A018(Lanzhou University)

One of the most widespread diseases recognized all over the world is diabetes, accounting for 1.5 million deaths each year. Recent studies have demonstrated benzimidazole derivatives as potential antidiabetic agents. Hence, the present study is focused on designing new derivatives of 2-mercaptobenzimidazole by C-S cross-coupling reaction and are subjected to computational screening to identify the most promising candidate. Molecular docking and MM-GBSA calculations were performed to ascertain the binding potential with different antidiabetic targets, including α-glucosidase, PPaR-γ, DPP-4, and AMPK. We observed somewhat moderate binding interactions of the synthesized compound against the α-glucosidase. Since binding affinities can be improved using synthetic chemistry approaches, synthesis of analogues (A-18a-c) by designing hybrids at sites such as the acidic functionality of A-18 was done. The analogue A-18a, with p-fluorobenzyl substitution, exhibited enhanced binding affinity (-4.339 Kcal/mol) with the α-glucosidase compared to the parent compound (-3.827 Kcal/mol). The synthesized analogues were also subjected to an in-vitro α-glucosidase inhibitory assay. Among them, A-18a exhibited the most significant inhibitory potential, with an IC₅₀ value of 0.521 ± 0.01 µM as compared to the standard drug Acarbose (IC₅₀ 21.0 ± 0.5 µM). This aligns with the computational study findings, where A-18a exhibited stronger binding interactions within the active site of the enzyme. Hence, a promising analogue of the designed compound was synthesized through a computationally guided approach as an anti-hyperglycaemic agent. Additionally, most of the designed compounds showed significantly greater binding affinity with PPaR-γ as compared to the standard pioglitazone. A-18 was successfully synthesized by S-arylation reaction using CuI in 89% yield and was subjected to MD-simulation against PPaR-γ, which revealed stable binding throughout the 200 ns run. Future studies will focus on exploring the activity of the designed drugs against PPaR-γ through in-vitro and in-vivo assays.

The scaffold hopping strategy of chain extension is widely used in medicines and pesticides, many of which have introduced alkynes to increase rigidity and activity. Therefore, an alkyne molecule is introduced into the biphenyl structure to form alkyne-containing difluoropyrazole derivatives. Most of the compounds had excellent activity in in vitro activity tests against Rhizoctonia solani. The EC₅₀ values of compounds A1, A13, A15, and A18 were 0.0214, 0.0189, 0.0223, and 0.0173 mg/L, respectively, which were similar to fluxapyroxad (EC₅₀ = 0.0237 mg/L). Activity tests in vivo revealed that compound A12 still had 57.1% control against R. solani at 5 mg/L. The inhibition effects of compounds A12 and A16 against succinate dehydrogenase were 3.58 and 2.22 μM, respectively, better than fluxapyroxad (IC₅₀ = 4.24 μM). The mode of action of these compounds was further explored by molecular docking and scanning electron microscopy analysis, and the results were found to be similar to those of fluxapyroxad. These results demonstrate a new concept of introducing alkyne-based chain extension in succinate dehydrogenase inhibitor fungicides.