3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine N-acetyltransferase, in Mycobacteria

Abstract

<jats:p>In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound 2 to be an extremely potent inhibitor of Mycobacterium tuberculosis H37Rv growth (MIC: 0.031 mg/L) in vitro, performing better than the currently used first-line antituberculosis drugs such as isoniazid, rifampicin, ethambutol, and pretomanid in vitro. Furthermore, compound 3 was equipotent to pretomanid against a multidrug-resistant M. tuberculosis clinical isolate. The derivatives were selective and bactericidal towards slow-growing mycobacteria. They showed low cytotoxicity towards murine RAW 264.7 and human THP-1 cell lines, with high selectivity indices. Compound 1 effectively eliminated the intracellular mycobacteria in a mycobacteria-infected macrophage model. The derivatives were assessed for their potential to inhibit mycobacterial arylamine N-acetyltransferase (NAT) and were identified as good inhibitors of recombinant mycobacterial NAT, a novel target essential for the intracellular survival of M. tuberculosis. This study provided hits for designing new potent and selective antituberculosis leads, having mycobacterial NAT inhibition as their possible endogenous mechanisms of action.</jats:p>

The role of adjuvants in overcoming antibacterial resistance due to enzymatic drug modification

“…Westwood et al described the characteristics of an ideal NAT inhibitor derived from 1,2,4-triazole-3-thiones and, based on their work, three nitrofurans were found to be potential NAT inhibitors and to have anti-mycobacterial activity of their own. 213,214 The maximum N-acetyltransferase inhibition occurred when the substituent on a 1,2,4-triazole was an aliphatic or planar aromatic group. An increase in chain length meant more hydrophobic contacts with the active site occurred.…”

Arylnitro monocarbonyl curcumin analogues: Synthesis and in vitro antitubercular evaluation

“…They generally act as pro‐drugs, which undergo bio‐reduction of their nitro group in order to display their anti‐infective properties (Hurdle et al, 2008). Nitroaromatic compounds that are currently on the market or in clinical development against TB are pretomanid, delamanid, and macozinone (PBTZ‐169) (see Figure 1) (Agre et al, 2020). These compounds have been reported to exhibit potent activity against both drug‐susceptible and drug‐resistant TB (Makarov et al, 2014; Zhang & Aldrich, 2019).…”

Nitrofurans: Revival of an “old” drug class in the fight against antibiotic resistance

“…One prominent trend is to search for nitrofuran analogs that have a broadened spectrum and increased potency in comparison to the existing clinically used nitrofurans, such as IITR06114, a novel nitrofuran recently discovered in a small molecule screen [ 19 ], and compound 17 identified in a hit-to-lead optimization effort ( Fig 2A ) [ 20 ]. Extensive medicinal chemistry efforts have been undertaken to design novel antimycobacterial agents from the nitrofuran scaffold, culminating in a number of candidates with the submicromolar to nanomolar in vitro MICs [ 21 , 22 ]. It remains to be seen whether these nitrofuran candidates will be successfully brought to clinical trials in the years to come.…”