Preclinical Evaluation of 2-Aminobenzothiazole Derivatives: In Silico, In Vitro, and Preliminary In Vivo Studies as Diabetic Treatments and Their Complications.

Type 2 diabetes is a multifactorial disease characterized by chronic hyperglycemia, insulin resistance, oxidative stress, inflammation, and dyslipidemia, factors that contribute to the development of long-term complications. In this context, the 2-aminobenzothiazole scaffold has emerged as a promising candidate due to its broad spectrum of biological properties. In this study, we performed a multidisciplinary evaluation of benzothiazole derivatives (5a-d, 8a-d, 11a-d, and 12c-d), starting with the in silico prediction of their properties, along with molecular docking against aldose reductase (ALR2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). All compounds complied with the main rules of pharmacological similarity and optimal affinity, highlighting 8d (ΔG = -8.39 kcal/mol for ALR2 and -7.77 kcal/mol for PPAR-γ). Selected compounds from families C and D were synthesized in moderate yields (~60%) and showed low acute oral toxicity (LD50 > 1250 mg/Kg). Compounds 8c and 8d inhibited ALR2 at concentrations below 10 µM. In vivo studies using a streptozotocin-induced diabetic rat model with a high-fat diet revealed that compound 8d produced sustained antihyperglycemic effects and reduced insulin resistance, dyslipidemia, and polydipsia, without inducing hepatotoxicity or displaying intrinsic antioxidant or anti-inflammatory activity. These findings suggest that 8d is a promising candidate for further development in diabetes-related therapeutic strategies.