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

Nov 3, 2024Bioorganic & medicinal chemistry letters

New dihydropyrimidine compounds with strong sugar-digesting enzyme blocking and antioxidant effects for diabetes treatment

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Abstract

Compound 13 demonstrated potent α-glucosidase inhibition with an IC of 18.9 ± 0.72 µM, significantly lower than the standard.

The synthesized compounds from five series were evaluated for their potential to inhibit α-glucosidase, an enzyme linked to diabetes management.
Most compounds showed greater α-glucosidase inhibitory effects compared to deoxynojirimycin, with IC values ranging from 12.5 ± 0.21 to 47.3 ± 0.23 μM.
Compounds from series B and C exhibited high activity, while series D compounds were generally less effective.
Structural features such as C-5 carboxamides and N,S-dimethyl groups were associated with increased inhibition of α-glucosidase.
Active compounds interacted with the targeted site of human lysosomal acid α-glucosidase through van der Waals and alkyl bonds.
Significant antioxidant effects were observed in all compounds, with IC values between 21.4 ± 0.45 and 92.1 ± 0.38 μM.

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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,HNMR,CNMR, 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 (IC = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC = 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 (IC = 21.4 ± 0.45 to 92.1 ± 0.38 μM) as compared to the standard butylated hydroxyanisol (IC = 44.2 ± 0.36 μM). Among all, compound 13, 14 and 19 with potent α-glucosidase inhibition (IC = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC = 21.4 ± 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. 1 13 50 50 50 50 50 50

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

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