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Amide-Amine Replacement in Indole-2-carboxamides Yields Potent Mycobactericidal Agents with Improved Water Solubility.

ABSTRACT: 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_90Mtb 0.13 μM, MBC_99.9Mtb 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.

SUBMITTER: Tan YJ

PROVIDER: S-EPMC8155280 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Amide-Amine Replacement in Indole-2-carboxamides Yields Potent Mycobactericidal Agents with Improved Water Solubility.

Tan Yu Jia YJ Li Ming M Gunawan Gregory Adrian GA Nyantakyi Samuel Agyei SA Dick Thomas T Go Mei-Lin ML Lam Yulin Y

ACS medicinal chemistry letters 20201116 5

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, MIC90Mtb ...[more]

PMID: 34055215

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