TY - JOUR
T1 - Integrative bioinformatic and experimental analysis of benzoylbenzodioxol derivatives
T2 - hypoglycemic potential in diabetic mice
AU - Hawash, Mohammed
AU - Jaradat, Nidal
AU - Abualhasan, Murad
AU - Jadallah, Jazeel
AU - Fashafsheh, Lama
AU - Zaid, Salsabeela
AU - Qamhia, Naim
AU - Qneibi, Mohammad
AU - Qaoud, Mohammed T.
AU - Tari, Ozden
AU - Merski, Matthew
AU - Boşnak, Ahmet S.
AU - Mousa, Ahmed
AU - Issa, Linda
AU - Eid, Ahmad M.
N1 - Publisher Copyright:
© King Abdulaziz City for Science and Technology 2024.
PY - 2024/10
Y1 - 2024/10
N2 - 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.
AB - 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.
KW - Benzoylbenzodioxol
KW - Bioinformatics
KW - Liver
KW - Molecular docking
KW - Mouse model
KW - Streptozotocin
KW - α-Amylase
UR - http://www.scopus.com/inward/record.url?scp=85205263312&partnerID=8YFLogxK
U2 - 10.1007/s13205-024-04103-6
DO - 10.1007/s13205-024-04103-6
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C2 - 39350934
AN - SCOPUS:85205263312
SN - 2190-572X
VL - 14
JO - 3 Biotech
JF - 3 Biotech
IS - 10
M1 - 255
ER -