Synergistic effect of hydrogen bonding and C–H…π interactions to modulate the supramolecular assemblies of isobenzofuranones: X-ray crystallography, DFT analysis and antihyperglycemic potential

• Published in: Journal of molecular structure 2025-02, Vol.1321, p.140263, Article 140263
• Main Authors: Zaib, Sumera, Khan, Imtiaz, Ibrar, Aliya, Ali, Hafiz Saqib, Rana, Nehal, Munir, Rubina, Zahra, Shabab, Al-Odayni, Abdel-Basit, McAdam, Christopher John, Hökelek, Tuncer, Frontera, Antonio
• Format: Article
• Language: English
• Subjects: DFT calculations; Hydrogen bonding; Isobenzofuranone; Noncovalent interactions; Supramolecular network; α-glucosidase inhibitors
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140263

•Synthesis of two new isobenzofuranones as new antidiabetics.•Synergistic effects of hydrogen bonding and C–H…π interactions.•Combined X-ray crystallographic and DFT analysis of noncovalent interactions.•Compound 3b showed the best potency with an IC50 value of 13 ± 0.01 µM.•Compound 3b follows the druggable criteria with a safe toxicity profile. This manuscript reports the synthesis, X-ray characterization and antihyperglycemic potential of two isobenzofuranone derivatives. The Suzuki-Miyaura cross-coupling of 5-bromoisobenzofuran-1(3H)-one with phenylboronic acid and p-tolylboronic acid under the action of palladium catalysis afforded the desired compounds in good yields. The structures were fully established using FTIR and NMR spectroscopy and X-ray crystallography. The study further delves into the synergistic effects of hydrogen bonding and C–H…π interactions on the supramolecular assemblies of isobenzofuranones, leveraging a holistic approach that combines X-ray crystallography, Density Functional Theory (DFT) analysis, and evaluation of antihyperglycemic activity. Focusing on two isobenzofuranone derivatives, we meticulously elucidate their structural features and how noncovalent interactions shape their crystal packing. Our exploration extends to assessing the antihyperglycemic potential of these compounds, underpinned by α-glucosidase inhibitory assays and augmented by molecular docking analysis. Compound 3b showed the best potency with an IC50 value of 13 ± 0.01 µM which is 67-folds strong inhibition than acarbose (IC50 = 870.2 ± 1.54 µM). Furthermore, the admetSAR and ProTox-II demonstrated that compound 3b follows the druggable criteria with a safe toxicity profile. Overall, these findings highlight the pivotal role of noncovalent interactions in modulating the supramolecular architectures of isobenzofuranones, thereby offering insights into their therapeutic potential against diabetes mellitus. [Display omitted] Combined X-ray crystallographic and DFT investigation of two isobenzofuranone derivatives for assessing the role of noncovalent interactions in the formation of complex molecular architectures. In vitro glucosidase inhibitory assay revealed compound 3b as the best potent inhibitor with 67-folds strong inhibition than acarbose.