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Synthesis and Inhibitory Effect of Some Indole-Pyrimidine Based Hybrid Heterocycles on ?-Glucosidase and ?-Amylase as Potential Hypoglycemic Agents.

ABSTRACT: The Michael addition reaction of barbituric acid with chalcones incorporating the indole scaffold was achieved by using a highly efficient bimetallic Iron-palladium catalyst in the presence of acetylacetone (acac). This catalytic approach produced the desired products in a simple operation and low catalyst loading with acceptable yield of the new hybrids. All tested compounds were subjected for biological activity on ?-glucosidase and ?-amylase. The results revealed that all synthesized compounds exhibited very good activity against both enzymes when compared to positive control (acarbose). Moreover, compound 5o showed the best activity whereas its IC50 (?M) are 13.02+0.01 and 21.71+0.82 for ?-glucosidase and ?-amylase respectively. Both compounds 5o and 5l exhibited high similarity in binding mode and pose with amylase protein (4UAC). The obtained data may be used for developing potential hypoglycemic agents.

SUBMITTER: Badria FA

PROVIDER: S-EPMC6804419 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Synthesis and Inhibitory Effect of Some Indole-Pyrimidine Based Hybrid Heterocycles on α-Glucosidase and α-Amylase as Potential Hypoglycemic Agents.

Badria Farid A FA Atef Saleh S Al-Majid Abdullah Mohammed AM Ali M M Elshaier Yaseen A M M YAMM Ghabbour Hazem A HA Islam Mohammad Shahidul MS Barakat Assem A

ChemistryOpen 20191022 10

The Michael addition reaction of barbituric acid with chalcones incorporating the indole scaffold was achieved by using a highly efficient bimetallic Iron-palladium catalyst in the presence of acetylacetone (acac). This catalytic approach produced the desired products in a simple operation and low catalyst loading with acceptable yield of the new hybrids. All tested compounds were subjected for biological activity on α-glucosidase and α-amylase. The results revealed that all synthesized compound ...[more]

PMID: 31649838

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Project description:A series of tetra-O-acetyl-α-d-glucopyranosyl thioureas 8a-l of substituted 2-aminopyrimidines 4a-l have been designed and synthesized. The latter were prepared from corresponding chalcones 3a-l of p-bromoacetophenone and appropriate substituted benzaldehydes by their reaction with guanidine. The target thiourea compounds 8a-l exhibited significant inhibitory activity in vitro against enzymes that were related to type 2 diabetes mellitus, including α-amylase, α-glucosidase, DPP-4, and PTP1B. Amongst these thioureas, compound 8k with an ortho-methoxy group was the most potential enzyme inhibitor against α-amylase with an IC50 value of 9.72 ± 0.34 μM. Its meta-isomer 8j was the strongest inhibitor against α-glucosidase with IC50 = 9.73 ± 0.72 μM. In the inhibition against DPP-4, compound 8f with a para-bromo substituent exhibited the strongest activity with an IC50 value of 2.53 ± 0.03 nM. In the inhibition against PTP1B, compound 8h with a para-isopropyl substituent had the strongest inhibitory activity with an IC50 value of 2.74 ± 0.03 μM. The enzyme kinetics of the most active compounds, including 8j, 8f and 8h against α-glucosidase, DPP-4, and PTP1B, respectively, were studied. The obtained results showed that 8j was a competitive α-glucosidase inhibitor with an inhibitory constant K I value of 9.31 μM. Compound 8f was a non-competitive inhibitor for DDP-4 with an inhibitory constant K I value of 12.57 μM. Compound 8h was also a non-competitive inhibitor for DDP-4 with an inhibitory constant K I value of 12.41 μM. The cytotoxicity of the most active compounds, including 8f and 8k (against α-amylase), 8i and 8j (against α-glucosidase), 8a, 8f, and 8g (against DPP-4), and 8d, 8f, and 8h (against PTP1B) was screened. The obtained cytotoxicity showed that all tested inhibitors were noncytotoxic to human normal cell line 3T3. Induced fit docking simulations of all synthesized compounds 8a-l were performed on four enzymes 4W93 (for α-amylase), 3TOP (for α-glucosidase), 3W2T (for DPP-4), and 1NNY (for PTP1B). Key interactions of each of these ligands with residues in the active pocket of each studied enzyme have been shown.

Dataset Information

Synthesis and Inhibitory Effect of Some Indole-Pyrimidine Based Hybrid Heterocycles on ?-Glucosidase and ?-Amylase as Potential Hypoglycemic Agents.

Publications

Synthesis and Inhibitory Effect of Some Indole-Pyrimidine Based Hybrid Heterocycles on α-Glucosidase and α-Amylase as Potential Hypoglycemic Agents.

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