - 886 (2007/10/03)
We report the synthesis of a second generation of tricyclic analogues of clozapine, investigating the length and nature of the chain between an ionizable nitrogen atom at physiological pH and the introduced aryl moiety. The chemistry, structural characterization, and pharmacological evaluation of this series of 4′-arylalkyl analogues of clozapine are described. Preliminary findings on the effects on activity of the nature and length of the linker, degree of unsaturation, and type of aryl moiety on blockade of dopamine D4 and serotonin 5-HT2A receptors are discussed and animal behavioural data for key compounds presented.
