In Silico and In Vivo Evaluation of Novel 2-Aminobenzothiazole Derivative Compounds as Antidiabetic Agents

Currently, there are several drugs used for the treatment of type 2 diabetes (T2D); however, all of them have adverse effects. Benzothiazoles have a broad spectrum of biological activities such as antidiabetic. This study aimed to evaluate in silico and in vivo two series of 2-aminobenzothiazole derivatives linked to isothioureas (3a-w) or guanidines (4a-z) for the treatment of T2D. The ADMET properties were determined in silico, from which it was possible to select nine compounds (two isothioureas and seven guanidines), and, with molecular docking, it was shown that compounds methyl (E)-N'-(benzo[d]thiazol-2-yl)-N-methylcarbamimidothioate (3b) and 2-(benzo[d]thiazol-2-yl)-1,3-di-tert-butylguanidine (4y) showed a high affinity for PPARγ (ΔG = -7.8 and -8.4 kcal/mol, respectively). In vivo, the LD50 value was estimated in rats based on OECD Guideline 425, being >1750 mg/kg for both compounds. The pharmacological effect of 3b and 4y was evaluated in the T2D rat model, showing that after oral administration in an equimolar ratio to pioglitazone (15 mg/kg) for 4 weeks, both compounds were able to reduce blood glucose levels (<200 mg/dL) and improve the lipid profile. Therefore, 3b and 4y could be used in the future as antidiabetic agents.