- Synthesis and Antileishmanial Evaluation of Arylimidamide-Azole Hybrids Containing a Phenoxyalkyl Linker
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Due to the limitations of existing medications, there is a critical need for new drugs to treat visceral leishmaniasis. Since arylimidamides and antifungal azoles both show oral activity in murine visceral leishmaniasis models, a molecular hybridization approach was employed where arylimidamide and azole groups were separated by phenoxyalkyl linkers in an attempt to capitalize on the favorable antileishmanial properties of both series. Among the target compounds synthesized, a greater antileishmanial potency against intracellular Leishmania donovani was observed as the linker length increased from two to eight carbons and when an imidazole ring was employed as the terminal group compared to a 1,2,4-triazole group. Compound 24c (N-(4-((8-(1H-imidazol-1-yl)octyl)oxy)-2-isopropoxyphenyl) picolinimidamide) displayed activity against L. donovani intracellular amastigotes with an IC50 value of 0.53 μM. When tested in a murine visceral leishmaniasis model, compound 24c at a dose of 75 mg/kg/day p.o. for five consecutive days resulted in a modest 33% decrease in liver parasitemia compared to the control group, indicating that further optimization of these molecules is needed. While potent hybrid compounds bearing an imidazole terminal group were also strong inhibitors of recombinant CYP51 from L. donovani, as assessed by a fluorescence-based assay, additional targets are likely to play an important role in the antileishmanial action of these compounds.
- Abdelhameed, Ahmed,Feng, Mei,Joice, April C.,Zywot, Emilia M.,Jin, Yiru,La Rosa, Chris,Liao, Xiaoping,Meeds, Heidi L.,Kim, Yena,Li, Junan,McElroy, Craig A.,Wang, Michael Zhuo,Werbovetz, Karl A.
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- Discovery of Diphenoxy Derivatives with Flexible Linkers as Ligands for β-Amyloid Plaques
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The highly rigid and planar scaffolds with π-conjugated systems have been widely considered to be indispensable for β-amyloid (Aβ) binding ligands. In this study, a library of diphenoxy compounds with different types of more flexible linkers as Aβ ligands were synthesized and evaluated. Most of them displayed good affinity (Ki1-42aggregates, and some ligands even showed values of Kiless than 10 nM. Structure-activity relationship analysis revealed that modification on the linkers or substituents tolerated great flexibility, which challenged the long-held belief that rigid and planar structures are exclusively favored for Aβ binding. Three ligands were labeled by iodine-125, and they exhibited good properties in vitro and in vivo, which further supported that this flexible scaffold was potential and promising for the development of Aβ imaging agents.
- Jia, Jianhua,Zhang, Longfei,Song, Jia,Dai, Jiapei,Cui, Mengchao
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p. 4089 - 4100
(2020/12/13)
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- Diphenoxyl flexible molecules with high affinity with A[beta] plaque and preparation method and applications thereof
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The invention discloses diphenoxyl flexible molecules with high affinity with A[beta] plaque and a preparation method and applications thereof. After the molecules are labeled by radionuclide, the molecules can be used as an A[beta] plaque developing agen
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Paragraph 0073; 0074; 0083; 0084
(2017/12/09)
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- Hybrid ortho/allosteric ligands for the adenosine A1 receptor
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Many G protein-coupled receptors (GPCRs), including the adenosine A 1 receptor (A1AR), have been shown to be allosterically modulated by small molecule ligands. So far, in the absence of structural information, the exact location of
- Narlawar, Rajeshwar,Lane, J. Robert,Doddareddy, Munikumar,Lin, Judy,Brussee, Johannes,Ijzerman, Adriaan P.
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supporting information; experimental part
p. 3028 - 3037
(2010/09/07)
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- Synthesis of potent non-imidazole histamine H3-receptor antagonists
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Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N(α)-position followed by removal of the imidazole ring. The resulting compound, N-ethyl- N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 μM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N- (5-phenoxypentyl)pyrrolidine (Ki = 0.18 ± 0.10 μM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki= 39 ± 11 nM), ED50 = 1.1 ± 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.
- Ganellin, C. Robin,Leurquin, Fabien,Piripitsi, Antonia,Arrang, Jean-Michel,Garbarg, Monique,Ligneau, Xavier,Schunack, Walter,Schwartz, Jean-Charles
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p. 395 - 404
(2007/10/03)
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- Topologically Controlled Coulombic Interactions, a New Tool in the Developing of Novel Reactivity. Photochemical and Electrochemical Cleavage of Phenyl Alkyl Ethers
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The hypothesis that a specific placement of a positive charge would dramatically alter the behavior of a charged intermediate has been tested.Phenyl ethers substituted by electron-attracting groups do not undergo reductive fragmentation.However, related α-piperidino-ω-(4-substituted-phenoxy)alkanes give alkyl ether photocleavage when the linker between the redox centers is short, or the usual substitution-reduction photochemistry when it is long.Mechanistic experiments suggest that the photofragmentation process operates through space intramolecular electron transfer to the triplet aromatic chromophore and that a coplanar relative orientation of the alkyl ether bond and the phenyl ring is compulsory for the photofragmentation to be observed.Configuration interaction AM1 calculations justify the described facts, indicating that the fragmentation process is only operative when a Coulombic stabilization of a ?* intramolecular electron transfer excited state is produced.Electrochemical studies carried out with the corresponding quaternary salts (intermolecular generation of the phenyl ether radical anion) confirm the conclusions derived from the photochemical experiments.
- Marquet, Jorge,Cayon, Eduard,Martin, Xavier,Casado, Francisco,Gallardo, Iluminada,et al.
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p. 3814 - 3825
(2007/10/02)
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