180-94-9Relevant articles and documents
Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity
Nyantakyi, Samuel Agyei,Li, Ming,Gopal, Pooja,Zimmerman, Matthew,Dartois, Véronique,Gengenbacher, Martin,Dick, Thomas,Go, Mei-Lin
supporting information, p. 5733 - 5750 (2018/06/20)
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.
Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance
Dittrich, Torsten,Hanekop, Nils,Infed, Nacera,Schmitt, Lutz,Braun, Manfred
supporting information, p. 1700 - 1704 (2013/01/15)
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.
Quinoline, naphthyridine and pyridobenzoxazine derivatives
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, (2008/06/13)
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