Integrative bioinformatic and experimental analysis of benzoylbenzodioxol derivatives: hypoglycemic potential in diabetic mice

Mohammed Hawash*, Nidal Jaradat, Murad Abualhasan, Jazeel Jadallah, Lama Fashafsheh, Salsabeela Zaid, Naim Qamhia, Mohammad Qneibi, Mohammed T. Qaoud, Ozden Tari, Matthew Merski, Ahmet S. Boşnak, Ahmed Mousa, Linda Issa, Ahmad M. Eid

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We investigated the hypoglycemic activity and pharmacokinetic study of two synthesized benzoyl benzodioxol derivatives, compound I (methyl 2-(6-(2-bromobenzoyl)benzo[d][1,3]dioxol-5-yl)acetate), and compound II, 2-(6-benzoylbenzo[d][1,3]dioxol-5-yl)acetic acid, which showed very strong α-amylase inhibiting activity in our previous study. Then, diabetes was induced by the injection of streptozotocin to mice. The molecular docking simulations and analyses of density functional theory analyses were conducted to study the binding interactions with human pancreatic alpha-amylase, and their pharmacokinetic properties were further evaluated by ADMET profiling. Compound I showed the most important hypoglycemic effect, decreasing the blood glucose by 32.4%, higher than that of compound II by 14.8% and even the positive control acarbose by 22.9%. Histopathological examination revealed that diabetic livers showed portal inflammation with some apoptotic hepatocytes due to streptozotocin treatment, whereas controls without any treatment maintained normal liver architecture. Molecular docking studies gave results for the best binding affinity of the compound I, through its strong water bridges and π–π interactions, and also through analysis with density functional theory, was more stable and reactive when compared to compound II. Further ADMET analysis showed that both compounds shared a promising pharmacokinetic profile, and compound I had the potential for CNS penetration. Thus, compound I was selected as the best candidate for developing new hypoglycemic agents with potent efficacy, good binding interactions, and excellent pharmacokinetic properties.

Original languageEnglish
Article number255
Journal3 Biotech
Volume14
Issue number10
DOIs
StatePublished - Oct 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© King Abdulaziz City for Science and Technology 2024.

Keywords

  • Benzoylbenzodioxol
  • Bioinformatics
  • Liver
  • Molecular docking
  • Mouse model
  • Streptozotocin
  • α-Amylase

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