Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches

Abstract

Diabetes mellitus (DM) is counted among one of the leading challenges in the recent era, and it is a life-threatening disorder. Compound 4-hydroxy 3-methoxy phenylacetone (compound 1) was previously isolated from Polygonum aviculare. This compound was reacted with N-benzylmaleimide to synthesize the targeted compound 3. The purpose of this research is to exhibit our developed compound 3's ability to concurrently inhibit many targets that are responsible for hyperglycemia. Compound 3 was capable of inhibiting α-amylase, α-glucosidase, and protein tyrosine phosphatase 1 B. Even so, outstanding in vitro inhibition was shown by the compound against dipeptidyl peptidase-4 (DPP-4) with an IC₅₀ value of 0.07 µM. Additionally, by using DPPH in the antioxidant activity, it exhibited good antioxidant potential. Similarly, in the in vivo activity, the experimental mice proved to be safe by treatment with compound 3. After 21 days of examination, the compound 3 activity pattern was found to be effective in experimental mice. Compound 3 decreased the excess peak of total triglycerides, total cholesterol, AST, ALT, ALP, LDL, BUN, and creatinine in the STZ-induced diabetic mice. Likewise, the histopathology of the kidneys, liver, and pancreas of the treated animals was also evaluated. Overall, the succinimde moiety, such as compound 3, can affect several targets simultaneously, and, finally, we were successful in synthesizing a multi-targeted preclinical therapy.

Keywords: acute toxicity; antioxidant; diabetes; histopathology; succinimide.

Scheme 1

Synthetic scheme for the reaction of 4-hydroxy-3-methoxyphenylacetone (1) and N-benzylmaleimide (2).

Figure 1

The organ weight and body weight in response to the treatment of the synthesized compound in diabetic mice. The results are presented as mean ± SE (n = 3), ** p < 0.01; * p < 0.05; vs. control group, ^# p < 0.05; ^## p < 0.01 vs. STZ group. Metformin (MET) and streptozotocin (STZ). Tg-1 (control), Tg-2 (STZ), Tg-3 (compound 3), Tg-4 (STZ + metformin), and Tg-5 (STZ + compound 3).

Figure 2

Effect of compound 3 treatments on plasma insulin and serum lipid profile of diabetic mice. The results are presented as mean ± SEM (n = 3), ** p < 0.01, and * p < 0.05; vs. control group, ^# p < 0.05; ^## p < 0.01 vs. STZ group. Metformin (MET) and streptozotocin (STZ). Low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Control (Tg-1), STZ (Tg-2), compound 3 (Tg-3), STZ + metformin (Tg-4), and STZ + compound 3 (Tg-5).

Figure 3

Effect of compound 3 on serum markers ALT, AST, ALP, BUN, and creatinine level in diabetic mice. The results are presented as mean ± SEM (n = 3), ** p < 0.01, and * p < 0.05; vs. control group, ^# p < 0.05; ^## p < 0.01 vs. STZ group. Aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and alkaline phosphatase (ALP). Tg-1 (control), Tg-2 (STZ), Tg-3 (compound 3), Tg-4 (STZ + metformin), and Tg-5 (STZ + compound 3).

Figure 4

Effect of the tested synthesized compound treatments on histology of the liver (A), kidneys (B), and pancreas (C) of diabetic mice.