Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents

Abstract

Scavenging reactive oxygen species (ROS) by antioxidants is the important therapy to cerebral ischemia-reperfusion injury (CIRI) in stroke. The antioxidant with novel dual-antioxidant mechanism of directly scavenging ROS and indirectly through antioxidant pathway activation may be a promising CIRI therapeutic strategy. In our study, a series of chalcone analogues were designed and synthesized, and multiple potential chalcone analogues with dual antioxidant mechanisms were screened. Among these compounds, the most active 33 not only conferred cytoprotection of H 2 O 2 -induced oxidative damage in PC12 cells through scavenging free radicals directly and activating NRF2/ARE antioxidant pathway at the same time, but also played an important role against ischemia/reperfusion-related brain injury in animals. More importantly, in comparison with mono-antioxidant mechanism compounds, 33 exhibited higher cytoprotective and neuroprotective potential in vitro and in vivo. Overall, our findings showed compound 33 could emerge as a promising anti-ischemic stroke drug candidate and provided novel dual-antioxidant mechanism strategies and concepts for oxidative stress-related diseases treatment.

Gender Differences in the Association between Frailty, Cognitive Impairment, and Self-Care Behaviors Among Older Adults with Atrial Fibrillation

“…Therefore, further research to validate these tools is required. Finally, we did not include possible risk factors, such as oxidative stress [48], cardiovascular reactivity [49], or risk of stroke [50], which can influence AF. More research is needed to identify the adverse health outcomes of risk factors on AF.…”

Recent Advances in Chalcones: Synthesis, Transformation and Pharmacological Activities

“…Stepanic et al found compound 109 potent in 1,1-diphenyl-2-picrylhydrazyl (DPPH•) radical scavenging activity, through single electron transfer followed by a proton transfer (SET-PT) mechanism as revealed by density functional theory (DFT) modeling [28]. Likewise, compound 110 played protective and therapeutic roles against ischemia/reperfusion-related brain injury for both in vitro and in vivo as free radical scavengers or Nuclear factor erythroid 2-related factor 2 (NRF2) pathway stimulators [29] (Fig. 10).…”

“…Chalcones are multifunctional molecules that possess promising pharmacological activities. Chalcones have been found useful as anticancer [23][24][25], antioxidant [26][27][28][29], antiinflammatory [30][31][32], anti-microbial [23,[33][34][35][36], anti-tubercular [34,37,38], antileishmanial [39], antimalarial [40][41][42], anthelmintic [27], osteogenic activity [43]. This review article focuses on recent applications of Claisen-Schmidt condensation reaction employed in the synthesis of chalcone, its transformation to heterocyclic compounds and pharmacological activities.…”

Design, Facile Synthesis and Characterization of Dichloro Substituted Chalcones and Dihydropyrazole Derivatives for Their Antifungal, Antitubercular and Antiproliferative Activities

“…The α,β-unsaturated ketone moiety is highly reactive, making the chalcones valuable starting materials for the synthesis of a range of heterocyclic compounds of ring size of 5, 6, or 7 with nitrogen, oxygen, and sulfur as hetero atoms [ 1 ]. Chalcone derivatives, which are excellent starting points in drug design [ 2 , 3 , 4 , 5 , 6 , 7 ], are well-known for varied biological activities such as antimicrobial, anticancer, antimalarial, antioxidant, anti-tubercular, anti-inflammatory, and anti-tumor activities [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Dihydropyrazole is an interesting heterocyclic compound, which can be synthesized from chalcones.…”