Facile one-pot synthesis, butyrylcholinesterase and α-glucosidase inhibitory activities, structure–activity relationship, molecular docking and DNA–drug binding analysis of Meldrum’s acid derivatives

• Published in: Research on chemical intermediates 2020-05, Vol.46 (5), p.2437-2456
• Main Authors: Mehfooz, Haroon, Saeed, Aamer, Faisal, Muhammad, Larik, Fayaz Ali, Muqadar, Urooj, Khatoon, Saira, Channar, Pervaiz Ali, Ismail, Hammad, Bilquees, Salma, Rashid, Sajid, Shafique, Shagufta, Mirza, Bushra, Dilshad, Erum, Ahmad, Fawad
• Format: Article
• Language: English
• Subjects: Binding; Biological activity; Catalysis; Chemistry; Chemistry and Materials Science; Deoxyribonucleic acid; Derivatives; DNA; Enzymes; Gibbs free energy; Glucosidase; Hydrophobicity; Inhibitors; Inorganic Chemistry; Molecular docking; Molecular structure; NMR; Nuclear magnetic resonance; Physical Chemistry; Residues
• ISSN: 0922-6168; 1568-5675
• DOI: 10.1007/s11164-020-04100-3

Meldrum’s acid derivatives were facile synthesized by one-pot condensation process and characterized by NMR ( 1 H, 13 C, DEPT-90 and DEPT-135) and EI-MS. The synthesized compounds were screened for their potential to inhibit butyrylcholinesterase (BChE) and α-glucosidase enzymes. Interestingly, the derivative 3a showed potent α-glucosidase inhibitory activity, with the IC 50 value equal to 2.1 mg/mL as compared to standard acarbose (IC 50  = 4.7 mg/mL), whereas, in terms of BChE inhibitory activity investigation, the derivatives 3a and 3c showed novel results, with the IC 50 values equal to 1.2 and 2.9 mg/mL, respectively, as compared to standard galantamine hydrobromide (IC 50  = 4.7 mg/mL), making derivative 3a a dual inhibitor of both enzymes. Further, structure–activity relationship, comparative molecular docking analysis and the DNA–drug binding interaction were studied to investigate relationship between the chemical structure and its biological activity, inhibition of mechanism, interaction of compounds, DNA binding constant and Gibbs free energy. Structural insights into inhibitor binding to the α-glucosidase and BuChE revealed significant contribution of hydrophobic regions and significant residues of active sites. Comparative molecular docking studies showed that the residues of oxyanion hole, catalytic triad and hydrophobic pocket were actively engaged in interaction with the inhibitor. DNA binding constant was found in the order K b 3e >  K b 3c >  K b 3a >  K b 3b >  K b 3d, while Gibbs free energy was found in the order ∆ G 3e > ∆ G 3a > ∆ G 3b > ∆ G 3c > ∆ G 3d.