Design and Hantzsch Multicomponent Synthesis of Unsymmetrical 1,4-Dihydropyridines as Potential DPP-4 Inhibitors

Type 2 diabetes mellitus is a disease characterized by insulin resistance and hyperglycemia¹. Among the drugs used in glycemic control are antidiabetic agents that inhibit the DPP-4 enzyme². Previous computational studies have identified 1,4-dihydropyridine (1,4-DHP) derivatives as potential inhibitors (IC₅₀ = 0,18nm; IC₅₀ sitagliptin (reference drug)  = 18 nM³). This work aimed at the synthesis of differently substituted 1,4-DHP derivatives via the Hantzsch multicomponent reaction. Initially, the enaminonitrile (2) was synthesized via the Thorpe reaction⁴ under mechanochemical conditions (31% yield). The Hantzsch MCR was optimized, overcoming the formation of byproducts, such as the symmetric compound (5) (8% yield). The compound (6) was isolated and characterized by ¹H and ¹³C NMR, obtained in 6% yield. Attempts at direct amidation with 1-aminopiperidine were unsuccessful. Nevertheless, the overall findings support the feasibility of the proposed synthetic route, providing a foundation for further optimization and future DPP-4 inhibition assays.