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 (<b>5a</b>-<b>d</b>, <b>8a</b>-<b>d</b>, <b>11a</b>-<b>d</b>, and <b>12c</b>-<b>d</b>), 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 <b>8d</b> (ΔG = -8.39 kcal/mol for ALR2 and -7.77 kcal/mol for PPAR-γ). Selected compounds from families <b>C</b> and <b>D</b> were synthesized in moderate yields (~60%) and showed low acute oral toxicity (LD₅₀ > 1250 mg/Kg). Compounds <b>8c</b> and <b>8d</b> 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 <b>8d</b> 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 <b>8d</b> is a promising candidate for further development in diabetes-related therapeutic strategies.