Received: 21 June 2023 | Revised: 20 August 2023 | Accepted: 30 August 2023

DOI: 10.1002/ddr.22113

REVIEW ARTICLE

Carbamate as a potential anti‐Alzheimer's pharmacophore:

A review

Yash Pal Singh1 | Navneet Kumar2 | Brijesh Singh Chauhan3 | Prabha Garg2

1
Department of Medicinal Chemistry, Virginia
Commonwealth University, Richmond, Abstract
Virginia, USA
Alzheimer's disease (AD) is a progressive age‐related neurodegenerative brain
2
Department of Pharmacoinformatics,
National Institute of Pharmaceutical
disorder, which leads to loss of memory and other cognitive dysfunction. The
Education and Research (NIPER), S.A.S. Nagar, underlying mechanisms of AD pathogenesis are very complex and still not fully
Punjab, India
explored. Cholinergic neuronal loss, accumulation of amyloid plaque, metal ions
3
Department of Biological Science, University
of Texas, Dallas, Texas, USA dyshomeostasis, tau hyperphosphorylation, oxidative stress, neuroinflammation, and
mitochondrial dysfunction are major hallmarks of AD. The current treatment options
Correspondence
for AD are acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine)
Prof. Prabha Garg, Department of
Pharmacoinformatics, National Institute of and NMDA receptor antagonists (memantine). These FDA‐approved drugs mainly
Pharmaceutical Education and Research
provide symptomatic relief without addressing the pathological aspects of disease
(NIPER), Sector 67, S.A.S. Nagar 160062,
Punjab, India. progression. So, there is an urgent need for novel drug development that not only
Email: [email protected]
addresses the basic mechanisms of the disease but also shows the neuroprotective
property. Various research groups across the globe are working on the development
of multifunctional agents for AD amelioration using different core scaffolds for their
design, and carbamate is among them. Rivastigmine was the first carbamate drug
investigated for AD management. The carbamate fragment, a core scaffold of
rivastigmine, act as a potential inhibitor of acetylcholinesterase. In this review,
we summarize the last 10 years of research conducted on the modification of
carbamate with different substituents which primarily target ChE inhibition, reduce
oxidative stress, and modulate Aβ aggregation.

KEYWORDS
Alzheimer's disease, carbamate, cholinesterase inhibitors

1 | INTRODUCTION neurodegeneration (Benatar et al., 2021; Singh, 2021). Neuro-

degenerative diseases (NDDs) are non‐curable and debilitating
Neurodegeneration is a wide array of neurological diseases in which conditions that result in the unremitting deterioration or death of
progressive impairment of neurons occurs in specified regions of the nerve cells (Babazadeh et al., 2020). Changes in nerve cell
brain (Malik et al., 2019). Many diseases, including Parkinson's morphology lead to functional abnormality and eventually result in
disease, frontotemporal dementia, Alzheimer's disease (AD), amyo- the demise of the cell (Castelli et al., 2019). As the investigation
trophic lateral sclerosis, and Huntington's disease, occur due to progresses, a lot of similarities have been reported that correlate

Abbreviations: Ach, acetylcholine; AChE, acetylcholinesterase; AChEI, AChE inhibitor; AD, Alzheimer's disease; APP, amyloid precursor protein; Aβ, amyloid beta; BBB, blood–brain barrier;
BChE, butyrylcholinesterase; CAS, catalytic anionic site; ChEI, cholinesterase inhibition; EWG, electron‐withdrawing group; FAAH, fatty acid amide hydrolase; IC50, half maximal inhibitory
concentration; MAO, monoamine‐oxidase; MTDLs, multitargeted directed ligands; NFTs, neurofibrillary tangles; NMDA, N‐methyl‐D‐aspartic acid or N‐methyl‐D‐aspartate; PAS, peripheral
anionic site; ROS, reactive oxygen species.

Drug Dev Res. 2023;1–28. wileyonlinelibrary.com/journal/ddr © 2023 Wiley Periodicals LLC. | 1

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2 | SINGH ET AL.

these diseases with each other on a cellular and molecular level progression (Oumata et al., 2022; Srivastava et al., 2021). How-
(Bachiller et al., 2018). ever, no theory has been fully assorted to be correlated with AD
Among them, AD is a progressive age‐related neurodegenerative (Singh et al., 2022; Wang et al., 2021). Despite these obstacles,
disorder, characterized by the gradual loss of memory and other research into AD is still a hot topic, and numerous efforts are being
cognitive functions (DeTure & Dickson, 2019). It is the sixth leading made by scientific groups throughout the world to find an effective
cause of dementia associated with death in the United States and is treatment.
predicted to affect 1 in 85 people globally by the year 2050. As the In this review, we aimed to focus on the potential role of a
disease worsens, noncognitive symptoms like psychiatric and behav- specific core scaffold of rivastigmine (i.e., carbamate fragment), which
ioral instability such as depression, hallucinations, delusions, and acts as an inhibitor of cholinesterase (ChEI) in AD. According to
agitation get developed (Cerejeira et al., 2012). The person may different studies, ChEIs are one of the important therapy for the
experience difficulties with performing daily routine activities over treatment of AD. It was also noted that the carbamate moiety that is
time, and it further leads to a decline in body functions in the late chemically and functionally similar to ACh binds to the active site of
stage of the disease, and the person becomes bedridden (Åvik both cholinesterases like organophosphorus inhibitors (Stanciu
Persson et al., 2018). Today, around 50 million people globally live et al., 2020). Thus, primarily carbamates bind to acetylcholinesterase
with dementia and this figure may be counted to increase to 152 (AChE) reversibly which effectively protects the neurons by
million by 2050. The annual cost of dementia was estimated to be carbamylation of AChE at neuronal synapses and enhances neuro-
around 259 billion USD in the year 2017 and it is estimated to reach transmission (Zhang et al., 2022). Recent, reports have shown that
up to 1.1 trillion USD by 2050 (Bhatt et al., 2019). AD has become a novel carbamate is an active pharmacophore of cannabidiol and
huge burden to the world because there are no promising disease‐ rivastigmine for treating AD by targeting cholinesterases (ChEs) such
modifying potential remedies available to date that fix Alzheimer's as AChE and butyrylcholinesterase (BChE) (Dorababu, 2019; Jiang
sickness (Huang et al., 2020). Currently available treatments only et al., 2021). Therefore, the focus of this review is on significant
provide symptomatic relief for a period, after that disease progres- advances in the design and development of various molecules having
sion continues (Cummings, 2021). carbamate scaffold, or its derivative that could be a potential agent
Several reports revealed that Amyloid peptides aggregate for the treatment of AD.
extracellularly to form senile plaques (SPs), while intracellular
accumulation of hyperphosphorylated Tau protein results in
neurofibrillary tangles (NFTs) (Sun et al., 2015). The pathophysio- 2 | HYPOTHESES OF AD
logical feature of AD includes the presence of SPs and NFTs in the
brain, especially in the cerebral cortex and hippocampal region but AD is an NDD caused by the degeneration of neurons in the cortex
the expression and regulation of these proteins are not yet fully and some subcortical region of the brain (Singh et al., 2020). The
understood. However, the low levels of acetylcholine (ACh), pathogenesis of AD is yet unclear entirely. A series of hypotheses
deposition of toxic Amyloid β (Aβ) aggregates, Tau hyperpho- explain the causes of AD, among which the hypotheses like a
sphorylation, neuro‐inflammation, disturbance of calcium cholinergic pathway, amyloid beta (Aβ), tau, oxidative stress, and
homeostasis, bio‐metals dyshomeostasis, increased oxidative metal ion are of vital importance (Figure 1) (Liu et al., 2019;
stress, and so forth are the major factors involved in the AD Singh et al., 2021).

FIGURE 1 Hypotheses of Alzheimer's disease (AD).

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SINGH ET AL. | 3

2.1 | Cholinergic hypothesis Figure 2). Thus, inhibition of AChE to increase the concentration of
ACh is crucial for the management of AD (Singh et al., 2021).
The cholinergic hypothesis is one of the oldest hypotheses of AD
(Honghua Zhang et al., 2022). ACh is the main neurotransmitter
involved in the learning and memory function (the pathway of ACh 2.2 | Aβ hypothesis
synthesis is shown in Figure 2) (Li et al., 2018). Instead of this,
butyrylcholine (BCh), a neurotransmitter is also associated with Aβ has been evidenced to play a vital role in AD pathophysiology.
learning and memory. These hypotheses state that there is a huge Overproduction or decreased clearance of Aβ is majorly thought to
loss of cholinergic neurons in the brain which lead to the impairment of be a critical event in AD (Singh, 2021; Singh et al., 2019). Amyloid
memory and other cognitive function (Zhang et al., 2017). The precursor protein (APP) is a large family of transmembrane proteins
development of ChEIs based on the cholinergic hypothesis is still the responsible for the regulation of synapse formation, neuronal
most widespread clinical approach for AD treatment (Sameem plasticity, and iron export. The proteolysis of APP happens in two
et al., 2017; Sang, Wang, Bai, et al., 2020). The cholinergic theory ways: (i) amyloidogenic and (ii) non‐amyloidogenic (Figure 3)
clearly states that the low level of ACh is one of the rate‐limiting (Malafaia et al., 2021; Mohamed et al., 2016). The earlier produces
factors to the characteristic cognitive impairment in the patient (Zhang a neurotoxic Aβ fragment (Aβ1–42) by cleavage of APP using
et al., 2017). Cholinesterase (ChE) is the key enzyme that hydrolyzes β‐secretase followed by γ‐secretase. Aβ1–42 fragment aggregated
ACh to choline and acetic acid. ChEs are classified into (i) AChE and (ii) to form Aβ oligomer, Aβ fibrils, and finally toxic hydrophobic Aβ
BChE, but ACh is majorly disintegrated by AChE instead of BChE plaque (Salahuddin et al., 2016). On the other hand, cleavage of APP
(Martin Krátký et al., 2016) (ACh hydrolysis by AChE is presented in by α‐secretase initiates a non‐amyloidogenic pathway, fabricating

FIGURE 2 (a, b) Schematic view of synthesis and hydrolysis by acetylcholinesterase (AChE).

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4 | SINGH ET AL.

FIGURE 3 (a, b) A diagrammatic overview of the amyloid beta (Aβ) and tau hypothesis.

membrane‐bound C‐terminal and large soluble N‐terminal fragments evidence, the tau hypothesis is being recognized as a hopeful target
of APP and hence are nontoxic (Pande & Srivastava, 2019). It is now for the development of drug candidates for the management of AD.
thought that misfolded oligomers can induce other Aβ molecules to
take the misfolded oligomeric form, leading to a chain reaction (Singh
et al., 2022). These oligomers are toxic to nerve cells. Therefore, Aβ is 2.4 | Oxidative stress hypothesis
characterized as a potential target for AD.
The oxidative stress hypothesis of aging points that the accumulation of
excessive reactive oxygen species (ROS) like superoxide (O2−), peroxides
2.3 | Tau hypothesis (O22−), hydroxyl radical (OH.), and hydrogen peroxides (H2O2) leads to the
damage of major cellular components such as the nucleus, mitochondrial,
Tau is a microtubule‐linked protein, largely presented in the axon and cytoplasm (Liguori et al., 2018). ROS is a highly unstable and reactive
where it boosts microtubule maintenance and helps in the transport species, having a very short half‐life. They are primarily produced due to
of proteins, and neurotransmitters such as ACh or dopamine (Verma the imbalance in the redox system of the mitochondria (Snezhkina
et al., 2022). Under biological environments, tau is in a dynamic et al., 2019). Overproduction of ROS leads to reduced antioxidant
balance between the microtubule bound and unbound forms and function and induces toxicity via oxidation of proteins, membrane
regulated by specific kinases. But, under extreme conditions, damage, lipid peroxidation, and DNA and RNA damage (Juan et al., 2021).
hyperphosphorylated tau loses its microtubule‐stabilizing and axonal Increased oxidative damage to DNA and RNA can initiate transcription
transport purpose (Brunello et al., 2020). Predominantly, hyperpho- and replication of essential genes (Figure 4) (Bokhari & Sharma, 2019).
sphorylated tau becomes prone to misfolding and aggregation,
eventually resulting in the formation of aggregated NFTs (Kadavath
et al., 2015). The tau aggregation cascade, once originated, is self‐ 2.5 | Metal ion hypothesis
replicating, depleting the biological tau pool in the neuron, and
altering it to toxic NFTs, which continue to accumulate, finally leading Certain metals, such as iron (Fe), copper (Cu), and zinc (Zn)
to neuronal damage (Figure 3) (Vogels et al., 2019). In view of all this are necessary for our body to perform normal body functions
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SINGH ET AL. | 5

(a) (b)

FIGURE 4 (a, b) A diagrammatic outline of oxidative stress and metal ion hypothesis.

(a)

(b)

F I G U R E 5 (a) Currently available FDA‐approved drugs for the treatment of Alzheimer's disease. (b) Mechanism of action of carbamate
derivatives at CAS (catalytic anionic site).

(Chitturi et al., 2015). These are commonly known as bio‐metals. (Valko et al., 2005). Oxidative stress is a biochemical process that
They perform various biological functions such as mitochondrial leads to the generation of ROS that steadily leads to neuronal
oxidation, synthesis and metabolism of neurotransmitters, cell damage and ageing (Singh et al., 2019).
growth, and synaptic plasticity (Todorova & Blokland, 2017). It is
evident from the literature and our publication that increased level of
bio‐metal, mainly Cu and Fe, plays a crucial role in AD progression 3 | CURRENT TREATMENT FOR AD
(Kawahara & Kato‐Negishi, 2011). However, excessive production of
the bio‐metals has been found inside the Aβ plaques, which Currently, available treatment option for AD is classified into two
ultimately enhances neuronal damage and cell death. Copper (Cu) categories (i) AChE inhibitor and (ii) NMDA receptor antagonist
and iron (Fe) are believed to contribute to oxidative stress (Figure 4) (Figure 5a) (Parsons et al., 2013). ChEIs are based on the oldest
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6 | SINGH ET AL.

FIGURE 6 Design and SAR study of ferulic acid‐O‐carbamoyl derivatives.

hypothesis of AD and the most common treatment option for mild to BChE and AChE both with long‐lasting binding to their active sites,
moderate AD (Grossberg, 2003). Donepezil (Aricept, 1) is an FDA‐ lasting up to 10 h (Emre et al., 2004).
approved drug for the treatment of AD, which came into the market
in 1996 (Knowles, 2006). Donepezil has been considered a safe and
well‐tolerated drug for mild to moderate AD. It interacts with CAS 4 | C ARBAM ATE‐ BA SED H YBRIDS AS A
and PAS of the AChE through aromatic π‐interactions (Junaid POT E N TI A L AN TI‐ AD AGENTS
et al., 2019). The benzyl‐piperidine and indanone groups of donepezil
interact with Trp84 of the anionic subsite and indole ring of Trp279 at A carbamate is a class of synthetic compounds that are originally
the peripheral site of the enzyme, respectively (Caliandro et al., 2018). derived from carbamic acid, which contain carbonyl compounds
The pharmacological profile of donepezil produced interest in the directly linked with nitrogen (N) and oxygen (O). Carbamate scaffold
development of other N‐benzyl‐piperidine derivatives as potential exhibited diverse pharmacological activities, including anti‐AD
anti‐AD agents. Galantamine (2), a competitive and reversible activity (Xie et al., 2017). It is the important pharmacophore
inhibitor of AChE, is an alkaloid that has been isolated from the responsible for the anti‐cholinesterase activity of rivastigmine.
bulbs and flowers of Galanthus nivalis, Galanthus caucasicus, and some Carbamate derivatives are pseudo‐irreversible inhibitors of AChE
other genera of the Amaryllidaceae family (Kong et al., 2020). It also (Zhang et al., 2022). It interacts at the CAS site of AChE. Cleavage of
allosterically interacts with nicotinic acetylcholine receptors (nAChR) carbamate at the AChE catalytic site takes place by amino acid
and increases the release of ACh (Hamouda et al., 2013). Galantamine residues, Ser203, His447, and Glu334, to respective phenol and
is less potent (IC50 = 500 nM); however, its unique dual interaction carbamylated Ser203 residue, which ultimately block the ChE site
and less toxic side effects make it an important drug used to manage (Figure 5b) (Colovic et al., 2013).
mild to moderate dementia associated with AD. Rivastigmine (3) is a
new‐generation carbamate derivative and covalent inhibitor of AChE
(Kandiah et al., 2017). This is a pseudo‐irreversible noncompetitive 4.1 | Ferulic acid‐O‐carbamoyl hybrids
inhibitor of AChE (Colovic et al., 2013). Rivastigmine exhibits a
10‐fold greater affinity for brain AChE than for the peripheral one, In the year 2020, Sang et al. developed a new series of novel ferulic
although it is a weak inhibitor of BChE. Rivastigmine inhibits acid‐O‐carbamoyl derivatives as a potential multifunctional molecule
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SINGH ET AL. | 7

for the treatment of AD (Sang, Wang, Bai, et al., 2020). The design is to couple cinnamic acid (antioxidant fragment) with
developed compound is based on the hybrid approach. Ferulic acid (a rivastigmine (ChE inhibitor fragment) to impart antioxidant and ChE
known antioxidant) was coupled with rivastigmine to impart multi- inhibitory activity to developed molecules (Figure 7). The enzyme
functional properties to developed molecules (Figure 6). Among all, inhibition study clearly represented potential ChE inhibition by
most of the developed hybrids presented noteworthy inhibitory developed molecules. Among all, compound 6 presented 23.42%
activity against hAChE and hBChE with IC50 values ranging from inhibition, and 23.99% inhibition against AChE at 1 and 5 μM,
6.8 ± 0.37 to 32.1 ± 2.2 and 0.97 ± 0.02 to 36.7 ± 3.6 μM, respec- respectively. While in the case of BChE compound 6 presented
tively. Among the 21 synthesized molecules, the result revealed 76.32% inhibition, and 91.95% inhibition at 1 and 5 μM, respectively.
shows that derivative 5 was the most effective AChE/MAO‐B dual The main SAR study indicates that the linker length from C = 0 to
inhibitor with an IC50 value of 0.97 μM for AChE and IC50 = 5.3 μM C = 2 carbon spacer increases ChE inhibitory activity to the
for monoamine oxidase‐B (MAO‐B), respectively. The SAR study developed molecules. Furthermore, replacing −OH with −OCH3
indicated that the introduction of N‐di‐substituted (carbamoyl‐ significantly improved ChE inhibitory activity. In the in vitro DPPH
NR1R2) moieties increases ChE inhibitory activity. Furthermore, assay, compound 6 showed 51.7% inhibition at 10 μM. Compound 6
compound 5 modulates Aβ aggregation with 58.2% inhibition and was submitted to Aβ aggregation experiments to understand the Aβ
disaggregates preformed Aβ fibrils with 43.3% inhibition in self‐ modulation property. Aβ aggregation study clearly revealed that
mediated Aβ aggregation. A molecular docking study on hBChE (PDB compound 6 inhibits the Aβ aggregation with % values of 85.3%,
code:4tpk) revealed that compound 5 interacted with Trp82, Gln119, which is like that of the standard drug (Congo red, 86.5%). A
Pro285, Ser287, Val288, Ala328, and Phe329, respectively. Further- molecular docking study on Aβ (PDB: 1BA4) clearly revealed that
more, compound 5 significantly improves learning and memory in the compound 6 interacted with the residues of Asp1, Asp7, Asp23, Gly9,
scopolamine‐induced amnesia model. Therefore, the overall study and Lys16 with five hydrogen bonds. The overall finding suggested
demonstrates that compound 5 could be a multifunction lead for the that compound 6 can be a potential candidate for further lead
treatment of AD. optimization against AD treatment.

4.2 | Hydroxycinnamic acid–rivastigmine hybrids 4.3 | Cannabidiol‐carbamate hybrids

In the year 2017, Chen et al. rationally designed, synthesized, and Recently, Jiang et al. have reported a new series of novel series of
biologically evaluated a series of hydroxycinnamic acid–rivastigmine cannabidiol‐carbamate hybrids as a potential therapeutic agent against
analogs as potential multitargeted directed ligands (MTDLs) for the AD (Jiang et al., 2021). The basic concept behind this is to develop novel
management of AD (Chen et al., 2017). The basic concept behind this ChEs inhibitors through a fragment reassembling approach. They couple

FIGURE 7 Design and SAR study of hydroxycinnamic acid–rivastigmine derivatives.

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8 | SINGH ET AL.

cannabidiol core with rivastigmine (ChEs fragment) to impart ChEs 36 compounds against ChEs (AChE and BChE) and MAOs (MAO‐A and
inhibitory property to developed molecules (Figure 8). They systematically MAO‐B). Among all, four compounds showed promising ChEs
developed 17 novel compounds and evaluate them against ChEs. Most of inhibitory activity, that is, IC50 = 7.31 μM toward AChE, IC50 = 0.56 μM
the developed derivatives are ineffective against AChE, but good BChE toward BChE, and IC50 = 26.1 μM toward MAO‐B for compound 8,
inhibitors. Among all, compound 7 was a highly selective BChE inhibitor IC50 = 2.25 μM toward AChE and IC50 = 0.81 μM toward BChE for
with an IC50 value of 5.30 nM. Furthermore, compound 7 presented compound 11, selective IC50 = 0.06 μM toward BChE for compound 9,
pseudo‐irreversible BChE inhibition with Kd = 13 nM, a good antioxidant, and selective IC50 = 0.18 μM toward MAO‐B for compound 10. SARs
neuroprotection, and BBB penetrating ability. The systematic SAR study of 1,3‐disubstituted N‐alkylpiperidine‐carbamate is depicted in
revealed that the introduction of carbamate significantly increases ChEs Figure 9. Enzyme kinetic study revealed that compound 9 presented
inhibitory activity. Furthermore, chain fatty amine, tert‐benzylamine, and a noncovalent mechanism of inhibition. Furthermore, compound 10 is
4‐substituted halogen significantly increase BChE inhibitory activity. an irreversible inhibitor or MAO‐B while compound 8 is a reversible
Molecular docking study revealed that compound 7 showed p–π inhibitor. Compounds 8, 9, 10, and 11 presented good BBB
interactions with Met437 and Trp430 with BChE. In vivo studies clearly permeability and cytoprotective effect in SH‐SY5Y cells. Furthermore,
indicate that compound 7 effectively ameliorated the scopolamine‐ compounds 8 and 10 protect neuronal cells from Aβ1–42 induced
induced cognition impairment in the morris water maze (MWM) test. cell death.
Furthermore, Aβ1–42 (intra‐cerebro‐ventricular injection) induced cogni-
tion impaired model also proved the anti‐AD profile of compound 7.
4.5 | Chalcone‐O‐carbamate hybrids

4.4 | N‐alkylpiperidine carbamate hybrids Sang et al. (2019) recently developed a series of 12 novel
multifunctional molecules for the management of AD. In this design,
In the year 2020, Košak et al. developed a new series of they couple chalcone with carbamate to impart ChE inhibition,
N‐alkylpiperdine derivatives as potential anti‐AD analogs (Košak antioxidant, and metal chelation properties to developed molecules
et al., 2020). They systematically designed, synthesized, and evaluated (Figure 10). In vitro biological evaluation includes ChEs inhibition,

FIGURE 8 Design and SAR study of cannabidiol‐carbamate hybrids.

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SINGH ET AL. | 9

FIGURE 9 Design and SAR study of N‐alkylpiperidine carbamate hybrids.

MAO inhibition, antioxidant, Aβ1–42 modulation, and metal‐chelation displacement assay revealed the interaction of compound 14 at the
properties. Among all, compounds 12 and 13 presented the most PAS‐inducing Aβ1–42 modulation property.
promising BChE inhibitory activity with IC50 values of 3.1 and 1.2 μM,
respectively. On MAO‐B compounds 12 and 13 presented IC50
values of 1.3 and 3.7 μM, respectively. Furthermore, compounds 12 4.7 | Pyridine carbamate hybrids
and 13 could modulate Aβ1–42 aggregation with 63.9% and 53.1%
inhibition, respectively. Compound 12 selectively chelates copper A novel series of pyridine‐carbamate hybrids were developed by
(Cu2+) and aluminum (Al3+) and also presented good neuroprotection Pandolfi et al. in the year 2017. The developed molecules were evaluated
properties against H2O2‐mediated cell death in PC12 cells. Finally, an for their cholinesterases (ChEs) inhibitory property against EeAChE,
in vivo experiment displayed that compound 12 significantly hAChE, eqBChE, and hBChE (Pandolfi et al., 2017). All the synthesized
improves learning and memory in the scopolamine‐induced cognitive derivatives presented good to moderate ChE inhibitory properties.
impairment model. Among all, compound 15 was found to be the most active hAChE with
IC50 = 0.153 ± 0.016 μM (Figure 10). Compound 15 presented mixed
inhibition with eeAChE with ki (nM) value of 38.6 ± 16.1. Furthermore, a
4.6 | Quinoline–carbamate hybrids molecular docking study revealed that compound 15 interacted with both
CAS and PAS sites (Trp86, Tyr337, Tyr124, Phe295, Ser293, and
In the year 2018, Ţînţaş et al. developed a new series of Trp286). Compound 15 was able to inhibit Aβ1–42 self‐aggregation and
quinoline–carbamate‐based bio‐oxidizable prodrug‐based analogs presented very low toxicity against HeLa cell lines.
for the treatment of AD (Figure 10) (Ţînţaş et al., 2018). The
synthesized 16 compounds were tested for AChE. Compound 14 was
found to be the most potent AChE inhibitor with an IC50 value of 4.8 | Diosgenin‐carbamate hybrids
6 nM and binds to AChE‐PAS to the same extent as donepezil. A
molecular docking study revealed that compound 14 binds both CAS In the year 2019, Yang et al. rationally developed a series of
(Trp84 and Phe330) and PAS (Tyr70 and Trp279). Moreover, a PAS diosgenin–carbamate hybrids and tested them for their anti‐
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10 | SINGH ET AL.

inflammatory, antioxidant, and anti‐Aβ activities (Figure 10) (Yang 4.9 | Tryptamine‐carbamate hybrids
et al., 2020). They systematically synthesized 40 molecules,
among all, compound 16 was the most potent anti‐inflammatory Recently Toublet et al. designed and synthesized a novel series of
derivative with nitric oxide (NO) inhibition value of 22.7 ± 2.2% at tryptamine–carbamate hybrids in which the tryptamine core was
10 μM and protect H2 O2 mediated cell death in SH‐SY5Y with selected for antioxidant activity and the carbamate scaffold was
cellular protection value of 75.3 ± 3.4% at 10 μM. Furthermore, chosen for ChEs inhibition (Figure 11) (Toublet et al., 2021). They
molecular docking studies demonstrated the strong binding systematically developed seven compounds and evaluated them for
affinity of 16 to the active site of Aβ1–42 and pro‐inflammatory ChEs inhibition and 5‐HT6R binding study. Among these compounds,
proteins. In addition, 16 reduces H 2O2 ‐induced ROS production hybrid 17 exhibits the highest ChEs inhibition with an IC50 value of
and hence acts as a potential antioxidant candidate. The results 0.97 μM and high 5‐HT6 receptors antagonistic activity (Ki = 11.4
indicated that p.o. (oral) administration of compound 16 attenu- nM). Furthermore, the Lineweaver–Burk plot demonstrates the
ated memory deficits in the D‐gal ageing mouse model. Overall, it mixed type of BChE inhibition by compound 17. All these studies
was concluded that compound 16 could be considered a potential concluded that compound 17 can be a potential lead for further
multifunctional neuroprotective agent for the treatment of AD. exploration as an anti‐AD agent.

F I G U R E 10 Design of chalcone, quinoline, pyridine, and diosgenin‐carbamate hybrids.

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SINGH ET AL. | 11

4.10 | Naringenin carbamate hybrids 4.11 | Tacrine‐carbamate hybrids

Recently, Wu et al. designed, synthesized, and biologically evaluated Ozten et al. (2021) reported a novel series of tacrine–carbamate
a novel series of naringenin carbamate hybrids, in which naringenin hybrid in which tacrine (ChE inhibitor) was coupled with carbamate to
was selected for antioxidant activity and carbamate was chosen for improve ChEs inhibitory property of developed molecules (Figure 11).
ChE inhibition (Figure 11) (Wu et al., 2021). The enzyme assay Among all, hybrid 19 showed potent ChEs inhibitory activity IC50
experiment clearly revealed that developed derivatives presented value of 22.15 nM for AChE and 16.96 nM for BChE, respectively.
moderate to good AChE and BChE inhibitory activities in the Further molecular docking study revealed that hybrid 19 interacted
submicromolar to micromolar range (IC50 = 12.91–62.52 μM and with both CAS and PAS sites with amino acid residue His478, Gly153,
0.094–13.72 μM for AChE and BChE, respectively). The most and Glu233. The systematic SAR revealed that electronegativity,
promising compound, hybrid 18 exhibited the maximum inhibitory halogen position, and electron‐withdrawing groups significantly
activity against BChE (IC50 = 0.094 ± 0.0054 μM). Enzyme kinetic affect ChEs inhibitory activity.
study and molecular modeling studies verified that compound 18
binds both CAS and PAS of BChE. Furthermore, all analogs presented
good free radical scavenging ability compared to that of vitamin C. In 4.12 | Trihydroquinoline‐carbamate hybrids
addition, compound 18 exhibited metal chelation and Aβ modulation
properties. All the obtained biology results indicate that compound Roy et al. (2012) reported a novel family of trihydroquinoline–carbamate
18 can be the potential anti‐AD agent for the management of AD. hybrids in which trihydroquinoline was conjugated with carbamate in

F I G U R E 11 Design of tryptamine, naringenin, tacrine, and dihydroquinoline‐carbamate hybrids.

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12 | SINGH ET AL.

such a way as to address multifaceted AD (Figure 11). All the developed 23 presented the highest Aβ modulation at 1, 10, and 20 μM
derivatives were evaluated for enzyme inhibition study using mouse brain compared to that of the parent compound (artigenin) (Figure 12).
AChE. The most promising hybrid 20 exhibited selective inhibition of
AChE (IC50 = 0.70 μM). Furthermore, a molecular docking study revealed
that compound 20 interacted with CAS through amino acid residue 4.15 | Salicylanilide and 4‐chlorophenol‐based
Trp84, Phe330, and Phe331. N‐monosubstituted carbamate hybrids

Krátký et al. (2018) synthesized 20 novel salicylanilide N‐

4.13 | Smilagenin carbamate hybrids monosubstituted carbamates, and evaluate them for their in vitro
eeAChE and eqBChE inhibitory activity (Figure 13). All the developed
In the year 2019, Zhang et al. developed a series of smilagenin‐ compounds presented mild to moderate ChEs inhibitory property
carbamate hybrids as potential anti‐AD agents (Zhang et al., 2019). (IC50 from 5 to 235 μM). Most of the hybrid's analogs 24, 25, and 26
They systematically synthesized 14 hybrids, in which analog 21 presented higher ChEs inhibition compared to rivastigmine against
showed the highest neuroprotection property among all devel- both the enzyme (AChE, IC50 = 43.88 ± 0.69, 45.51 ± 0.69, and
oped derivatives with 40.5 ± 2.3% cell viability at 10 μM 51.50 ± 0.54 μM for compounds 24–26, respectively). The SAR study
(Figure 12). Furthermore, compound 21 also presented good revealed that N‐phenyl‐ethyl carbamates showed the highest BChE
cytoprotective properties against H2 O2 ‐mediated cell death, inhibition compared to the other analogs.
oxygen glucoside privation‐mediated cytotoxicity in neuroblas-
toma (SH‐SY5Y) cells, and lipopolysaccharides‐induced NO
release in RAW264.7 cells. 4.16 | Thymol/carvacrol carbamate hybrids

In the year 2017, Kurt et al. developed a series of thymol/carvacrol

4.14 | Arctigenin‐4‐yl carbamate hybrids derivatives coupled with carbamate moiety and evaluated for its
ChEs inhibition study (Kurt et al., 2017). Thymol and carvacrol are the
In the year 2016, Xu et al. systematically synthesized a series of 27 naturally occurring compounds obtained from the plant Thymus
arctigenin‐carbamate hybrids and evaluated them for their Aβ vulgaris and showed potential antioxidant properties in in vitro and in
modulation property in HEK293‐APPswe cells (Xu et al., 2016). Most vivo studies. They systematically develop 38 semisynthetic analogs of
of the synthesized analogs presented good Aβ modulation properties. thymol and carvacrol (Figure 14). Among all, compound 27 was found
Among all, hybrid 23 exhibited the highest Aβ aggregation inhibition to be the most active AChE inhibitor (IC50 = 2.22 μM), and compound
property with 78.7% inhibition at 20 μM. Moreover, hybrids 22 and 28 presented the highest BChE inhibition (IC50 = 0.02 μM).

F I G U R E 12 Design of smilagenin and arctigenin‐carbamate hybrids.

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13
|

Design and SAR study of salicylanilide and 4‐chlorophenol‐based carbamate hybrids.

Design of thymol/carvacrol and benzothiazole‐based carbamate hybrids.

F I G U R E 13

F I G U R E 14
ET AL.
SINGH
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14 | SINGH ET AL.

F I G U R E 15 Design and SAR study of pyraoisoflavone and 4′‐aminochalcone–rivastigmine hybrids.

Furthermore, a molecular docking study revealed that compounds 27 4.18 | Pyranoisoflavone‐carbamate hybrids
and 28 exhibited the greatest binding affinity for AChE and BChE,
respectively. Wu et al. in the year 2019 developed a new series of natural inspired
pyranoisaflavone derivatives as a potential BChE inhibitor (Wu
et al., 2019). They systematically synthesized a series of 26 analogs and
4.17 | Benzothiazole‐carbamate hybrids evaluated them against AChE and BChE. Results clearly indicated that all
the developed analogs presented better BChE inhibitory activity (IC50
Pejchal et al. in the year 2017 synthesized a new series of 1‐[(1R)‐1‐ value from 13.10% inhibition at 10 μM to IC50 value 0.093 ± 0.001 μM).
(6‐fluoro‐1,3‐benzothiazol‐2‐yl)ethyl]‐3‐alkyl carbamate derivatives Among all compounds 33 and 34 showed highest activity against BChE
as a potential pseudo‐irreversible ChEs inhibitor for the management (IC50 = 0.22 ± 0.01 μM for 33 and 0.093 ± 0.001 μM for 34, respectively).
of AD (Pejchal et al., 2016). They couple benzothiazole with Moreover, the enzyme kinetics study revealed a mixed type of inhibition
carbamate to develop a SAR by systematic modification on the side in compounds 33 and 34. In the docking study, compound 33 containing
chain. Among, all compounds 29, 30, 31 and 32 exhibited the carbamate moiety interacted with the catalytic site and displayed
greatest AChE inhibitory activity and were presented with 10‐fold hydrogen bonds with Ser198 (2.1 Å) and His438 (2.9 Å), respectively. In
higher potency than reference drug rivastigmine (IC50 value the case of compound 34 similar docking result was observed (one
6.06 ± 0.02 μM for 29, 9.26 ± 0.04 μM for 30, 8.14 ± 0.04 μM for hydrogen bond with the carbonyl group of 34 with Gly117 (2.9 Å), and
31, and 6.75 ± 0.02 μM for 32). SAR study revealed that the electron‐ the heptyl group interacted with π‐alkyl interactions with Tyr332 and
withdrawing group (EWG) on carbamate increases ChE inhibitory Trp430). Cytotoxicity study revealed that compounds 33 and 34 are safe
activity. Furthermore, a cytotoxicity study revealed that the devel- up to 1 μM concentration, and with increased concentration to 5 μM, 33
oped compound presented negligible toxicity on human breast and 34 induced a decrease in cell viability (64.2% and 66.2%, respectively)
adenocarcinoma cell line SK‐BR‐3. (Figure 15).
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SINGH ET AL. | 15

4.19 | 4′‐aminochalcone‐carbamate hybrids respectively (Li et al., 2014). Most of the developed analogs
exhibited good to excellent ChE inhibitory activity. Among all the
In the year 2017, Nesi G. et al. rationally developed a new series of 4′‐ analogs, 49 were found to show good activity with an IC 50 value
amino‐chalcone rivastigmine derivatives as a multifactorial agent for the of 0.097 μM against AChE, which is 20‐fold better than
treatment of AD (Nesi et al., 2017). The rationale behind the design was rivastigmine. SAR study demonstrated that para‐substituted
focused on the two fragments (i) chalcone (antioxidant and metal analogs containing piperidine and morpholine favored the AChE
chelation property) and (ii) rivastigmine (AChE inhibition property). They activity. Furthermore, 48, 49, and 50 presented Aβ modulation
systematically developed 18 novel analogs and were evaluated for their properties in TEM assay, free radical scavenging activity in ABTS
ChE inhibition, antioxidant, self‐induced Aβ1–42 aggregation inhibition, assay, and potent Cu 2+ ion chelating activity in vitro. The overall
Cu2+ induced Aβ1–42 aggregation inhibition, and monoamine oxidase B finding indicates that 49 can be a potential MTDL for the
inhibitory (MAO‐B) activities. Among all, compound 35 showed potent management of AD (Figure 17).
AChE activity (IC50 = 4.91 μM), and noteworthy antioxidative activity
(2.83‐fold of Trolox equivalent). The SAR study revealed that a small
group of carbamate favors AChE inhibition (pyrrolidine over piperidine 4.22 | Arylcarbamate‐N‐acyl hydrazone hybrids
and benzylpiperazine). Enzyme kinetics study revealed that 35 showed
mixed‐type inhibition against AChE and bound both CAS and PAS of In 2021, Yamazaki et al. synthesized a novel series arylcarbamate‐N‐
AChE. Furthermore, 35 significantly modulate self‐induced Aβ1–42 acylhydrazones by introducing hydrazone group into the carbamate
aggregation and metal‐mediated Aβ1–42 aggregation with the percent- fragment (Yamazaki et al., 2021). They systematically developed 12
age of 89.5% and 79.7% at 25 μM, respectively, and selective MAO‐B compounds and evaluated them against AChE and BChE. The
inhibitor (IC50 = 0.29 μM). Metal chelation studies demonstrate that the enzyme‐based assay revealed that developed compounds 51–54,
2‐hydroxy and ketone group of 35 significantly chelates bio‐metal (Cu). 56, and 58 exhibited the highest selectivity toward BChE with weak
Based on these findings, 35 can be considered a promising first‐ AChE inhibition (Figure 18). One of the lead 53 (IC50 = 0.07 μM)
generation lead candidate for the management of AD (Figure 15). exhibited the highest BChE inhibitory activity, which is 50 times
higher than the donepezil (IC50 = 3.54 μM). SAR study clearly
revealed that the carbamate group on the aromatic ring affect the
4.20 | N‐Phenylcarbamate hybrids ChE inhibitory activity of the developed analogs. Furthermore, an
enzyme kinetics study showed competitive inhibition by 53.
In the year 2018, Vorčáková et al. developed a new series of N‐phenyl‐ Molecular docking study confirmed in vitro results by interacting
carbamate hybrids based on the multifunctional approach to treating with Tyr128, Trp82 with π–π interaction, and CH⋯O interactions
AD (Vorčáková et al., 2018). They systematically developed two series with His438, Gly121, and Glu197, respectively. Based on this study,
of compounds with substituted carbamate analogs by introducing 53 could be a promising lead for further development in AD
monosaccharide moieties such as galactosyl, fructosyl and PG‐galactosyl treatment.
on one side of carbamate moieties. They evaluated the developed
analogs (36–47) on electric eel AChE (eeAChE), BChE from equine
serum (eqBChE), and the IC50 (inhibitory activity) was compared with 4.23 | Pyrazolopyrimidinone‐carbamate hybrids
that of the current drugs rivastigmine and galantamine. The SAR study
revealed that analogs bearing two carbamate moieties significantly In the year 2017, Yu et al. designed and synthesized a series of
inhibit ChEs compared to monosubstituted ones. The IC50 of developed pyrazolopyrimidinone carbamate derivatives by incorporating carba-
compounds are depicted in Figure 16. Furthermore, analogs with di‐ mate moiety in pyrazolopyrimidinone with suitable aryl spacer to
carbamate functionality presented mixed inhibition and the compounds introduce ChE and Phosphodiesterase 9A inhibitory potency to
with monosaccharide moiety (galactosyl, fructosyl, and PG‐galactosyl) developed molecules (Yu et al., 2017). They systematically developed
showed noncompetitive inhibition for eeAChE. Molecular docking study 13 molecules; the structure–activity‐relationship study revealed that
revealed that phenyl‐carbamate orient itself toward the CAS site of the most of the developed analogs possess good BChE (from 0.27 to
enzyme. Overall results concluded that the developed compound can 18.8 μM) and phosphodiesterase 9A (from 14 ± 2 to 69 ± 3 nM)
act as a potential lead for the further exploration of a new candidate for inhibitory properties but poor AChE activity. Among all, 59
the management of AD. (Figure 19) presented the highest activity with an IC50 value of
3.3 μM against BChE and 0.014 μM against PDE9A which is far
better than reference drug donepezil (IC50, BChE = 8.14 μM). More-
4.21 | 2‐Methoxy‐phenyl dimethyl‐carbamate over, a molecular docking study revealed that 59 interacted with
hybrids amino acid residue Gln453 with hydrogen bonding, Gln453 and
Phe456 with π–π stacking which is the key residue for PDE9A.
In the year 2014, Li et al. investigated a series of rivastigmine and Furthermore, 59 exhibited no cytotoxicity in SH‐SY5Y cells and are
curcumin hybrids for their ability to inhibit AChE and BChE, safe up to 20 μM concentration.
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16 | SINGH ET AL.

F I G U R E 16 Design, IC50, and SAR study of

N‐phenyl‐carbamate hybrids.

4.24 | Dihydroquinoline carbamate hybrids preclinical evaluation (Figure 19). The in vitro and in vivo study
revealed that compound 60 presented potent ChE inhibition with
In the year 2019, A. Florent and co‐workers developed a new selectivity for huAChE (IC 50 = 0.077 μM). Furthermore, the in vivo
series of pseudo‐irreversible inhibitor by coupling quinoline with study showed that compound 60 does not show any toxic effects
carbamate (Bohn et al., 2015). Among the various synthesized after 1 h of drug administration (effects like dyspnea, tremors,
analogs, 60 possesses an excellent physiochemical profile and hunched posture, decreased grasping reflex, and so forth). All
was selected for further investigation as a therapeutic lead before these findings collectively suggested that compound 60 could be
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SINGH ET AL. | 17

F I G U R E 17 Design of 2‐methoxy‐phenyl
dimethyl‐carbamate hybrids.

F I G U R E 18 Structures and SAR of arylcarbamate‐N‐acyl hydrazone hybrids.

the potential preclinical lead for the development of an anti‐AD incorporate multifunctional property to the developed molecule
agent. against AD (Sestito et al., 2019) (Figure 19). In vitro biological
experiment includes AChE/BChE inhibition, ROS scavenging activity,
cytotoxicity, metal chelation, and neuroprotection study. Among all, 61
4.25 | Clioquinol‐carbamate hybrids presented good ChE inhibition (% inhibition @ 0.05 μM = 3.36 ± 1.08%
for AChE and 14.16 ± 3.49% for BChE), antioxidant activity
Sestito et al., in the year 2019, designed and synthesized a series of (IC50 = 26.49 ± 0.34 in DPPH experiment), metal chelation, and good
clioquinol‐carbamate hybrids by using the fragment of clioquinol to neuroprotection against glutamate‐induced cytotoxicity on HT‐22
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18 | SINGH ET AL.

F I G U R E 19 Design of pyrazolopyrimidinone, quinoline, cinnamic acid, chalcone, apigenin, scutellarin, alkylamine, and tryptamine‐carbamate
hybrids.

cells. Overall evidence suggested that hit 61 can be a potential ChE species (ROS) in SH‐SY5Y cell lines. Overall data revealed that 62
inhibitor and metal chelator candidate for the management of AD. is worthy of further development of potential anti‐AD agents.

4.26 | Chalcone‐carbamate hybrids 4.27 | Apigenin‐carbamate hybrids

Wang et al., in the year 2017, designed and synthesized a novel In the year 2020, Sang et al. designed and synthesized a novel series
series of (E)‐3‐(4‐hydroxyphenyl)‐1‐phenylprop‐2‐en‐1‐one of apogenin‐carbamate hybrids as a multifunctional agent for the
substituted derivatives as a chalcone‐carbamate hybrid with a treatment of AD (Sang, Wang, Bai, et al., 2020). They systematically
potential of AChE/BChE inhibition for the management of AD developed 11 derivatives, among these derivatives 63 presented very
(Wang et al., 2017) (Figure 20). They systematically developed 24 good AChE/BChE inhibitory property (IC50 = 6.8 μM for hAChE and
analogs and tested them for ChE inhibition (AChE and BChE), IC50 = 16.1 μM for huBChE) (Figure 19). Docking study revealed that
enzyme kinetics study, cytotoxicity, and ROS estimation assay on 63 covered the entire hAChE site and interacted with residue Trp86
SH‐SY5Y cell line. In particular, 62 presented excellent ChE (sigma‐p interactions), carbonyl group with Phe295 (intramolecular
inhibitory activity (IC 50 = 0.87 μM for AChE and 0.36 μM for hydrogen bonding), –OH with Ser293 (intra‐H‐bonding), and apigenin
BChE). Moreover, enzyme kinetics study displays kinetic constant core with Trp286 (three p–p interactions). Furthermore, in BChE
(Ki ) of 0.52 ± 0.04 μM for hAChE and 0.16 ± 0.01 μM for hBChE. carbamate functionality coupled with Trp82 (H‐bonding), apigenin
Furthermore, the docking study revealed that the carbamate core with Trp82 (p–p interaction), and the oxygen atom of carbamate
ester of 62 directed toward the CAS of hAChE by interacting with moiety interacted with Asp70 (H‐bonding). Furthermore, 63 selec-
Ser203 and His447 residue, and other interactions are Phe338, tively chelate metal ions (Cu2+), and modulate self, Cu2+ induced, and
Phe295, Phe297, Trp86, and Trp286 with the gorge and PAS site. AChE induced Aβ aggregation. Moreover, the in vivo assay
Cell viability study strongly showed that 62 exhibited 96.66% and demonstrates that 63 showed extraordinary dyskinesia recovery in
94.62% cell viability at 12.5 and 25 μM, respectively. In ROS the AD zebrafish model and did not show any toxicity up to
estimation assay, 62 blocks the production of reactive oxygen 2000 mg/kg oral dose in mice and improved learning and memory in
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19
|

Miscellaneous hybrids analogs (67–75).

Miscellaneous hybrids analogs (76–90).

F I G U R E 20

F I G U R E 21
ET AL.
SINGH
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20 | SINGH ET AL.

TABLE 1 Classification of carbamate‐based hybrid analogs.

Sl. No. Class of hybrids Target Other activity

1. Ferulic acid‐O‐carbamoyl derivatives hAChE, hBChE, MAO‐B, Improve learning and memory in scopolamine‐induced amnesia
and Aβ mice model

2. Hydroxycinnamic acid‐carbamate AChE, BChE, and Aβ, Free radical scavenging activity
derivatives

3. Cannabidiol−carbamate hybrids AChE and BChE Improve learning and memory in scopolamine‐induced
cognition impairment in Morris water maze (MWM) test,
Improve learning and memory in Aβ1–42 (intra‐cerebro‐
ventricular injection) induced cognition impaired model

4 N‐alkylpiperidine carbamate hybrids AChE, BChE, MAO‐A, and Protect neuronal cells from Aβ1–42 induced cell death
MAO‐B

5 Chalcone‐O‐carbamate hybrids AChEs, BChE, MAO, and Antioxidant, chelate copper (Cu2+), neuroprotective properties
Aβ1–42 against H2O2‐mediated cell death in PC12 cells, improves
learning and memory in the scopolamine‐induced cognitive
impairment model.

6 Quinoline‐carbamate hybrids AChE and Aβ1–42

7 Pyridine carbamate hybrids AChE, BChE, and Aβ1–42

8 Diosgenin‐carbamate hybrids Aβ Antioxidant, anti‐inflammatory, protect H2O2‐mediated cell

death in SH‐SY5Y

9 Tryptamine‐carbamate hybrids ChEs and 5‐HT6 receptor

10 Naringenin carbamate hybrids AChE, BChE, and Aβ Metal chelation, free radical scavenging ability

11 Tacrine‐carbamate hybrids AChE and BChE

12 Trihydroquinoline‐carbamate hybrids AChE, and BChE

13 Smilagenin carbamate hybrids Cytoprotective property against H2O2‐mediated cell death,

lipopolysaccharides‐induced NO release in RAW264.7 cells,
oxygen glucoside privation mediated cytotoxicity in
neuroblastoma (SH‐SY5Y) cells

14 Arctigenin‐4‐yl carbamate hybrids Aβ

15 Salicylanilide and 4‐chlorophenol‐based N‐ AChE and BChE

substituted carbamate hybrids

16 Thymol/carvacrol carbamate hybrids AChE and BChE

17 Benzothiazole‐carbamate hybrids AChE Negligible toxicity on human breast adenocarcinoma cell line
SK‐BR‐3

18 Pyranoisoflavone‐carbamate hybrids AChE and BChE

19 4′‐aminochalcone‐carbamate hybrids AChE, BChE Aβ1–42, and Chelates bio‐metal (Cu), and antioxidant property
MAO‐B

20 N‐phenylcarbamate hybrids AChE and BChE

21 2‐Methoxy‐phenyl dimethyl‐carbamate AChE, BChE, and Aβ Free radical scavenging activity in ABTS assay and potent Cu2+
hybrids ion chelating activity in vitro

22 Arylcarbamate‐N‐acyl hydrazone hybrids AChE and BChE

23 Pyrazolopyrimidinone‐carbamate hybrids AChE and

phosphodiesterase 9A

24 Dihydroquinoline carbamate hybrids AChE

25 Clioquinol‐carbamate hybrids AChE and BChE Radical scavenging activity, metal chelation, and good
neuroprotection against glutamate‐induced cytotoxicity on
HT‐22 cells

26 Chalcone‐carbamate hybrids AChE and BChE Neuroprotection in ROS estimation assay on SH‐SY5Y cell line
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SINGH ET AL. | 21

TABLE 1 (Continued)

Sl. No. Class of hybrids Target Other activity

27 Apigenin‐carbamate hybrids AChE, BChE, and Aβ Chelate metal ion (Cu2+), self, Cu2+ induced, and AChE induced
Aβ aggregation, showed extraordinary dyskinesia recovery
in AD zebrafish model, and improve learning and memory in
scopolamine‐induced amnesia mice model

28 Scutellarin‐carbamate hybrids AChE and BChE Neuroprotection in PC12 cell line, antioxidant, bimetal
chelation, and improve learning and memory in scopolamine
induced amnesia mice model

29 Alkylamine‐carbamate hybrids AChE, BChE, and FAAH Excellent memory improvement in Morris water maze mice
experiment at a dose

30 Tryptamine carbamate hybrids AChE, BChE, and Aβ Reduces inflammatory activities on pro‐inflammatory cytokines
NO, iNOS, IL‐6, TNF‐α, and modulates the self‐induced
Aβ1–42 aggregation, and improves learning and memory in
Morris water maze experiment in mice model

the scopolamine‐induced amnesia mice model. The overall result presented mixed inhibition for AChE and noncompetitive inhibition
clearly indicates that 63 could be the potential lead for the treatment mechanism for BChE. Furthermore, 65 showed excellent memory
of AD. improvement in the Morris water maze mice experiments at a dose of
10 mg/kg compared to reference drug rivastigmine at 2.5 mg/kg.

4.28 | Scutellarin‐carbamate hybrids

4.30 | Tryptamine carbamate hybrids
Sang et al., in the year 2015, synthesised and biologically evaluated a
new series of Scutellarin‐carbamate hybrids as a potential multi- In the year 2021 Liu et al. developed a novel series of N‐salicyloyl
functional agent for the treatment of AD (Sang et al., 2015). They tryptamine‐carbamate hybrids as a multifunctional agent for the
systematically developed 36 new molecules and tested them for management of AD (Liu et al., 2022). Among these derivatives, 66
multifunctional properties like ChE inhibition, antioxidant, bimetal present good mixed type dual inhibitory property against AChE/
chelation, and neuroprotection in the PC12 cell line. The result of in BChE (IC50, AChE = 1.84 ± 0.14 µM and BChE = 3.24 ± 1.42 µM)
vitro experiment shows that 64 presented potent AChE/BChE (Figure 19). Moreover, 66 reduces inflammatory activities on
inhibitory property (IC50 = 0.57 μM for AChE and 22.5 μM for BChE, proinflammatory cytokines NO, iNOS, IL‐6, and TNF‐α, and modu-
respectively) (Figure 19). Compound 64 also showed excellent metal lates the self‐induced Aβ1–42 aggregation. The in vivo study also
chelation, BBB permeation, and improved learning and memory in the revealed that 66 improved learning and memory in the Morris water
scopolamine‐induced amnesia mice model. Considering all the maze experiment in the mice model. Furthermore, 66 turned out to
results, the author concluded that compound 64 might be a potential be safe at an oral dose of 2000 mg/kg with no abnormality in an
multifunctional candidate for the management of AD. organ like brain, liver, spleen, and heart compared to control in
histopathology examination.

4.29 | Alkylamine‐carbamate hybrids

4.31 | Miscellaneous hybrids
In the year 2021 Maleki et al. designed and synthesize a new series of
alkylamine carbamate hybrids, and tested all compounds against In the year 2017, Nesi et al. developed a new series of naturally
AChE/BChE, and fatty acid amide hydrolase (FAAH) by using the inspired multifunctional molecules by coupling carbamate with gallic
Ellman method and Cayman assay kit (Maleki et al., 2021). All the acid, lipoic acid, and chromone‐carboxylic acid to address the
developed candidates presented mild to good inhibitory properties in multifactorial nature of AD (Nesi et al., 2017). They systematically
both the assay (IC50 from 0.39 ± 0.02 to 100 µM in AChE and developed nine different molecules and evaluated them against
0.83 ± 0.04 to 108 ± 5.67 in FAAH). Among all, 65 showed highest AChE, BChE, radical scavenging activity assay (DPPH), and self‐
inhibitory activity for AChE (IC50 = 0.39 ± 0.02 µM) and FAAH induced Aβ aggregation assay. Among all, lipoic acid derivatives
(IC50 = 0.83 ± 0.04), respectively (Figure 19). The SAR study revealed showed the most potent BChE inhibitory activity with IC50 values of
that phenyl linker is a more potent inhibitor compared to the 0.35 µM for 70, 0.378 µM for 71, and 0.34 µM for 72, respectively.
piperazine ethyl linker. Enzyme kinetic study indicates that 65 Furthermore, the SAR study revealed that long chain lipoic acid is
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22 | SINGH ET AL.

well tolerated for BChE compared to that gallic acid and chromone‐ N‐phenylpiperazine, N‐benzylpiperazine, and 4‐benzylpiperidine moi-
carboxylic acid. Cytotoxicity study clearly revealed that 70–72 turned eties (Bajda et al., 2018). A pharmacological study revealed that most
out to be safe candidates up to 100 µM in HT22 cells (Figure 20). of the developed analogs exhibited significant activity against BChE.
Bajda et al. in the year 2018, designed, synthesized, and Among all compound 76 (3‐(4‐phenyl‐piperazin‐1‐ylmethyl)‐phenyl
biologically evaluated another series of carbamate derivatives with phenylcarbamate) exhibited IC50 = 2.00 µM against BChE (Figure 21).

TABLE 2 Structures of carbamate‐based drugs of different application.

Pharmacological
S. No. Name of drug Structure activity Other activity Reference

1. Rivastigmine AChE, and BChE Birks et al. (2000)

inhibitor

2. Neostigmine — Myasthenia gravis Corea (2007)

3. Physostigmine Reversible ChE Glaucoma treatment Coelho and

inhibitor Birks (2001)

4. Pyridostigmine AChE inhibitor Muscle strengthener Tripathi

et al. (2003)

5. Febendazole — Anthelmintic Papich (2016)

6. Mebendazole — Anthelmintic Wilson (2012)

7. Albendazole — Anthelmintic Albendazole

(2016)

8. Retigabine — Anticonvulsant, partial‐ Stafstrom

onset seizures et al. (2011)

9. Felbamate — Anticonvulsant Thakkar

et al. (2015)

10. Methocarbamol — Muscle relaxants Baker et al. (2019)

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SINGH ET AL. | 23

For all synthesized analogs lipophilicity and ADMET profile were They systematically designed 26 derivatives and biologically eval-
accessed using computer programs. Furthermore, a molecular dock- uated them for eqBChE and hAChE inhibition assay (Figure 21). All
ing study was also performed to check binding interaction with BChE. the developed analogs exhibited mild to excellent ChE inhibitory
Saxena et al. in the year 2015 developed a new series of ethynyl activity in the enzyme assay experiment with IC50 values from 2.1 to
phenyl carbonates and carbamates as dual‐action acetylcholin- 196.1 µM. Among all, compound 80 was the most potent inhibitor of
esterase inhibitors (AChEIs) and anti‐inflammatory agents (Saxena eqBChE (KC = 14.3 nM) and of hBChE (KC = 19.7 nM). The SAR study
et al., 2015). All the developed molecules showed mild to moderate revealed that pyridyl residues decreased ChE inhibition activity and
AChE inhibitory activity with IC50 range of 28–86 µM. Compound 77 the thiophene residues as less polar bioisosteres increased ChE
was the most potent candidate among all with IC50 = 28.4 µM for inhibition more than fivefold to IC50 against eqBChE of 22 nM for 81
AChE (Figure 21). Furthermore, these molecules have the potential to and 14 nM for 80. Furthermore, the molecular simulation study
treat neuroinflammation and could also dually target AD through the proved how the tetrahydroquinazoline scaffold containing carbamate
restoration of cholinergic balance and inflammation suppression. moieties interacted with the active site of AChE. Moreover, the
Kratký et al. in the year 2021 developed a novel series of neuroprotection study revealed high radical scavenging properties of
multitarget‐directed ligands by combining carbamate, propargyla- the phenolic heterocycle carrier with carbamate fragment. In
mine, and salicylic scaffolds to impart ChE and MAOs inhibitory and summary, compound 80 is the most potent lead for the development
antioxidant properties to developed analogs (Krátký et al., 2021). of other pseudo‐irreversible enzyme inhibitors. In the year 2021, the
They systematically evaluated all the developed compounds for in same research group Scheiner et al. developed a new series of
vitro study against AChE, BChE, and MAO. All the compounds act as multitarget‐directed ligands (MTDLs) as a pseudo‐irreversible
dual inhibitors. Most of the analogs are potent inhibitors of AChE, the BChE inhibitor for the management of AD (Hoffmann et al., 2019;
best activity showed (4‐bromo‐2‐[(prop‐2‐yn‐1‐yl)carbamoyl]phenyl‐ Scheiner et al., 2021). The obtained hybrids were investigated in vitro
ethyl(methyl)carbamate 78 and 2,4‐dibromo‐6‐[(prop‐2‐yn‐1yl) for their hBChE and hAChE inhibition, enzyme kinetics, antioxidant,
carbamoyl]phenyl ethyl(methyl)carbamate 79 were selective and and physicochemical properties (DPPH, ORAC, metal chelating). All
the most active for BChE (25.10 and 26.09 µM) (Figure 21). the developed analogs were found to be good to excellent inhibitor
Furthermore, in silico prediction of physicochemical parameters of hBChE with IC50 values from 5.03 ± 0.2 to 8.19 ± 0.2 nM. All the
acknowledges that the candidate would be active after oral developed analogs (82–90) exhibit excellent activity with an IC50
administration and able to reach brain tissue. value of 6.32 ± 0.03 nM for 82, 6.90 ± 0.01 nM for 83, 6.69 ± 0.02 nM
In year 2016, Edgar Sawatzky et al. reported a new series of for 84, 6.94 ± 0.02 nM for 85, 6.78 ± 0.02 nM for 86, 6.66 ± 0.03 nM
pseudo‐irreversible BChE inhibitors by coupling of tetrahydroquina- for 87, 6.35 ± 0.04 nM for 88, 6.10 ± 0.05 nM for 89, and
zoline scaffold with a carbamate fragment (Sawatzky et al., 2016). 5.03 ± 0.02 nM for 90, respectively. Furthermore, the antioxidant

F I G U R E 22 Pictorial representation of carbamate‐based analogous as multifunctional agents for the management of AD.
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24 | SINGH ET AL.

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