- Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity
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The inclusion of an azaspiroketal Mannich base in the membrane targeting antitubercular 6-methoxy-1-n-octyl-1H-indole scaffold resulted in analogs with improved selectivity and submicromolar activity against Mycobacterium tuberculosis H37Rv. The potency enhancing properties of the spiro-fused ring motif was affirmed by SAR and validated in a mouse model of tuberculosis. As expected for membrane inserting agents, the indolyl azaspiroketal Mannich bases perturbed phospholipid vesicles, permeabilized bacterial cells, and induced the mycobacterial cell envelope stress reporter promoter piniBAC. Surprisingly, their membrane disruptive effects did not appear to be associated with bacterial membrane depolarization. This profile was not uniquely associated with azaspiroketal Mannich bases but was characteristic of indolyl Mannich bases as a class. Whereas resistant mycobacteria could not be isolated for a less potent indolyl Mannich base, the more potent azaspiroketal analog displayed low spontaneous resistance mutation frequency of 10-8/CFU. This may indicate involvement of an additional envelope-related target in its mechanism of action.
- Nyantakyi, Samuel Agyei,Li, Ming,Gopal, Pooja,Zimmerman, Matthew,Dartois, Véronique,Gengenbacher, Martin,Dick, Thomas,Go, Mei-Lin
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supporting information
p. 5733 - 5750
(2018/06/20)
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- Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein
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Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9 nM and 6.1 nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's = 10.2 and 30.4 nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.
- Tai, Vincent W.-F.,Garrido, Dulce,Price, Daniel J.,Maynard, Andrew,Pouliot, Jeffrey J.,Xiong, Zhiping,Seal, John W.,Creech, Katrina L.,Kryn, Luz H.,Baughman, Todd M.,Peat, Andrew J.
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p. 2288 - 2294
(2014/05/20)
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- Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance
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The inhibition of ABC (ATP binding cassette) transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrugresistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.
- Dittrich, Torsten,Hanekop, Nils,Infed, Nacera,Schmitt, Lutz,Braun, Manfred
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supporting information
p. 1700 - 1704
(2013/01/15)
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- Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus
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Amantadine has been used for decades as an inhibitor of the influenza A virus M2 protein (AM2) in the prophylaxis and treatment of influenza A infections, but its clinical use has been limited by its central nervous system (CNS) side effects as well as emerging drug-resistant strains of the virus. With the goal of searching for new classes of M2 inhibitors, a structure-activity relation study based on 2-[3-azaspiro(5,5)undecanol]-2-midazoline (BL-1743) was initiated. The first generation BL-1743 series of compounds has been synthesized and tested by two-electrode voltage-clamp (TEV) assays. The most active compound from this library, 3-azaspiro[5,5]undecane hydrochloride (9), showed an IC50 as low as0.92 ± 0.11 μM against AM2, more than an order of magnitude m ore potent than amantadine (IC50 = 16 μM). 15N and 13C solid-state NMR was employed to determine the effect of compound 9 on the structure and dynamics of the transmembrane domain of AM2 (AM2-TM) in phospholipid bilayers. Compared to amantadine, spiro-piperidine 9 (1) induces a more homogeneous conformation of the peptide,(2) reduces the dynamic disorder of the G34-I35 backbone near the water -filled central cavity of the helical bundle, and (3) influences the dynamics and magnetic environment of more residues within the transmembranehelices. These data suggest that spiro-piperidine 9 binds more extensiv ely with the AM2 channel, thus leading to stronger inhibitory potency.
- Wang, Jun,Cady, Sarah D.,Balannik, Victoria,Pinto, Lawrence H.,DeGrado, William F.,Hong, Mei
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experimental part
p. 8066 - 8076
(2009/12/03)
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- Quinoline, naphthyridine and pyridobenzoxazine derivatives
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Novel antibacterial compounds are disclosed having the formula STR1 as well as pharmaceutically acceptable salts, esters, amide and prodrugs thereof, wherein R1 is selected from the group consisting of (a) lower alkyl, (b) halo(lower alkyl), (c
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