Novel Thiazolo[5,4-b]phenothiazine Derivatives: Synthesis, Structural Characterization, and In Vitro Evaluation of Antiproliferative Activity against Human Leukaemia

Abstract

The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The synthetic strategy applied was based on oxidative cyclization of <i>N</i>-(phenothiazin-3-yl)-thioamides and it was validated by the preparation of new 2-alkyl- and 2-aryl-thiazolo[5,4-<i>b</i>]phenothiazine derivatives. Optical properties of the series were experimentally emphasized by UV-Vis absorption/emission spectroscopy and structural features were theoretically modelled using density functional theory (DFT). In vitro activity as antileukemic agents of thiazolo[5,4-<i>b</i>]phenothiazine and <i>N</i>-(phenothiazine-3-yl)-thioamides were comparatively evaluated using cultivated HL-60 human promyelocytic and THP-1 human monocytic leukaemia cell lines. Some representatives proved selectivity against tumour cell lines, cytotoxicity, apoptosis induction, and cellular metabolism impairment capacity. 2-Naphthyl-thiazolo[5,4-<i>b</i>]phenothiazine was identified as the most effective of the series by displaying against THP-1 cell lines a cytotoxicity close to cytarabine antineoplastic agent.