Synthesis, highly potent α-glucosidase inhibition, antioxidant and molecular docking of various novel dihydropyrimidine derivatives to treat diabetes mellitus

Abstract

1,4-dihydropyrimidine-2-thiones were synthesized in five series that include 5-carboxylic acid derivatives of dihydropyrimidine (series A, 6–8), novel 5-carboxamide derivatives of dihydropyrimidine (series B, 9–14), N,S-dimethyl-dihydropyrimidine (series C, 15–20), N-hydrazinyl derivatives of dihydropyrimidine (series D, 21–24) and tetrazolo dihydropyrimidine derivatives (series E, 25–28), and evaluated for anti-diabetic capability. The prepared novel compounds were structurally established by FTIR, ¹HNMR, ¹³CNMR, ESI and HRMS. All of these compounds from series A—E were first time examined for α-glucosidase inhibition as to evaluate their anti-diabetic potential. Most of the compounds for example 8, 11–14, 15, 17–21, 25 and 28 demonstrated greater α-glucosidase inhibitory effects (IC₅₀ = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC₅₀ = 52.02 ± 0.36 μM). Compounds from series B and C found to be highly active however, the compounds from series D found generally less active. The structure–activity relationships demonstrated the importance of C-5 carboxamides, C-5 ethyl ester functionality, and the presence of N,S-dimethyl groups at pyrimidine ring for α-glucosidase inhibition. The docking studies demonstrated that all the active compounds have van der Waals and alkyl bonds interactions with the targeted site of the human lysosomal acid α-glucosidase. All these compounds were also tested for antioxidant potential by DPPH radical scavenging protocol that exhibited significant antioxidant effects (IC₅₀ = 21.4 $\pm$ 0.45 to 92.1 $\pm$ 0.38 μM) as compared to the standard butylated hydroxyanisol (IC₅₀ = 44.2 $\pm$ 0.36 μM). Among all, compound 13, 14 and 19 with potent α-glucosidase inhibition (IC₅₀ = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC₅₀ = 21.4 $\pm$ 0.45 to 31.2 ± 0.23 μM) indicated their ability to use as valuable leads for the development of anti-diabetic drugs with the combined effects of antioxidants.