Dual Monoamine Oxidase and Cholinesterase Inhibitors with Different Heterocyclic Scaffolds.

For the last two decades, there has been research interest on the design of molecules possessing dual inhibitory potential on cholinesterase and monoamine oxidase enzymes, particularly for the treatment of two major neurodegenerative diseases, Alzheimer's Disease (AD) and Parkinson's disease (PD). Many compounds have been synthesized for this purpose, and some of them have been shown to display activities comparable or superior to the activities of current drugs used for the treatment of AD and PD. Within the concept of this review study, we have aimed to present the current drugs used for the treatment of AD and PD, their mechanism of action, the discussion behind the theory of designing dual inhibitor agents, and the presentation of the most active compounds with diverse heterocyclic scaffolds displayed in research studies published in the recent period.

Amendatory Effect of Flavonoids in Alzheimer's Disease Against Mitochondrial Dysfunction.

Flavonoids are chromene analogues abundantly found in plants. It has always been of interest to discover natural flavonoid structures, since living things, including humans, are routinely exposed to these compounds through many dietaries. So far, numerous studies have been conducted on flavonoids with diverse biological actions. The activity results obtained, particularly regarding the effects of flavonoids on various validated and non-validated targets of Alzheimer's Disease (AD), make these compounds promising agents either to be directly employed in clinical trials or to be utilized as important scaffolds for flavonoid-based drug design studies. Although there are many review articles on the treatment and protective effects of flavonoids on AD, within this review, the effects of flavonoids on mitochondrial dysfunction developing throughout AD have been presented concomitant to their structural organization.

Design, synthesis and biological evaluation of new benzoxazolone/benzothiazolone derivatives as multi-target agents against Alzheimer's disease.

In this study, four series of compounds with benzoxazolone and benzothiazolone cores were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). Additionally, in order to shed light on the effect of the carbonyl groups of benzoxazolone/benzothiazolone, benzoxazole/benzothiazole-containing analogues were also synthesized and evaluated. Inhibition potency of all final compounds towards cholinesterase enzymes and their antioxidant activity were tested. Subsequently, the anti-inflammatory activity, cytotoxicity, apoptosis, and Aß aggregation inhibition tests were also performed for selected compounds. The results indicated that compounds 11c, a pentanamide derivative with benzothiazolone core, and 14b, a keton derivative with benzothiazolone core, were considered as promising multi-functional agents for further investigation against AD. The reversibility, kinetic and molecular docking studies were also performed for the compounds with the highest AChE 14b (eeAChE IC50 = 0.34 µM, huAChE IC50 = 0.46 µM) and BChE 11c (eqBChE IC50 = 2.98 µM, huBChE IC50 = 2.56 µM) inhibitory activities.

Design, synthesis, and biological evaluation of new urolithin amides as multitarget agents against Alzheimer's disease.

A series of urolithin amide (i.e., URO-4-URO-10 and THU-4-THU-10) derivatives was designed and synthesized, and their chemical structures were confirmed with spectroscopic techniques and elemental analysis. The title compounds and synthesis intermediates (THU-1-THU-10 and URO-1-URO-10) were evaluated for their potential to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase B (MAO-B). Compounds THU-4 and THU-8 were found to be the most potent inhibitors for the cholinesterases and MAO-B, respectively. The docking studies were also employed to evaluate the binding modes of the most active compounds with AChE, BuChE, and MAO-B. Furthermore, the moderate-to-strong activities of the compounds were also displayed in amyloid-beta inhibition and antioxidant assay systems. The results pointed out that the urolithin scaffold can be employed in drug design studies for the development of multitarget ligands acting on various cascades shown to be important within the pathophysiology of Alzheimer's disease.

Synthesis, anti-inflammatory activity, and molecular docking studies of some novel Mannich bases of the 1,3,4-oxadiazole-2(3H)-thione scaffold.

A series of novel ibuprofen and salicylic acid-based 3,5-disubstituted-1,3,4-oxadiazole-2(3H)-thione derivatives was synthesized, and they were evaluated as potential anti-inflammatory agents. Following the structure identification studies employing IR, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and elemental analysis, the title compounds were tested by cyclooxygenase (COX)-1 and COX-2 inhibition assays concomitant to lipopolysaccharide (LPS)-induced nitric oxide and prostaglandin production prevention experiments. The results indicated that the majority of the compounds displayed either a superior or comparable activity in preventing both LPS-induced NO production and COX-1 activity in comparison to the activities of the reference molecules. Furthermore, docking studies were also performed to reveal possible interactions with the COX enzymes.

The Main Targets Involved in Neuroprotection for the Treatment of Alzheimer's Disease and Parkinson Disease.

With respect to the total cure failure of current drugs used in the treatment of neurodegenerative diseases, alternative strategies are followed. Particularly, neuroprotection approaches are questioned. Metal chelation, antioxidant towards oxidative stress, modulation of the amyloidogenic pathway, MAO-B inhibition, and NMDA receptor antagonism is more or less typical examples. Some of the representative drug candidates with promising neuroprotective features are assessed in clinical trials. Although initial attempts were found hopeful, none of the candidates have been found successful in each required clinical trials, particularly depending on the failures in terms of cognitive enhancement and slowing the progressive characteristics of neurodegenerative diseases. Today, neuroprotection is evaluated using multi-target ligand-based drug design studies. Within this study, the clinical outcomes of these studies, the rationale behind the design of the molecules are reviewed concomitant to the representative drug candidates of each group.

A Recent Look into Natural Products that have Potential to Inhibit Cholinesterases and Monoamine Oxidase B: Update for 2010-2019.

With respect to the unknowns of pathophysiology of Alzheimer's Disease (AD)-, and Parkinson's Disease (PD)-like neurodegenerative disorders, natural product research is still one of the valid tools in order to provide alternative and/or better treatment options. At one hand, various extracts of herbals provide a combination of actions targeting multiple receptors, on the other hand, the discovery of active natural products (i.e., secondary metabolites) generally offers alternative chemical structures either ready to be employed in clinical studies or available to be utilized as important scaffolds for the design of novel agents. Regarding the importance of certain enzymes (e.g. cholinesterase and monoamine oxidase B), for the treatment of AD and PD, we have surveyed the natural product research within this area in the last decade. Particularly novel natural agents discovered within this period, concomitant to novel biological activities displayed for known natural products, are harmonized within the present study.

Design, Synthesis and Investigation of New Diphenyl Substituted Pyridazinone Derivatives as Both Cholinesterase and Aß-Aggregation Inhibitors.

BACKGROUND: With respect to the increase in the average life expectancy, Alzheimer Disease (AD), the most common form of age-related dementia, has become a major threat to the population over the age of 65 during the past several decades. The majority of AD treatments are focused on cholinergic and amyloid hypotheses. OBJECTIVE: In this study, three series of diphenyl-2-(2-(4-substitutedpiperazin-1-yl)ethyl)pyridazin- 3(2H)-one derivatives were designed, synthesized and investigated for their ability to inhibit both cholinesterase enzymes and amyloid-ß aggregation. METHOD: The inhibitory activities of the synthesized compounds on AChE (from electric eel) and BChE (from equine serum) were determined by the modified Ellman's method. The reported thioflavin T-based fluorometric assay was performed to investigate the effect of the selected compounds on the aggregation of Aß1-42. The cytotoxic effect of the compounds (4g, 11g and 18g) was monitored in 3T3 cell lines to gain insight into therapeutic potential of the compounds by using MTT assay. The crystal structures of the AChE (1EVE) and BChE (1P0I) enzymes were retrieved from the RCSB Protein Data Bank and Molecular Operating Environment (MOE) software was used for molecular docking of the ligands. RESULTS: Among the tested compounds, 5,6-diphenyl derivative 18g was identified as the most potent and selective AChE inhibitor (IC50 = 1.75 µM, Selectivity Index for AChE > 22.857). 4,6- Diphenyl derivative 11g showed the highest and the most selectivity for BChE (IC50= 4.97 µM, SI for AChE < 0.124). Interestingly, 4,5-diphenyl derivative 4g presented dual cholinesterase inhibition (AChE IC50= 5.11 µM; BChE IC50= 14.16 µM, SI for AChE = 2.771). CONCLUSION: Based on biological activity results and low toxicity of the compounds, it can be said that diphenyl substituted pyridazinone core is a valuable scaffold. Especially, dual inhibitory potencies of 4,5-diphenylpyridazin-3(2H)-one core for the cholinesterase enzymes and Aß- aggregation makes this core a promising disease-modifying agent.

Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase.

A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC50 values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC50 = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC50 for AChE = 0.16 µM and IC50 for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC50 for AChE = 0.59 µM and IC50 for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aß aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.

Marginally designed new profen analogues have the potential to inhibit cyclooxygenase enzymes.

The current structure-activity relationship of profens (i.e., 2-arylpropionic acid derivatives, a class of non-steroidal anti-inflammatory drugs) discusses the importance of α-monomethyl substitution on these compounds, since the activities obtained through their corresponding arylacetic acid derivatives (i.e., α-demethylated derivatives) or α,α-dimethyl-substituted compounds are less than what is observed for the parent profens. Unfortunately, this implies a generalization in structure-activity relationships of profens in such a way that a mono-(non-methyl)alkyl group or dialkyl substituent replaced at the α-position of a profen analogue results in abolished activity. Therefore, within this study, we aimed to question this generalization employing ibuprofen, flurbiprofen, and naproxen as model compounds. A series of α-(non-methyl)alkyl-substituted ibuprofen and flurbiprofen analogues as well as α,α-dialkyl-substituted ibuprofen, flurbiprofen, and naproxen derivatives were synthesized and screened for their potential to inhibit cyclooxygenase enzymes. In addition, since profens have negligible potential to inhibit lipoxygenase enzymes, the effect of such derivatization was also questioned in lipoxygenase inhibition assays. The findings only partially agreed with the current structure-activity approach of profens and the activity results of some compounds were found as beyond ordinary.

Chemical and molecular aspects on interactions of galanthamine and its derivatives with cholinesterases.

Dual action of galanthamine as potent cholinesterase inhibitor and nicotinic modulator has attracted a great attention to be used in the treatment of AD. Consequently, galanthamine, a natural alkaloid isolated from a Galanthus species (snowdrop, Amaryllidaceae), has become an attractive model compound for synthesis of its novel derivatives to discover new drug candidates. Numerous studies have been done to elucidate interactions between galanthamine and its different derivatives and the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using in vitro and in silico experimental models. The in vitro studies revealed that galanthamine inhibits AChE in strong, competitive, long-acting, and reversible manner as well as BChE, although its selectivity towards AChE is much higher than BChE. The in silico studies carried out by employing molecular docking experiments as well as molecular dynamics simulations pointed out to existence of strong interactions of galanthamine with the active gorge of AChE, mostly of Torpedo californica (the Pasific electric ray) origin. In this review, we evaluate the mainstays of cholinesterase inhibitory action of galanthamine and its various derivatives from the point of view of chemical and molecular aspects.