Indole trimers with antibacterial activity against Gram-positive organisms produced using combinatorial biocatalysis

Abstract

The I100V isoform of toluene-4-monooxygenase was used to catalyze the oxidative polymerization of anthranil and various indoles under mildly acidic conditions, favoring the production of trimers. Compounds produced in sufficient yield were purified and tested for their ability to inhibit the growth of B. anthracis, E. faecalis, L. monocytogenes, S. aureus, and in some cases, F. tularensis. 15 of the compounds displayed promising antibacterial activity (MIC < 5 µg/ml) against one or more of the strains tested, with the best MIC values being <0.8 µg/ml. All of these compounds had good selectivity, showing minimal cytotoxicity towards HepG2 cells. The structure was solved for six of the compounds that could be crystallized, revealing that minimally two classes of indole based trimers were produced. One compound class produced was a group of substituted derivatives of the natural product 2,2-bis(3-indolyl) indoxyl. The other group of compounds identified was classified as tryptanthrin-like compounds, all having multi-ring pendant groups attached at position 11 of tryptanthrin. One compound of particular interest, SAB-J85, had a structure that suggests that any compound, with a ring structure that can be activated by an oxygenase, might serve as a substrate for combinatorial biocatalysis.

Mutagenesis and expression of methane monooxygenase to alter regioselectivity with aromatic substrates

“…There are reports in the literature of use of aromatic monooxygenases to produce tricyclic aromatic compounds as a result of addition reactions between oxygenate monoaromatic products (McClay et al. 2015 ), but to our knowledge the situation across the SDIMOs as a whole is the same as that obtained here, that oxygenation of triaromatic substrates has yet to be achieved and may reflect the size limitation of the active site across the wild-type enzymes of the class. Here, we have shown that the highly versatile sMMO can be engineered to alter the regioselectivty with aromatic substrates, including more precise hydroxylation of biphenyl at the 4-position, and we have achieved what to our knowledge is the highest specific activity (0.37 nmol min −1 mg −1 ) towards so large a substrate by cells expressing this group of enzymes.…”

An Integrative Approach to Study the Inhibition of Providencia vermicola FabD Using C2-Quaternary Indolinones

“…7 They possess antiviral bioactivities and show activity towards other infectious illnesses such as hepatitis, mumps, pneumonia, and influenza. 8 They are also identified as potential drugs for the therapeutic targets of SARS-CoV-2 using a computational technique. 9 Because of the diverse applications of the indolinone framework, a number of approaches for their synthesis have been established.…”

“…Generally, they are manufactured in the laboratory involving free radical pathways or metal-catalyzed, oxidant-driven, non-free radical approaches. [7][8][9][10][11][12][13][14][15] Bio-catalytically they are also synthesized from indoles using laccase catalysis, laccase-surfactant catalysis, biocatalytic process, and combinatorial biocatalytic approaches. 8,16,17 Likewise, these indolinone derivatives have been synthesized from indoles using a variety of reagents and conditions via some metal-free or metal-catalyzed routes.…”

Theoretical Investigation on the Molecular Structure, Electronic, Spectroscopic Studies and Nonlinear Optical Properties of 5-bromo-1-(2-cyano-pyridin-4-yl)-1H-indazole-3-carboxylic acid diethylamide: a DFT and TD-DFT Study

“…Indazoles are an important class of bicyclic nitrogencontaining aromatic heterocycles and have attracted a great deal of attention in the past as well as in recent years due to their wide variety of biological properties. The indazoles represent an important subunit in drugs with a broad range of biological activities including antibacterial [1], antifungal [2], antiviral [3], antihypertensive [4], anticancer [5], anti-inflammatory [6], and immunomodulatory [7]. Indazoles with pyridine substituted compounds also have anti-cancer properties [8].…”