Design, Synthesis and Evaluation of Antitubercular Activity of Mannich Bases of Isoniazid-Containing Thiazolidin-4-one Rings

Abstract

Isoniazid (INH), the established antitubercular drug was selected as the lead for the design and development of antitubercular agents by many researchers. 4-thiazolidinones are well known heterocyclic compounds for their spectrum of biological activities such as antibacterial, antifungal[1], anticancer[2],antitubercular, anthelmintic, anti-inflammatory [3], analgesic [4], antithyroid, local anaesthetic, monoamine oxidase inhibition, anti-Toxoplasma gondii activity etc [5]. Modification of thiazolidinones via Mannich reaction to improve biological activity is also reported [6]. A series of novel Mannich bases were designed from 4-thiazolidinones of INH using in silico studies. Docking studies were performed at Mtb enoyl acp reductase (4DRE) which is the binding site of INH. The derivatives exhibiting best docking scores were prepared from 2, 3-disubstituted-4-thiazolidinones by treating with formaldehyde and various secondary amines. 2, 3-disubstituted-4-thiazolidinones in turn were obtained from a series of INH Schiff bases by reaction with thioglycolic acid. Structures of the newly synthesized compounds were assigned on the basis of elemental analysis, IR, ¹H NMR, ¹³CNMR and mass spectral studies. The newly synthesized compounds were screened for their in vitro antitubercular activity using Alamar blue assay method and the hepatotoxicity was determined by MTT assay using Chang liver cells. MB1V-4—the Mannich base of N-[2-(4-chlorophenyl)-4-oxo-1, 3-thiazolidin-3-yl] pyridine-4-carboxamide with nitrotriazolone (NTO)—exhibited the best antitubercular activity (sensitive at 1.6 µg/ml); in comparison with the standard parent drug INH (sensitive at 3.12 µg/ml). The percentage viability produced by MB1V-4 for in vitro hepatotoxicity screening was better than the percentage viability produced by INH itself.

Keywords: Isoniazid (INH), 4-thiazolidinone, Mannich base, Nitrotriazolone (NTO), Alamar blue, Chang liver cell, in vitro hepatotoxicity

Cite this Article

Thomas B, Harindran J. Design, Synthesis and Evaluation of Antitubercular Activity of Mannich Bases of Isoniazid-Containing Thiazolidin-4-one Rings. Research and Reviews: A Journal of Pharmaceutical Science. 2016; 7(1): 1–12p.