Molecular Nutrition & Food Research RESEARCH ARTICLE Ameliorative Potential of Synthetic Flavone-Derivative in Diabetes-Associated Neurodegeneration Karishma Sen 1 Anita Sakarwal 1 Heera Ram 1 Suman K. Saha 2 Nirmal K. Rana 2 Dharamveer Yadav 3 Mukesh Kumar Yadav 4 Balachandar Vellingiri 5 Mariusz Jaremko 6 Habibullah Khalilullah 7 Amita Verma 8 Vikas Kumar 9, 10 Anil Panwar 11 1 Department of Zoology, Jai Narain Vyas University, Jodhpur, Rajasthan, India 2 Department of Chemistry, Indian Institute of Technology, Jodhpur, Rajasthan, India 3 Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India 4 Department of Microbiology, Central University of Punjab, Bhatinda, Punjab, India 5 Department of Zoology, Central University of Punjab, Bhatinda, Punjab, India 6 Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia 7 Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim, Kingdom of Saudi Arabia 8 Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, Uttar Pradesh, India 9 Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, SHUATS, Prayagraj, Uttar Pradesh, India 10 University Centre for Research and Development, Chandigarh University, Gharuan, Punjab, India 11 Department of Bioinformatics and Computational Biology, CCS Haryana Agricultural University, Hisar, Haryana, India Correspondence: Heera Ram (hr.zo@jnvu.edu.in) Received: 20 October 2024 Revised: 12 April 2025 Accepted: 5 June 2025 Funding: This research supported by specific grant received by Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Kingdom of Saudi Arabia. Keywords: 2-(1,3-benzodioxol-5-yl)-4H-chromen-4-one 5(2BDC45) | cortex | gene expression | hippocampus | neuroprotection ABSTRACT The current study was carried out to explore the neuroprotective efficacy of the synthesized compound 2-(1,3-benzodioxol- 5-yl)-4H-chromen-4-one 5 (2BDC45) in diabetes-associated neurodegeneration through in silico and in vivo assessments. In silico exploration of molecular docking showed a significant binding energies of -8.5, -9.3, and -7.4 kcal/mol for 2BDC45 against the target enzymes, i.e., acetylcholinesterase, butyrylcholinesterase, and DPP-4, respectively. These findings were further confirmed through 100 ns molecular dynamics simulations, assessing parameters like RMSD, RMSF, SASA, MMPBSA, and PCA. Treatment with 2BDC45 exhibited the neuroprotective changes in the hippocampus and cortex regions of type 2 diabetes-associated neurodegenerations. Consequently, histopathological analysis of these brain regions, supported by molecular biological analyses of key genes such as GLUT-3, GSK, MAP, and PPARγ corroborated the neuroprotection. The lipid profile, HOMA, and antioxidants exhibited notable changes by the interference of the treatments. The treatments shown significant ameliorations in glucose metabolism by following the expressions of GLUT-3 and GSK, while MAP kinase and PPARγ showed significant restorations in the cortex and hippocampus. In conclusion, it can be implied the test flavone derivative has the capacity to amplify neural plasticity by following the scavenging of free radicals, improved glucose metabolism, and targeted genes expression. Abbreviations: 2BDC45, 2-(1,3-benzodioxol-5-yl)-4H-chromen-4-one 5(2BDC45); HDL, high-density lipoproteins; LDL, low-density lipoproteins; MMPBSA, molecular mechanics Poisson-Boltzmann surface area; PCA, principal component analysis; RMSD, root mean square deviation; RMSF, root square mean fluctuations; SASA, solvent accessible surface area; VLDL, very low-density lipoproteins. © 2025 Wiley-VCH GmbH. Molecular Nutrition & Food Research, 2025; 0:e70172 https://doi.org/10.1002/mnfr.70172 1 of 21