Open AccessAmide–Amine Replacement in Indole-2-carboxamides Yields Potent Mycobactericidal Agents with Improved Water Solubility
Author(s) -
Yu Tan,
Ming Li,
Gregory Adrian Gunawan,
Samuel Agyei Nyantakyi,
Thomas Dick,
MeiLin Go,
Yulin Lam
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00588
Subject(s) - benzothiophene , indole test , amide , amine gas treating , chemistry , carboxamide , linker , ring (chemistry) , solubility , stereochemistry , combinatorial chemistry , organic chemistry , computer science , thiophene , operating system
Indolecarboxamides are potent but poorly soluble mycobactericidal agents. Here we found that modifying the incipient scaffold by amide-amine substitution and replacing the indole ring with benzothiophene or benzoselenophene led to striking (10-20-fold) improvements in solubility. Potent activity could be achieved without the carboxamide linker but not in the absence of the indole ring. The indolylmethylamine, N -cyclooctyl-6-trifluoromethylindol-2-ylmethylamine ( 33 , MIC 90 Mtb 0.13 μM, MBC 99.9 Mtb 0.63 μM), exemplifies a promising member that is more soluble and equipotent to its carboxamide equivalent. It is also an inhibitor of the mycolate transporter MmpL3, a property shared by the methylamines of benzothiophene and benzoselenophene.