The new thiazolidine-2,4-dione-based hybrids with promising antimycobacterial activity: design, synthesis, biological evaluation, and drug interaction analysis

Abstract

The ever-increasing drug-resistant tuberculosis (TB) has invigorated the focus on the discovery and development of novel therapeutic agents and treatment options. Thiazolidinone-based compounds have shown good antitubercular properties in vitro. Here, we report the design and synthesis of a number of new derivatives inspired by the structure of thiazolidine-2,4-dione (TZD). The TZD-based hybrids with the thiosemicarbazone or the pyridinecarbohydrazone moiety were synthesised and their antimycobacterial activity was investigated against the reference H₃₇Rv and two wild Mycobacterium tuberculosis (Mtb) strains. In further studies, a two-drug interaction analysis was also performed for assessing their synergism with the current first-line drugs used for the treatment of TB. It was found that some of the compounds showed high antimycobacterial activity with MICs (0.078-0.283 µM) and a synergistic effect with isoniazid or rifampicin, thereby demonstrating their potential as a promising scaffold for the development of novel coadjuvants for the effective treatment of TB.

Keywords: Thiazolidine-2,4-diones; antimycobacterial activity; cytotoxicity; structure–activity relationship; synergism.

Graphical abstract

Figure 1.

Structures of TZD-based compounds with promising activity against Mycobacterium tuberculosis H₃₇Ra strain^,.

Figure 2.

The main modifications and general structure of newly designed compounds with the TZD-TSC 1a–1e and TZD-PCH 2a–2e scaffolds.

Scheme 1.

Synthesis pathway of TZD-based thiosemicarbazone and pyridinecarbohydrazide derivatives. Reagents and conditions: (i) KOH, anhydrous ethanol; (ii) ethyl bromoacetate, reflux; HCl, reflux; (iii) thionyl chloride, toluene, reflux; (iv) corresponding hydroxybenzaldehyde, pyridine; acidified HCl to pH = 2–3; (v) thiosemicarbazide or 4-(3-chlorophenyl)-3-thiosemicarbazide, anhydrous ethanol, reflux for 0.5–3 h; (vi) dimethyl acetylenedicarboxylate, methanol, reflux for 30 min; (vii) corresponding pyridinecarbohydrazide, anhydrous ethanol, reflux for 1–3 h.

Figure 3.

The SAR for TZD compounds with (a) thiosemicarbazone (1a, 1c, 1d, 6c, and 6d) and (b) pyridinecarbohydrazone (2c, 2e, 3c, 3e, 4c, and 4e) moieties.

Figure 4.

Cell viability of HEK-293 cell line treated by (a) TZD-TSC (1a–1d) and (b) TZD-PCH (2a, 2c–2e, 4c, and 4e).