European Journal of Medicinal Chemistry (2020)
Update date:2022-08-17
Topics:
Barreca, Maria Letizia
Bojarski, Andrzej J.
Cecchetti, Violetta
Cook, Gregory M.
Desantis, Jenny
Felicetti, Tommaso
Franzblau, Scott G.
Handzlik, Jadwiga
Hards, Kiel
Latacz, Gniewomir
Manfroni, Giuseppe
Massari, Serena
Mazzarella, Maria Angela
Nakatani, Yoshio
Nizi, Maria Giulia
Rushton-Green, Rowena
Sabatini, Stefano
Shetye, Gauri
Tabarrini, Oriana
Kolá?, Michal H.
Sata?a, Grzegorz
Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.
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