Naphthoquinone Derivatives as Scaffold to Develop New Drugs for Tuberculosis Treatment

Abstract

Despite being a curable disease, tuberculosis (TB) remains a public health problem worldwide mainly due to lengthy treatment, as well as its toxic effects, TB/HIV co-infection and the emergence of resistant Mycobacterium tuberculosis strains. These barriers reinforcing the need for development of new antimicrobial agents, that ideally should reduce the time of treatment and be active against susceptible and resistant strains. Quinones are compounds found in natural sources and among them, the naphthoquinones show antifungal, antiparasitic, and antimycobacterial activity. Thus, we evaluated the potential antimycobacterial activity of six 1,4-naphthoquinones derivatives. We determined the minimum inhibitory concentration (MIC) of the compounds against three M. tuberculosis strains: a pan-susceptible H37Rv (ATCC 27294); one mono-resistant to isoniazid (ATCC 35822); and one mono-resistant to rifampicin (ATCC 35838); the cytotoxicity in the J774A.1 (ATCC TIB-67) macrophage lineage; performed in silico analysis about absorption, distribution, metabolism, and excretion (ADME) and docking sites. All evaluated naphthoquinones were active against the three strains with MIC between 206.6 and 12.5 μM, and the compounds with lower MIC values have also showed low cytotoxicity. Moreover, two naphthoquinones derivatives 5 and 6 probably do not exhibit cross resistance with isoniazid and rifampicin, respectively, and regarding ADME analysis, no compound violated the Lipinski’s rule-of-five. Considering the set of findings in this study, we conclude that these naphthoquinones could be promising scaffolds to develop new therapeutic strategies to TB.

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates

“…Most recently, 1,4-naphthoquinones, such as menadione (vitamin K3), have aroused a lot of interest due to relevant anticancer activity [ 16 ]. With specific attention on the anti-tubercular activity, studies have reported on the potential of using naphthoquinones as active agents against drug-resistant M. tuberculosis strains, although their mechanism of action has yet to be unveiled [ [17] , [18] , [19] ].…”

Inhibition of Escherichia coli and Bacillus subtilis FtsZ Polymerization and Bacillus subtilis Growth by Dihydroxynaphtyl Aryl Ketones

“…A plausible explanation for this behavior is that this compound has an additional inhibitory effect on cellular growth that does not rely on FtsZ function, possibly the production of reactive oxygen species (ROS). In this regard, it was demonstrated that naphtoquinones cause M. tuberculosis cell death through inducing NADH oxidation, ROS production, and possibly acting over other targets of the cellular redox metabolism (Heikal et al, 2016; Halicki et al, 2018).…”

Naturally Derived Photoinitiators for Dental and Biomaterials Applications

“…Naphthoquinone derivatives, such as 5-hydroxy-1,4-naphthoquinone, are naturally derived PIs of plants, microbes, and marine origins, 50 and possess antibacterial properties. 51 They are yellow, red, orange, or purple in color and show maximum absorption (max) at 420 nm in visible blue light region. They are type II PIs that can initiate the free radical Naturally Derived Photoinitiators Abdul-Monem polymerization of acrylates.…”