The synthesis and in vitro biological evaluation of novel fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones against Mycobacterium tuberculosis.

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.

Synthesis of 2-Fluoro-1,4-benzoxazines and 2-Fluoro-1,4-benzoxazepin-5-ones by Exploring the Nucleophilic Vinylic Substitution (S(N)V) Reaction of gem-Difluoroenamides.

N-Benzoyl ß,ß-difluoroenamides and N-benzoyl fluoroynamides are novel structural units which have been explored as precursors in heterocyclic synthesis. The presence of two fluorine atoms at the ß-position of the enamide moiety endows unique electrophilic reactivity. Treatment of these enamides with oxygen nucleophiles gives rise to a nucleophilic vinylic substitution (S(N)V) reaction, which was directed toward 2-fluoro-1,4-benzoxazines and 2-fluoro-1,4-benzoxazepin-5-ones. Furthermore, fluorinated ynamides, a new type of building block, were prepared in excellent yields for the first time. In this case, ß-addition of nucleophiles across the triple bond is observed also.

Synthesis of novel ß-aminocyclobutanecarboxylic acid derivatives by a solvent-free aza-Michael addition and subsequent ring closure.

Novel ß-aminocyclobutanecarboxylic acid derivatives were prepared via a sequential solvent-free aza-Michael addition of benzophenone imine across 3-halopropylidenemalonates and base-induced ring closure. These highly substituted cyclobutanedicarboxylic acid derivatives were subjected to a reactivity study which demonstrated the tendency of these donor-acceptor substituted four-membered rings to be converted into their corresponding ring-opened products.