anti-Alzheimer's Disease Research Articles

Synthesis and evolution of neuroprotective effects of oxymatrine derivatives as anti-Alzheimer's disease agents.

While screening for natural product scaffolds as potential anti-Alzheimer's disease (AD), oxymatrine (OMT) was found to relieve symptoms of AD through diminishing death of neuronal cells caused by microglia-induced inflammation. In this study, 13 derivatives of OMT were synthesized and their neuroprotective effects were evaluated on Aβ1-42 -induced PC12 cells using MTT method. In addition, the best neuroprotective potencies were obtained with compounds 4, 6e, and 6f, which were selected for evaluation of decrease in IL-1β and TNF-α in Aβ1-42 -treated PC12 cells. Collectively, these data reveal that derivatives 6e and 6f possess the best ability of diminish IL-1β production and reverse cell damage in all compounds, which are possible to develop as therapeutic agents for AD.

A Novel Heptapeptide, GPPGPAG Transfers to the Brain, and Ameliorates Memory Dysfunction and Dendritic Atrophy in Alzheimer's Disease Model Mice.

We investigated the effects of a heptapeptide, GPPGPAG, on memory improvement and neuritic regeneration in Alzheimer’s disease models to evaluate its potency as a new anti-Alzheimer’s disease (AD) therapy. The anti-AD effects of GPPGPAG were evaluated in Aβ-treated cortical neurons and 5XFAD, a mouse model of AD. Exposure of cortical neurons to Aβ25-35 for 3 days resulted in atrophy of axons and dendrites. Treatment with GPPGPAG improved the dendritic atrophy of Aβ-treated cortical neurons, but not axonal atrophy. Postsynaptic and presynaptic densities under Aβ1-42 exposure were increased by GPPGPAG post treatment. Oral administration of GPPGPAG to 5XFAD mice for 15 days improved significantly object recognition memory and dendritic density. Direct infusion of GPPGPAG into the lateral ventricle of 5XFAD mice for 28 days improved object recognition memory. Following oral administration of GPPGPAG in mice, the undigested heptapeptide was detected in the plasma and cerebral cortex. Analysis of target protein of GPPGPAG in neurons by DARTS method identified 14-3-3ε as a bound protein. The protective effect of GPPGPAG on Aβ1-42-induced dendritic atrophy was canceled by knockdown of 14-3-3ε. Taken together, these results suggest that GPPGPAG is orally available, transfers to the brain, and ameliorates memory dysfunction in AD brain, which is possibly mediated by 14-3-3ε-related dendritic restoration.

Exploration of Potent Multi-target-directed-ligands as Anti-alzheimer's Disease Agents: A Moiety Based Review.

Dementia is a chronic neurodegenerative disease, and a maximum number of the cases are directly related to Alzheimer's disease. More than 4 million people are living with Alzheimer's disease-related dementia in India, making it a national crisis. Alzheimer's disease deteriorates cognitive functions with the passage of time and consists of multi-faceted factors, such as the decline of acetylcholine level, amyloid β-aggregation, tau hyperphosphorylation, oxidative stress, etc. The classical drugs used to date, are focused on only one target and are not serving the cause properly. Hence, the community of scientists is rigorously working on multi-target-directed agents that incorporate two or more active scaffolds in one compound or hybrid of active moieties. This article aims to evaluate novel potential compounds and moieties, such as quinolines, chalcones, coumarins, chromenes, piperazine, carbazoles, cinnamic acids, tacrine hybrids, donepezil hybrids, etc., that have been introduced as multi-target-directed agents in the recent five years.

Chemical Constituents and their Antioxidant, Anti-Inflammatory and Anti-Acetylcholinesterase Activities from Pholidota cantonensis.

Alzheimer's disease (AD) has the third highest health expenditures after heart disease and cancer. It has emerged as a serious global health issue. The discovery of new drugs to prevent and treat AD is of utmost importance. Pholidota cantonensis is an edible medicinal plant consumed in China. It is widely used in traditional Chinese medicine to treat various diseases. P. cantonensis has been reported to have antioxidant, anti-inflammatory, antitumor and antibacterial activities. Among these properties, its potent antioxidant activity has attracted our attention, since oxidative stress is one of the important pathological mechanisms involved in AD. This study aimed to isolate the compounds from the active extract and evaluate their bioactivities. Fifteen compounds, including one new compound, were obtained. The isolates were tested for 2,2'-diphenyl-1-picrylhydrazyl (DPPH)/2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities, anti-acetylcholinesterase (anti-AChE) activities and inhibitory effects on nitrogen monoxide (NO) release in the BV-2 cells. Compounds 1, 2, 4, 6, 8, and 13-15 exhibited two kinds of AD-associated bioactivities. More importantly, compound 13 showed more potent NO inhibitory activity (IC50 = 0.72 ± 0.08μM) than the positive control quercetin (IC50 = 12.94 ± 0.08μM). Compound 13 also had a higher inhibitory rate (99.59 ± 0.43%) on AChE than that of the positive control galantamine (78.32 ± 1.16%) at the concentrate of 50μg/mL. Our studies provide new insights into this plant in terms of its potential in the development of new multi-target anti-Alzheimer's disease (anti-AD) drugs.

Polyoxygenated sesquiterpenoids from Salvia castanea and their potential anti-Alzheime's disease bioactivities

Salvia castanea (Family Labiatae), a perennial fragrant herb with castaneous flowers, is mainly distributed in areas with an altitude of 2500–3750 m. The roots of this plant were used as a tea drink by local residents to strengthen physical health. The aim of present study was to acquire secondary metabolites of the ethanol extract obtained from the whole plant of S. castanea and to evaluate their potential anti-Alzheimer's disease. Six new sesquiterpene lactones, salcastanins A-F (1–6), together with three known guaiane-type sesquiterpenoids nubiol (7), nubdienolide (8), and nubenolide (9), were separated from the whole plant of S. castanea. The structures of these compounds were determined by HRESIMS and NMR experiments. The absolute configurations of 1–6 were ascertained by electronic circular dichroism (ECD) experiments. The humanized Caenorhabditis elegans AD pathological model was used to evaluate anti-Alzheimer's disease (AD) activities of 1–9. The results showed the compounds 1–3 and 7 significantly delayed AD-like symptoms of worm paralysis phenotype, which could be used as novel anti-AD candidates.

Multi-Target Drug Design of Anti-Alzheimer's Disease based on Tacrine.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with concealed onset, which is characterized by the damage of the cholinergic system, deposition, and accumulation of β- amyloid protein (Aβ) and neurofibrillary tangles. Because the cholinergic system plays a key role in the process of brain memory, it has become one of the important targets in anti-AD research. In view of the complicated pathological characteristics of AD, the multi-target directed ligands (MTDLs) that can act on multiple targets are considered to be an effective treatment strategy at present. Tacrine, as the first acetylcholinesterase (AChE) inhibitor, has been discontinued because of its hepatotoxicity, but its core structure is simple and easy to modify. By using tacrine to target the active catalytic site (CAS), the tacrine-based MTDLs can act on both CAS and peripheral anion site (PAS) of AChE to serve as a dual-site AChE inhibitor. Additionally, the tacrine-based MTDLs can also be designed on the basis of other theories of AD, for example, introducing functional moieties to modulate the formation of β-amyloid (Aβ), oxidation resistance, or metal chelation. In this paper, the research progress of tacrine-based MTDLs is summarized.

Ellagic acid and its fermentative derivative urolithin A show reverse effects on the gp91-phox gene expression, resulting in opposite alterations in all-trans retinoic acid-induced superoxide generating activity of U937 cells

Ellagitannins (esters composed of glucose and ellagic acid) are hydrolyzed to generate ellagic acid in gut followed by conversion of ellagic acid to urolithins such as urolithin A by intestinal bacteria. Since urolithins are absorbed by gut easier than ellagitannins and ellagic acid, and show various physiological activities (e.g. anti-cancer, anti-cardiovascular disease, anti-diabetes mellitus, anti-obesity and anti-Alzheimer disease activities), they are expected as excellent health-promoting phytochemicals. Here, using human monoblast U937 cells, we investigated the effect of ellagic acid and urolithin A on the superoxide anion (O2−)-generating system of phagocytes, which is consisted of five specific protein factors (membrane proteins: p22-phox and gp91-phox, cytosolic proteins: p40-phox, p47-phox and p67-phox). Twenty micromolar of urolithin A enhanced the all-trans retinoic acid (ATRA)-induced O2−-generating activity (to ~175%) while 20 μM ellagic acid inhibited the ATRA-induced O2−-generating activity (to ~70%). Semiquantitative RT-PCR showed that transcription level of gp91-phox was certainly decreased (to ~70%) in ATRA plus ellagic acid-treated cells, while that of gp91-phox was significantly increased (to ~160%) in ATRA plus urolithin A-treated cells. Chromatin immunoprecipitation assay suggested that urolithin A enhanced acetylations of Lys-9 residues of histone H3 within chromatin surrounding the promoter region of gp91-phox gene, but ellagic acid suppressed the acetylations. Immunoblotting also revealed that ATRA plus urolithin A-treatment up-regulated protein levels of p22-phox (to ~160%) and gp91-phox (to ~170%) although ATRA plus ellagic acid-treatment down-regulated protein levels of p22-phox (to ~70%) and gp91-phox (to ~60%). These results suggested that conversion of ellagic acid to urolithin A in gut may bring about reverse effects on the gp91-phox gene expression, resulting in opposite alterations in O2−-generating activity of intestinal macrophages.

Enzyme-assisted Solvent Extraction of High-yield Paeonia suffruticosa Andr. Seed Oil and Fatty Acid Composition and Anti-Alzheimer's Disease Activity.

Enzyme-assisted solvent extraction (EASE) of Paeonia suffruticosa Andr. seed oil (PSO) was optimized by response surface methodology (RSM). The fatty acid composition and anti-Alzheimer's disease (AD) activity of PSO were analyzed. An enzyme mixture composed of cellulase and hemicellulase (1:1, w/w) was most effective in determining the extraction yield of PSO. The ideal extraction conditions were a pH value of 5.1, an enzymolysis time of 68 min, and a temperature of 50℃. The average extraction yield of PSO was 38.2 mL/100 g, 37.4% higher than that of untreated peony seed (27.8 mL/100 g). The fatty acid composition of PSO under optimal conditions for EASE was analyzed by gas chromatography-mass spectrometry (GC-MS). The predominant unsaturated fatty acids of PSO were determined to be more than 90.00%, including n-3 α-linolenic acid (43.33%), n-6 linoleic acid (23.40%) and oleic acid (23.59%). In this experiment, the anti-AD effect of PSO was also analyzed by performing learning and memory ability tests with Drosophila. PSO retarded the decrease in climbing ability in AD Drosophila. The 1% and 5% PSO groups were significantly different from the model group (b p < 0.05). The smell short-term memory ability test revealed the number of Drosophila in barrier and barrier-free centrifuge tubes in each group. PSO feeding improved learning and memory in AD Drosophila, with the highest number entering the barrierfree centrifuge tube. The performance index (PI) measured by the Pavlov olfactory avoidance conditioning test also demonstrated the effect of PSO on the learning and memory abilities of Drosophila. The PI of the PSO group was significantly increased compared to that of the model group. HE-stained brain tissue sections of AD Drosophila showed higher neurodegenerative changes, while PSO significantly reduced neurodegenerative damage. These results indicated that PSO can significantly improve the cognitive function of AD Drosophila and may help to prevent AD.

A new highly oxygenated germacranolide from Carpesium nepalense var. lanatum (C.B.Clarke) Kitam

A new highly oxygenated germacranolide, carcerlane A (1), together with four known highly oxygenated germacranolides (2–5), was isolated from an ethanol extract of the whole plant of Carpesium nepalense var. lanatum (C.B.Clarke) Kitam. The structures were determined by HRESIMS and extensive analysis of their spectroscopic data including IR, 1 D and 2 D NMR spectra. To our best knowledge, it was the first time to report the phytochemical investigation on this plant. The anti-Alzheimer’s disease (AD) activities of 1–5 were evaluated using Caenorhabditis elegans AD pathological model. All the tested compounds showed that they have the anti-AD bioactivities of delaying worms paralysis.

Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer's Agents.

The inadequate clinical efficacy of the present anti-Alzheimer's disease (AD) drugs and their low impact on the progression of Alzheimer's disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 μM; BuChE, IC50 value of 0.21 μM), was also found to possess significant self-mediated Aβ1-42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ1-42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.

A Simple and Effective Synthesis of 3- and 4-((Phenylcarbamoyl)oxy)benzoic Acids

Phenserine, posiphen, tolserine and cymserine and its derivatives are experimental Alzheimer's disease drugs that contain a phenyl phenylcarbamate moiety that is responsible for their anti-Alzheimer activities. We have developed a simple (3 steps) and effective (overall yields 76-90%) method for preparing 3- and 4-((phenylcarbamoyl)oxy)benzoic acids which can be reacted with amines to produce phenyl phenylcarbamate moiety containing amides as new potential anti-Alzheimer disease drugs. The synthesized carboxylic acids are thus important building blocks with potential use in medicinal chemistry and drug discovery.

A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer's disease agents: A review.

Monoamine oxidases (MAO-A and MAO-B) are mammalian flavoenzyme, which catalyze the oxidative deamination of several neurotransmitters like norepinephrine, dopamine, tyramine, serotonin, and some other amines. The oxidative deamination produces several harmful side products like ammonia, peroxides, and aldehydes during the biochemical reaction. The concentration of biochemical neurotransmitter alteration in the brain by MAO is directly related with several neurological disorders like Alzheimer's disease and Parkinson's disease (PD). Activated MAO also contributes to the amyloid beta (Aβ) aggregation by two successive cleft β-secretase and γ-secretase of amyloid precursor protein (APP). Additionally, activated MAO is also involved in aggregation of neurofibrillary tangles and cognitive destruction through the cholinergic neuronal damage and disorder of the cholinergic system. MAO inhibition has general anti-Alzheimer's disease effect as a consequence of oxidative stress reduction prompted by MAO enzymes. In this review, we outlined and addressed recent understanding on MAO enzymes such as their structure, physiological function, catalytic mechanism, and possible therapeutic goals in AD. In addition, it also highlights the current development and discovery of potential MAO inhibitors (MAOIs) from various chemical scaffolds.

(±)-Neonardochinone A, a pair of enantiomeric neoligans from Nardostachys chinensis with their anti-Alzheimer’s disease activities

Abstract A pair of new enantiomeric neoligans, (±)-neonardochinone A (1) were isolated from Nardostachys chinensis. The structure of 1 was determined by extensive spectroscopic analysis, containing IR, HRESIMS, NMR spectra and single crystal X-ray diffraction. The enantiomeric separation was finished by HPLC on a chiral column. The absolute configurations were assigned via comparison of their calculated and experimental ECD data. The anti-Alzheimer’s disease (AD) activities of 1, 1a, and 1b were also evaluated using the Caenorhabditis elegans AD pathological model, respectively, and 1 had the highest anti-AD activity.

Comprehensive chemical profiling of Jia-Wei-Qi-Fu-Yin and its network pharmacology-based analysis on Alzheimer's disease

Jia-Wei-Qi-Fu-Yin (JWQFY) is a newly developed anti-Alzheimer's disease (AD) prescription modified from a classical traditional Chinese medicine formula, Qi-Fu-Yin (QFY). However, a systematic understanding of its chemical constituents and molecular mechanisms is still elusive. To address this problem, comprehensive chemical profiling followed by network pharmacology-based analysis of JWQFY was performed. Firstly, a total of 136 compounds were characterized by high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF MS), 17 of them were specifically identified in JWQFY comparing with QFY. Seventy compounds were further quantified via a validated HPLC coupled with triple quadrupole tandem mass spectrometry (QQQ MS) method. Then the protein targets of the seventy compounds were gathered from public databases for network construction. As a result, fifty-seven compounds were filtered, which interacted with 655 targets. Thirty-four of them were mapped into the KEGG pathway of AD, indicating JWQFY might exert anti-AD effects by anti-inflammation, neuronal apoptosis intervening, Aβ production inhibition and phosphorylating tau protein moderating. Furthermore, in the compound-target-AD network, a list of hub compounds and hub targets was identified based on their topological features, including the degree, node betweenness and closeness. Four of the hub compounds were specifically originated from JWQFY, supporting the modification rationality of this formula. This study provided a scientific basis for understanding the bioactive compounds and the multi-target mechanism of JWQFY.

Study on mechanisms of anti-Alzheimer's disease action of absorbed components of Gardeniae Fructus based on network pharmacology

Gardeniae Fructus has the traditional effects of promoting intelligence and inducing resuscitation, but its mechanism is unclear. In this study, the relationship between Gardeniae Fructus's traditional effect of promoting intelligence and inducing resuscitation and anti-Alzheimer's disease effect was taken as the starting point to investigate the anti-Alzheimer's disease mechanism of the major absorbed components in Gardeniae Fructus by the network pharmacology method. The network pharmacology research model of &quot;absorbed composition-target-pathway-disease&quot; was adopted. In this study, the active components screening and target prediction technology were used to determine the active components and targets of Gardeniae Fructus in treatment of Alzheimer's disease. The enrichment pathway and biological process of Gardeniae Fructus were studied by using the bioinformatics annotation database(DAVID), and the results of molecular docking validation network analysis were used to elaborate the mechanism of Gardeniae Fructus in treatment of Alzheimer's disease. It was found that 35 absorbed components of Gardeniae Fructus not only regulated 48 targets such as cholines-terase(BCHE) and carbonic anhydrase 2(CA2), but also affected 11 biological processes(e.g. transcription factor activity, nuclear receptor activity, steroid hormone receptor activity, amide binding and peptide binding) and 7 metabolic pathways(MAPK signaling pathway, Alzheimer disease and estrogen signaling pathway, etc.). Molecular docking results showed that more than 60% of the active components could be well docked with key targets, and the relevant literature also showed that the active components could inhibit the MAPK1 expression of key targets, indicating a high reliability of results. These results indicated that Gardeniae Fructus may play its anti-Alzheimer's disease action via a &quot;multi-ingredients-multi-targets and multi-pathways&quot; mode, providing a scientific basis for further drug research and development.

Isolation, Characterization, and Possible Anti-Alzheimer's Disease Activities of Bisabolane-Type Sesquiterpenoid Derivatives and Phenolics from the Rhizomes of Curcuma longa.

One new bisabolane-type sesquiterpenoid, together with four known bisabolane-type sesquiterpenoid derivatives and seven phenolics, was isolated from the rhizomes of Curcuma longa. Their structures were elucidated by extensive spectroscopic (IR, HR-ESI-MS, and NMR) data analysis. The possible anti-Alzheimer's disease (AD) activities of the isolated compounds were also evaluated using Caenorhabditis elegans AD pathological model, and 1β-hydroxybisabola-2,10-dien-4-one had the highest possible anti-AD activity.

Generation Dependent Effects and Entrance to Mitochondria of Hybrid Dendrimers on Normal and Cancer Neuronal Cells In Vitro.

Dendrimers as drug carriers can be utilized for drugs and siRNA delivery in central nervous system (CNS) disorders, including various types of cancers, such as neuroblastomas and gliomas. They have also been considered as drugs per se, for example as anti-Alzheimer’s disease (AD), anti-cancer, anti-prion or anti-inflammatory agents. Since the influence of carbosilane–viologen–phosphorus dendrimers (SMT1 and SMT2) on the basic cellular processes of nerve cells had not been investigated, we examined the impact of two generations of these hybrid macromolecules on two murine cell lines—cancer cell line N2a (mouse neuroblastoma) and normal immortalized cell line mHippoE-18 (embryonic mouse hippocampal cell line). We examined alterations in cellular responses including the activity of mitochondrial dehydrogenases, the generation of reactive oxygen species (ROS), changes in mitochondrial membrane potential, and morphological modifications and fractions of apoptotic and dead cells. Our results show that both dendrimers at low concentrations affected the cancer cell line more than the normal one. Also, generation-dependent effects were found: the highest generation induced greater cytotoxic effects and morphological modifications. The most promising is that the changes in mitochondrial membrane potential and transmission electron microscopy (TEM) images indicate that dendrimer SMT1 can reach mitochondria. Thus, SMT1 and SMT2 seem to have potential as nanocarriers to mitochondria or anti-cancer drugs per se in CNS disorders.

Cadinane-type sesquiterpenes from the resinous exudates of Commiphora myrrha and their anti-Alzheimer's disease bioactivities

Commiphoins A-C (1–3), three new cadinane-type sesquiterpenes, together with two known cadinane-type sesquiterpenes (4 and 5) were isolated from the resinous exudates of Commiphora myrrha. Their structures and relative configurations were established on the basis of comprehensive spectroscopic methods, including HRESIMS, 1D and 2D NMR analyses. Compounds 1 and 3–5 were screened for anti-Alzheimer's disease (AD) activities using the AD pathological model in Caenorhabditis elegans. The results showed that they all had significant anti-AD activities.

Orientation-Inspired Perspective on Molecular Inhibitor of Tau Aggregation by Curcumin Conjugated with Ruthenium(II) Complex Scaffold.

Curcumin, a molecule of labile natural product, has multiplex pharmacological effects, including antioxidant, antimicrobial, and anticancer effects as well as anti-Alzheimer's disease (AD) properties. However, the drawbacks of curcumin such as poor stability and bioavailability seriously limited its application in drug development. Numerous literature studies suggested the conversion of curcumin to metal complexes and explored the clearance of β-amyloid fibrils by curcumin conjugates. However, the research about the inhibition effect of curcumin complex on τ protein aggregation is progressing slowly, and its interactive orientation with the related proteins from the steric effect has been ignored. Inspired by the perspective on interactive orientation, we conjugated curcumin molecule on the positive-charged scaffold of Ru(II) complexes (bipyridine for Ru1, phenanthroline for Ru2) to construct an octahedral structure. After being conjugated with a ruthenium octahedral framework, curcumin exhibited a stronger ability to not only inhibit aggregation of R3, the τ peptide corresponding to the third repeat unit of the microtubule binding domain (residues 306-336 in full τ) (Ru1 with an IC50 of 0.5 μM and Ru2 with an IC50 of less than 3 μM) but also disaggregate R3 fibers with dose-dependence through an exothermic and dynamic process. Autodock simulation was applied to get a hairpin-docking mode in the inhibition of R3 aggregation. Herein, our results provide a rational strategy emphasizing the interactive orientation from an octahedral steric structure to design the anti-AD drugs with natural compound.

Carbonic anhydrase and cholinesterase inhibitory activities of isolated flavonoids from Oxalis corniculata L. and their first-principles investigations

Phytochemical investigations of Oxalis corniculata L. shown the existence of biologically active secondary metabolites like phenols, flavanoids, alkaloids, tannins, triterpenes, sterols, and volatile oils. In this work, ethanolic extract of Oxalis corniculata L. was prepared to explore the carbonic anhydrase and cholinesterase inhibitory activities against epilepsy and anti-Alzheimer’s disease (AD) potential. Upon fractionation, chloroform and ethyl acetate fractions showed high phenolic (168.56 and 171.11 μg ascorbic acid/g extract) and flavonoid contents (115.72 and 99.35 μg (+)-catechin/g extract), respectively and were the most active ones against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carbonic anhydrase inhibition. The bioactivity-guided isolation from chloroform and ethyl acetate extract of Oxalis corniculata afforded nine flavonoids. The newly isolated flavonoid (1) and eight source compounds 2–9 screened by cholinesterase (AChE and BChE) and carbonic anhydrase-II (CA-II) inhibitory assays. Carbonic anhydrase inhibition rate for compounds 1–9 ranged 65.21–90.82 with the IC50 17.11–25.18, compared with reference acetazolamide. Cholinesterase (AChE and BChE) inhibitory potential (49.52 and 29.12 μg/mL) of newly isolated compound 1 whereas compounds 3, 5, 8 and 9 showed considerable significant inhibition potential using standard inhibitor serine. Moreover, the ground state geometries of all the nine compounds along with positive drugs were optimized by Density functional theory (DFT) at B3LYP/TZ2P level to explore the electronic properties and active sites. The effect of substituents on the molecular descriptors, frontier molecular orbitals, molecular electrostatic potential and Hirshfeld charges was explored.