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The Synthesis and in Vitro Biological Evaluation of Novel Fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones Against Mycobacterium Tuberculosis

The Synthesis and in Vitro Biological Evaluation of Novel Fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones Against Mycobacterium Tuberculosis

Davie Cappoen, Eveline Torfs, Tamara Meiresonne, Pieter Claes, Elena Semina, Francis Holvoet, Maíra Bidart de Macedo, Freya Cools, Tatiana Piller, An Matheeussen, Kevin Van Calster, Guy Caljon, Peter Delputte, etc.

Eur J Med Chem. 2019 Nov 1;181:111549.

PMID: 31376569

Abstract:

Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP229878	Phenanthridine		229-87-8	Price

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