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Mechanism of action and prodrug delivery of the proposed concept. The parent molecule (compound 5c (SP-04) has been chosen to illustrate the example) designed to simultaneously target AchE and the 1-receptor, while releasing the active metabolite (compound 4d (SP- 04m) in this example), designed to maintain antioxidant properties and also to be a 1-receptor ligand.
Source publication
We report herein the synthesis and biological evaluation of dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethyl-piperazine-1-carbonyl)-phenyl ester (SP-04), a new drug candidate that is designed to offer a multi-target therapeutic neuroprotective approach as a treatment for Alzheimer's disease (AD). SP-04 inhibits acetylcholinesterase (A...
Citations
... Among the studied ligands, two compounds (i.e., 2,3,4-trihydroxy-phenyl)butan-1one 1 and the corresponding N,N-dimethylcarbamoyloxy prodrug 2; Figure 1) showed the best compromise in terms of activity on the different targets. Compound 2 was able to (i) inhibit AChE with a potency comparable to reference compounds; (ii) bind σ1 receptors (high selectivity, sub-micromolar affinity, and antagonist activity); and (iii) prevent mitochondrial toxicity by inhibiting mitochondrial complex IV and V. On the other hand, compound 1, even if much less active than its bio-precursor toward σ1 receptors, was also able to attenuate reactive oxygen species (ROS), Aβ1-42-induced neurotoxicity, and mitochondrial toxicity by inhibiting complexes I, II, IV, and V. (1) and (2) and their Ki and IC50 values for σ1 receptor (σ1 R) and human acetylcholinesterase (hAChE) [77]. ...
... Behavioral studies on animal models are needed, but preliminary data suggest that this multi-target profile can represent a novel therapeutic strategy to treat AD [77]. ...
The sigma-1 (σ1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.
... In addition to piperidine, its bioisostere, piperazine scaffold is also used extensively to develop new anti-Alzeimer agents. Several mechanisms have been suggested for piperazine derivatives such as inhibition of AChE [15,[31][32][33][34] and b-secretase-1 [35][36][37] enzymes, blockage of Ab aggregation [31,34], as well as neuroprotective [32,34] and anti-platelet-activating factor effects [31]. For example, FK960, a novel putative piperazine derivative, exerts beneficial effects on memory deficits in various animal models of dementia in rats and monkeys [38,39]. ...
... In addition to piperidine, its bioisostere, piperazine scaffold is also used extensively to develop new anti-Alzeimer agents. Several mechanisms have been suggested for piperazine derivatives such as inhibition of AChE [15,[31][32][33][34] and b-secretase-1 [35][36][37] enzymes, blockage of Ab aggregation [31,34], as well as neuroprotective [32,34] and anti-platelet-activating factor effects [31]. For example, FK960, a novel putative piperazine derivative, exerts beneficial effects on memory deficits in various animal models of dementia in rats and monkeys [38,39]. ...
Background:
Acetylcholinesterase (AChE) inhibitors are frequently prescribed to mitigate the cognitive decline in Alzheimer's disease. Thus, we investigated the possible efficacy of the AChE inhibitor 2-[(6-Nitro-2-benzothiazolyl)amino]-2-oxoethyl4-[2-(N,N-dimethylamino)ethyl] piperazine-1 carbodithioate (BPCT) in a streptozotocin (STZ)-induced Alzheimer's disease model (SADM).
Methods:
First, we analyzed the molecular interaction of BPCT with AChE via a docking study. Then, the cognitive effects of BPCT (10 and 20mg/kg) were evaluated in intracerebroventricular STZ- and vehicle-administered rats with the elevated plus maze (EPM), Morris water maze (MWM), and active avoidance (AA) tests. Locomotor activity was also assessed.
Results:
Docking analysis indicated significant binding of BPCT to the AChE active site. In behavioral tests, STZ administration impaired cognitive performance in SADM rats versus control rats. Treatment with donepezil or BPCT significantly decreased the prolonged 2nd retention transfer latency and 2nd retention latency time values of the SADM group in the EPM and MWM tests, respectively. Further, prolonged latency times were decreased and reduced frequency of avoidance events were increased in the AA test. Locomotor activity between groups was not different.
Conclusion:
BPCT appears to function as a central AChE inhibitor, and its improvement of deficits in SADM rats suggests that it has therapeutic potential in Alzheimer's disease.
Alzheimer’s disease (AD) is a detrimental neurodegenerative disease that progressively worsens with time. Clinical options are limited and only provide symptomatic relief to AD patients. The search for effective anti-AD compounds is ongoing with a few already in Phase III clinical trials, yet to be approved. Heterocycles containing nitrogen are important to biological processes owing to their abundance in nature, their function as subunits of biological molecules and/or macromolecular structures, and their biological activities. The present review discusses previously used strategies, SAR, relevant in vitro and in vivo studies, and success stories of nitrogen-containing heterocyclic compounds in AD drug discovery. Also, we propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD.
A docking study of a novel series of benzofuran derivatives with ERα was conducted. In this study, we report the synthesis of a novel series of benzofuran derivatives and evaluation of their anticancer activity in vitro against MCF-7 human breast cancer cells, as well as their potential toxicity to ER-independent MDA-MB-231 breast cancer cells, human renal epithelial HEK-293 cells, and human immortal keratinocytes (HaCaT cells) by using the MTT colorimetric assay. The screening results indicated that the target compounds exhibited anti-breast cancer activity. The target compound 2-benzoyl-3-methyl-6-[2-(morpholin-4-yl)ethoxy]benzofuran hydrochloride (4e) exhibited excellent activity against anti-oestrogen receptor-dependent breast cancer cells and low toxicity. The preliminary structure-activity relationships of the target benzofuran derivatives have been summarised. In conclusion, the novel benzofuran scaffold may be a promising lead for the development of potential oestrogen receptor inhibitors.
The lack of an adequate therapy for Alzheimer's Disease (AD) contributes greatly to the continuous growing
amount of papers and reviews, reflecting the important efforts made by scientists in this field. It is well known that AD is
the most common cause of dementia, and up-to-date there is no prevention therapy and no cure for the disease, which
contrasts with the enormous efforts put on the task. On the other hand many aspects of AD are currently debated or even
unknown. This review offers a view of the current state of knowledge about AD which includes more relevant findings
and processes that take part in the disease; it also shows more relevant past, present and future research on therapeutic
drugs taking into account the new paradigm “Multi-Target-Directed Ligands” (MTDLs). In our opinion, this paradigm
will lead from now on the research toward the discovery of better therapeutic solutions, not only in the case of AD but
also in other complex diseases. This review highlights the strategies followed by now, and focuses other emerging targets
that should be taken into account for the future development of new MTDLs. Thus, the path followed in this review goes
from the pathology and the processes involved in AD to the strategies to consider in on-going and future researches.
Background:
In this study, benzothiazole-piperazine compounds were synthesized by condensing the functional groups of donepezil (DNP), FK-960, and sabeluzole, which are known to have therapeutic potential against Alzheimer's disease, with the aim of obtaining new and potent anti-Alzheimer agents.
Methods:
Initially, acetylcholinesterase/butyrylcholinesterase enzyme inhibition activities of the synthesized test compounds were investigated by Ellman's method. Effects of the compounds on a streptozotocin (STZ) model of Alzheimer's disease (SMAD) were investigated in rats. SMAD was established by intracerebroventricular (icv) injection of STZ (3 mg/kg), bilaterally. The elevated plus maze, Morris water maze, and active avoidance tests were used to examine the effects of test compounds (1, 5, and 10 mg/kg) on learning and memory parameters of icv STZ-injected rats. Effects of the test compounds on spontaneous locomotor activities of rats were examined with the activity cage test.
Results:
The compounds B2-B5 and DNP exhibited significant selective inhibitory potencies against acetylcholinesterase. Compounds B2 and B3 at 10 mg/kg doses and compounds B4 and B5 at 5 and 10 mg/kg doses, as well as the reference drug DNP (1 and 3 mg/kg), significantly improved the learning and memory parameters of animals in all cognition tests. None of the test compounds changed spontaneous locomotor activities.
Conclusion:
Results of the present study revealed that compounds B2-B5 repaired the parameters related to the learning and memory deficits of icv STZ-injected rats. Potencies of these test compounds were comparable to the activity of DNP.
Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years.
