New multitarget antidiabetic potential agents based on sulfaguanidine: design, synthesis, and biological evaluation

Diabetes-related morbidity and mortality rates are high, making type 2 diabetes (T2DM) a serious issue at an alarming rate. This work focused on the design and synthesis of a series of new sulfaguanidine derivatives connected through a hydrazine linker to five-membered heterocycles. All synthesized derivatives were screened for in vitro α-amylase, α-glucosidase, and glucose uptake activities. Interestingly, all the synthesized sulfaguanidine derivatives exhibited significant α-glucosidase and α-amylase inhibitory potentials that were more potent than acarbose. Sulfaguanidine derivative 10 (IC₅₀ = 0.39 µM) exhibited the most potent α-glucosidase inhibition among all the synthesized derivatives, which was 7.43-fold more potent than acarbose. Compound 4 (IC₅₀ = 0.33 µM) was the most potent derivative, exhibiting the strongest α-amylase inhibition and a glucose uptake activity, 1.20- to 1.92-fold higher than that of berberine. The prominent interactions with the α-amylase and α-glucosidase active sites can be used to computationally rationalize the significant in vitro inhibitory activity of the synthesized sulfaguanidine derivatives against both enzymes. This study reveals that sulfaguanidine-conjugated pyrazole or oxazole derivatives are prospective multitarget therapeutic candidates that can be employed for the treatment of T2DM, which is characterized by complicated etiologies.