In Vitro Activity of 3-Triazeneindoles against Mycobacterium tuberculosis and Mycobacterium avium

Abstract

Among 230 target-synthesized indole-based compounds, seven 3-triazenoindoles showed MICs of 0.2 to 0.5 g/ml against Mycobacterium tuberculosis strain H37Rv and isoniazid-resistant human isolate CN-40. The TU112 compound was active also against a dormant form of M. tuberculosis. Some of these triazenoindoles were active against Mycobacterium avium, with MICs of 0.05 to 0.5 g/ml. The selectivity indices (SI) for M. tuberculosis and M. avium were significantly higher than 10, making these compounds acceptable for the next testing step.A series of indole-based compounds possessing antimycobacterial activity were reported during last decade (1-3), including those from our panel of Mycobacterium-targeting N-N-containing indoles synthesized according the procedure described previously (4). Here, we present a few indole agents containing three lined-up nitrogen atoms representing a series of 3-triazenoindoles and demonstrating the most prominent antimycobacterial capacities. Synthesis of the target 3-triazenoindoles was performed using 2-ethoxycarbonyl-3H-diazoindole and appropriate secondary amines (or malononitrile for the compound TU113) by the method reported earlier (5). The characteristics of the compounds are displayed in Table 1.All reagents and solvents were purchased from commercial sources and were used without further purification. The yields refer to purified products and are not optimized. Melting points were uncorrected. Infrared (IR) spectra were run as KBr disks on an IR Fourier Magna-IR 750 Nicolet spectrometer. 1 H nuclear magnetic resonance (NMR) and 13 C NMR spectra were performed on a Bruker Avance-300 and Bruker Avance-400 (300 and 400 MHz, respectively), using tetramethylsilane (TMS) as an integral standard and hexadeuterodimethyl sulfoxide (DMSO-d6) and CDC1 as solvents. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br); chemical shifts are expressed as ␦ ppm, and the coupling constant (J) is given in hertz (Hz). Elemental analysis was performed at the laboratory of microanalysis of the A. N. Nesmeyanov Institute of Organoelement Compounds, Moscow, Russia. Mass spectra were recorded on Finnigan PolarisQ mass spectrometer.Mycobacterium tuberculosis strain H37Rv, a clinical isolate of isoniazid (INH)-resistant M. tuberculosis CN-40, and Mycobacterium avium strain 724R were obtained from the Department of Immunology of Central Institute for Tuberculosis (Moscow, Russia). The origin, storage conditions, properties, and preparation of bacterial cultures were described earlier (6-8). Initially, the compounds were tested for their capacity to inhibit [ 3 H]uracil incorporation (as preliminary screen) into M. tuberculosis H37Rv and CN-40 (4, 6), followed by MIC testing of the most active ones. MICs were determined by a standard microdilution assay using microtubes with Dubos medium containing 0.05% Tween 80. The lowest concentration of a compound resulting in no visible growth of M. tuberculosis for 2 weeks was considered the MIC (4, 9,...

In vitro Antitubercular Activity of 3‐Deoxysappanchalcone Isolated From the Heartwood of Caesalpinia sappan Linn.

“…We did not observe cytotoxicity up to a concentration of >100 μg/mL, which gives 3‐deoxysappanchalcone an SI of 8–16. The SI for strains of M. tuberculosis was significantly higher than 10, making 3‐deoxysappanchalcone acceptable for the next testing step (Nikonenko et al ., ).…”

“…We did not observe cytotoxicity up to a concentration of >100 μg/mL, which gives 3-deoxysappanchalcone an SI of 8-16. The SI for strains of M. tuberculosis was significantly higher than 10, making 3-deoxysappanchalcone acceptable for the next testing step (Nikonenko et al, 2016). Mycobacterial organisms have the ability to enter a host's alveolar macrophage cells and are able to colonize even under stressful conditions (Gupta and Bhakta, 2012).…”

Structural Modifications of 3-Triazeneindoles and Their Increased Activity Against Mycobacterium tuberculosis

“…Remarkably, MICs for the INH-resistant CN-40 strain were similar. The activity of some of these compounds is higher than of those described previously [7,8], which makes these candidates attractive for further preclinical studies using a widely accepted algorithm [9].…”

“…The compound TU112 was additionally active against an artificially created dormant M. tuberculosis strain. These compounds showed high selectivity indexes (SI) for M. tuberculosis and M. avium in the infected mouse macrophage model [7].…”

Antimicrobial activity of IDD-B40 against drug-resistant Mycobacterium tuberculosis

“…A series of indole-based compounds possessing anti-tuberculosis activity was reported during the last decade 6 – 8 . To extend the research on indole as a new class of anti-tubercular agent, we designed a chemical library based on indole.…”