Design, synthesis, and biological evaluation of ferulic acid based 1,3,4-oxadiazole hybrids as multifunctional therapeutics for the treatment of Alzheimer’s disease
“…Among all the four oxadiazole types, 1,2,4- and 1,3,4-isomers are the most investigated for medicinal applications [ 23 ], and they are present in numerous marketed drugs, such as the Ataluren [ 25 ], Azilsartan [ 26 ], Opicapone [ 27 ], Naldemedine [ 28 ], and Raltegravir [ 29 ]. Moreover, many oxadiazole derivatives have been studied as antibiotics [ 30 , 31 , 32 , 33 , 34 ], fungicides [ 35 ], antivirals [ 36 ], anticancer [ 37 , 38 , 39 ], and anti-inflammatory [ 40 , 41 , 42 ] agents, neuroprotectors [ 43 , 44 , 45 ], as well as antidiabetic drugs [ 46 ] in recent years. This significantly stimulates further structural and theoretical studies on various noncovalent interactions involving oxadiazole-based compounds.…”
A series of N-pyridyl ureas bearing 1,2,4- (1a, 2a, and 3a) and 1,3,4-oxadiazole moiety (1b, 2b, 3b) was prepared and characterized by HRMS, 1H and 13C NMR spectroscopy, as well as X-ray diffraction. The inspection of the crystal structures of (1–3)a,b and the Hirshfeld surface analysis made possible the recognition of the (oxadiazole)···(pyridine) and (oxadiazole)···(oxadiazole) interactions. The presence of these interactions was confirmed theoretically by DFT calculations, including NCI analysis for experimentally determined crystal structures as well as QTAIM analysis for optimized equilibrium structures. The preformed database survey allowed the verification of additional examples of relevant (oxadiazole)···π interactions both in Cambridge Structural Database and in Protein Data Bank, including the cocrystal of commercial anti-HIV drug Raltegravir.
“…Among all the four oxadiazole types, 1,2,4- and 1,3,4-isomers are the most investigated for medicinal applications [ 23 ], and they are present in numerous marketed drugs, such as the Ataluren [ 25 ], Azilsartan [ 26 ], Opicapone [ 27 ], Naldemedine [ 28 ], and Raltegravir [ 29 ]. Moreover, many oxadiazole derivatives have been studied as antibiotics [ 30 , 31 , 32 , 33 , 34 ], fungicides [ 35 ], antivirals [ 36 ], anticancer [ 37 , 38 , 39 ], and anti-inflammatory [ 40 , 41 , 42 ] agents, neuroprotectors [ 43 , 44 , 45 ], as well as antidiabetic drugs [ 46 ] in recent years. This significantly stimulates further structural and theoretical studies on various noncovalent interactions involving oxadiazole-based compounds.…”
A series of N-pyridyl ureas bearing 1,2,4- (1a, 2a, and 3a) and 1,3,4-oxadiazole moiety (1b, 2b, 3b) was prepared and characterized by HRMS, 1H and 13C NMR spectroscopy, as well as X-ray diffraction. The inspection of the crystal structures of (1–3)a,b and the Hirshfeld surface analysis made possible the recognition of the (oxadiazole)···(pyridine) and (oxadiazole)···(oxadiazole) interactions. The presence of these interactions was confirmed theoretically by DFT calculations, including NCI analysis for experimentally determined crystal structures as well as QTAIM analysis for optimized equilibrium structures. The preformed database survey allowed the verification of additional examples of relevant (oxadiazole)···π interactions both in Cambridge Structural Database and in Protein Data Bank, including the cocrystal of commercial anti-HIV drug Raltegravir.
“…The possible mechanism is that FA rescued the hypoxia-up-regulated BACE1 activity [ 29 ] and/or inhibited the NFκB-dependent transcription of BACE1 [ 70 ]. It has been also reported that FA may directly interact with BACE1 and inhibit its activity [ 71 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Some earlier preclinical studies also have demonstrated the protective effects of FA or FA based hybrids in AD mouse models. In these studies, FA was found to produce actions such as reducing Aβ deposition or promoting anti-inflammatory or antioxidant effects [ 37 , 69 , 71 , 81 – 83 ]. The present study further strengthened this idea, for which FA not only caused a reduction of Aβ plaques and aggregative microglial cells but also produced protective effects on capillaries possibly via the ETRA, which have not been reported before.…”
Section: Discussionmentioning
confidence: 99%
“…The possible mechanism is that FA rescued the hypoxia-up-regulated BACE1 activity [29] and/or inhibited the NFκB-dependent transcription of BACE1 [70]. It has been also reported that FA may directly interact with BACE1 and inhibit its activity [71]. We next performed co-immunostaining of Aβ plaque deposition with microglia in the hippocampus from AD mice at 7 months old after the 30-day FA or vehicle treatment.…”
Section: Fa Prevents Aβ Plaque Deposition Partiallymentioning
Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aβ) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aβ plaque deposition, the primary pathophysiology of Alzheimer’s disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aβ plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aβ plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aβ plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aβ plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.
“…[ 1 ] Furthermore, several derivatives of oxadiazole derivatives with high inhibitory activity against metabolic enzymes including human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α‐glucosidase have been reported. [ 2–5 ] Another important heterocycle in the design of new bioactive compounds is quinoxalin, which has a bicyclic aromatic structure with two nitrogen atoms. Several derivatives of this scaffold with biological activities such as antiproliferative, anti‐α‐glucosidase, anti‐acetylcholinesterase, and anti‐nitric oxide synthase have been reported.…”
A new series of quinoxalin‐1,3,4‐oxadiazole (10a–l) derivatives was synthesized and evaluated against some metabolic enzymes including human carbonic anhydrase (hCA) isoenzymes I and II (carbonic anhydrases I and II), cholinesterase (acetylcholinesterase and butyrylcholinesterase), and α‐glucosidase. Obtained data revealed that all the synthesized compounds were more potent as compared with the used standard inhibitors against studied target enzymes. Among the synthesized compounds, 4‐fluoro derivative (10f) against hCA I, 4‐chloro derivative (10i) against hCA II, 3‐fluoro derivative (10e) against acetylcholinesterase and butyrylcholinesterase, and 3‐bromo derivative (10k) against α‐glucosidase were the most potent compounds with inhibitory activity around 1.8‐ to 7.37‐fold better than standard inhibitors. Furthermore, docking studies of these compounds were performed at the active site of their target enzymes.
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