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

ID: ALA5226308

Journal: ACS Med Chem Lett

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

Authors: Tan YJ, Li M, Gunawan GA, Nyantakyi SA, Dick T, Go ML, Lam Y.

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.

CiteXplore: 34055215

DOI: 10.1021/acsmedchemlett.0c00588

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