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Curcumin-Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders.

ABSTRACT: Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H₂O₂ in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.

SUBMITTER: Quezada E

PROVIDER: S-EPMC8348017 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The severe acute respiratory syndrome coronavirus, identified as SARS-CoV-2, initially established in Wuhan, China at the end of 2019, affects respiratory infections known as COVID-19. In an extraordinary manner, COVID-19 is affecting human life and has transformed a global public health issue into a crisis. Natural products are already recognized owing to the massive advantageous window and efficient antioxidant, antiviral immunomodulatory, and anti-inflammatory belongings. Additionally, the object of the present study was to demonstrate the inhibitory potential of the natural products coumarins and its analogues alongside SARS coronavirus. The present work, focuses on the synthesis of new coumarin analogues and characterized by FT-IR, 1H and 13C NMR, elemental analyses, and mass spectra. The recently synthesised compounds were projected conceptual association for COVID-19 protease and also to explore in anticipation if this protein will help target protease inhibitor drugs such as Calanolide A, Cardatolide A, Collinin, Inophyllum A, Mesuol, Isomesuol, Pteryxin, Rutamarin, Seselin and Suksdorin. The natural coumarin analogues docking scores were compared to standard Hydroxychloroquine. While the 3D module of SARS coronavirus main protease was predicted with the SWISS MODEL web server, as well as biochemical interaction tests were performed with the AutoDock Vina tool between the target protein with ligands. This research further showed that all the protease inhibitors accessed the target protein with negative dock energy. Molecular docking studies found that the natural coumarin analogue Inophyllum A showed an exceptional potential for inhibition with a binding energy of -8.4 kcal/mol. The synthetic coumarin analogues 1m and 1p both demonstrated a similar binding energy, inhibition potential of -7.9 kcal / mol as opposed to hydroxychloroquine and co-crystallized ligand alpha-ketoamide with binding energy values of -5.8 and -6.6 kcal / mol. All compounds evaluated were known as drug-like in nature, passing Lipinski's "Law of 5" with 0 violations except for alpha-ketoamide, passing Lipinski's "Rule of 5" with 1 violation (MW > 500). The inhibitor binding in silico research thus offers a structural understanding of COVID-19 and molecular interactions across the known protease inhibitors centred on the findings of the multiple sequence alliance.

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Curcumin-Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders.

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