Abstract：
:The inclusion of an azaspiroketal Mannich base in the membrane targeting antitubercular 6-methoxy-1- n-octyl-1 H-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 p iniBAC. 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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Nyantakyi SA,Li M,Gopal P,Zimmerman M,Dartois V,Gengenbacher M,Dick T,Go MLdoi
10.1021/acs.jmedchem.8b00777subject
Has Abstractpub_date
2018-07-12 00:00:00pages
5733-5750issue
13eissn
0022-2623issn
1520-4804journal_volume
61pub_type
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