Discovery of new anti-diabetic potential agents based on paracetamol incorporating sulfa-drugs: Design, synthesis, α-amylase, and α-glucosidase inhibitors with molecular docking simulation

Jun 15, 2024European journal of medicinal chemistry

New anti-diabetic compounds combining paracetamol and sulfa-drugs that may block sugar-digesting enzymes, supported by computer simulations

AI simplified

GLP-1 Therapies on OpenScience ↗PubMed ↗DOI ↗

Abstract

The newly designed diazo-paracetamols exhibited inhibitory percentages of 92.5-96.5% against α-amylase at 100 μg/mL.

Diazo-paracetamols were synthesized using a strategy that combined paracetamol and sulfonamides.
These compounds demonstrated moderate to potent inhibition of α-amylase and α-glucosidase enzymes.
Compound 11 showed the highest potency against α-amylase with an IC value of 0.98 ± 0.015 μM.
Compound 10 exhibited the strongest inhibition of α-glucosidase with an IC value of 1.39 ± 0.021 μM.
The structure-activity relationship analysis indicated that specific chemical groups enhance inhibitory activity.

AI simplified

Uncontrolled diabetes can lead to hyperglycemia, which causes neuropathy, heart attacks, retinopathy, and nervous system damage over time, therefore, controlling hyperglycemia using potential drug target inhibitors is a promising strategy. This work focused on synthesizing new derivatives via the diazo group, using a hybridization strategy involving two approved drugs, paracetamol and several sulfonamides. The newly designed diazo-paracetamols 5-12 were fully characterized and then screened for in vitro α-amylase and α-glucosidase activities and exhibited inhibitory percentages (IP) = 92.5-96.5 % and 91.0-95.7 % compared to Acarbose IP = 96.5 and 95.8 %, respectively at 100 μg/mL. The ICvalues of the synthesized derivatives were evaluated against α-amylase and α-glucosidase enzymes, and the results demonstrated moderate to potent activity. Among the tested diazo-paracetamols, compound 11 was found to have the highest potency activity against α-amylase with ICvalue of 0.98 ± 0.015 μM compared to Acarbose IC = 0.43 ± 0.009 μM, followed by compound 10 (IC = 1.55 ± 0.022 μM) and compound 9 (IC = 1.59 ± 0.023 μM). On the other hand, for α-glucosidase, compound 10 with pyrimidine moiety demonstrated the highest inhibitory activity with IC = 1.39 ± 0.021 μM relative to Acarbose IC = 1.24 ± 0.029 μM and the order of the most active derivatives was 10 > 9 (IC = 2.95 ± 0.046 μM) > 11 (IC = 5.13 ± 0.082 μM). SAR analysis confirmed that the presence of 4,5-dimethyl-isoxazole or pyrimidine nucleus attached to the sulfonyl group is important for activity. Finally, the docking simulation was achieved to determine the mode of binding interactions for the most active derivatives in the enzyme's active site. 50 50 50 50 50 50 50 50 50

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

Discovery of new anti-diabetic potential agents based on paracetamol incorporating sulfa-drugs: Design, synthesis, α-amylase, and α-glucosidase inhibitors with molecular docking simulation

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the glp-1 therapies brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the glp-1 therapies brief