Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors.

Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors. Eur J Med Chem. 2020 Jun 05;201:112420 Authors: Nizi MG, Desantis J, Nakatani Y, Massari S, Mazzarella MA, Shetye G, Sabatini S, Barreca ML, Manfroni G, Felicetti T, Rushton-Green R, Hards K, Latacz G, Satała G, Bojarski AJ, Cecchetti V, Kolář MH, Handzlik J, Cook GM, Franzblau SG, Tabarrini O Abstract 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 synergize...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research