Piperidone Analogs
Piperidone Analogs
Review Article
PIPERIDONE ANALOGS: SYNTHESIS AND THEIR DIVERSE BIOLOGICAL APPLICATIONS
Ajay Kumar K1,* Pavithra G2, Renuka N1, Vasanth Kumar G1
1
Post Graduate Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore.
2
Department of Chemistry, JSS College for Women, SS Puram, Mysore, India
(Received: 01 December 2012; Accepted: 14 December, 2012; Published: 29 December, 2012)
Corresponding Author’s email: [email protected]
Abstract: Piperidones are of particular interest due to their unique biochemical properties. They serve as
precursors to the piperidine ring, which is a ubiquitous moiety in many alkaloid natural products and drug
candidates. In this frame, considerable efforts have been devoted to the synthesis of position isomeric
piperidones and their derivatives. The pipiridone analogs that are synthesized have been bio-assayed for their
varied activity. The structure-activity relationship of the piperidones has been established. This review article
describes up to date methodology for the synthesis of piperidone derivatives and their biological properties.
Br X N X
HO OH
MeCN, 60oC N
Br
+ O
Na2CO3 X X
N X X
H N
Br O 3
Scheme-4
CHO CHO
O
R2 R1 +
+
R R
EtOH/heat/
Conc. HCl NH4OAc
O
R2 R1
N
The reaction of N-tert-butoxycarbonyl-4- H
oxopiperidine-3-carboxylic acid ethyl ester with R
fermenting baker's yeast gave almost racemic N- R
tert-butoxycarbonyl-4-hydroxypiperidine-3- Scheme-9
carboxylic acid ethyl ester with complete
In search for nonsteroidal inhibitors of So- A facile and one pot synthesis of series of
reductase for the treatment of benign prostatic ethyl 3,5-dicyano-4,6-diaryl-piperid-2-one-5-
hyperplasia (BPH) and possibly prostate cancer, carboxylates (13) by the intermolecular
substrate mimicks (12) were synthesized condensation of imines with ethyl cyanoacetate in
comprising of a 1-methyl-2-pyridone or 1-methyl- absolute alcohol in the presence of sodium metal
2-piperidone moiety (mimicking steroidal ring A) under sealed tube conditions was reported by
and a diisopropyl or a tert-butyl benzamide Lokanatha Rai and co-workers.20 They carried out a
(mimicking steroidal ring D). The bridge reaction of an equimolar mixture of imines and
connecting the rings consisted of amide (Scheme- ethyl cyanoacetate in dry ethyl alcohol in the
10). The compounds (12) have been tested for Sa- presence of sodium metal under reflux conditions
reductase inhibitory properties using rat ventral on an oil bath and obtained the products in 55-78%
prostate, as well as human BPH and prostate yield (Scheme-12). The synthesized compounds
cancer. The study revealed that there was a have been evaluated for their antimicrobial
significant differences observed between rat and activity.21 They were prepared the required
human enzyme.17 precursor imines by the reaction of aromatic
aldehydes with amines/ammonia in the presence of
base sodium hydroxide under mild conditions.22
REACTIONS OF PIPERIDONES
Recently, Ajay Kumar and co-workers18,19
reported the synthesis of a series of ethyl N-aryl- The piperidine ring system is a frequently
2,6-dioxo-piperid-3-ene-4-carboxylates by thermal encountered heterocyclic unit in natural compounds
ring expansion reaction of ethyl N-aryl-2,4-dioxo- and drug candidates. Piperidine alkaloids exhibit a
3-azabicyclo[3.1.0]hexane-6-carboxylates in range of biological activities and as such represent
acetonitrile medium in the presence of K2CO3 and important synthetic targets. Piperidones serve an
they obtained in good yield. The products have important role as intermediates en route to
been evaluated in vitro for their antimicrobial and substituted piperidines and can be found as a part
antioxidant activity. The results of their study of more complex biologically active compounds.
revealed that these compounds exhibit remarkable For instance, 4-Piperidone and 4-alkyl piperidones
antimicrobial activity and relatively less react selectively with aromatic hydrocarbons in a
antioxidant activity (Scheme-11). mixture of trifluoromethanesulfonic acid (TFSA)
and CH2Cl2 to give linear polymers, while N-(2-
phenethyl)piperidone undergoes self-
polymerization to yield virtually 100%-
hyperbranched polymer (Scheme-13).23
Chloroacetylation of 2,6-diarylpiperidin-4- compounds (15) and (16) have been evaluated for
ones (14) with chloroacetyl chloride using their antibacterial activities against a wide number
triethylamine as base produces chloroacetyl of bacterial pathogens and antitubercular activity.
derivatives (15). Then, condensation of compounds The results of the study revealed that some
(15) with benzimidazole in the presence of derivatives have exhibited promising antibacterial
calcinated K2CO3 in DMF furnished the novel and antitubercular activity.24
compounds (16) (Scheme-14). The synthesized
Phenyl ethyl 4-piperidone reacts with different products (Scheme-15). The Schiff bases prepared
amines in toluene as a solvent to form have reported to exhibit remarkable microbial
corresponding Schiff bases. The Schiff bases on growth inhibiting properties.25
reduction with Zn-Hg /HCl to give reduced
O NR
RNH2 N
N
Zn-Hg/HCl
R
N PhCOCl NHR
CO
N N
Scheme-15
The reduction of piperidones (19) by sodium evaluated in vitro for their antioxidant activity. It
ethoxide, efficiently transformed in to a mixture of has been found that piperidone (19) demonstrated
isomeric alcohols (20,21) (Scheme-17). The much better radical scavenging activity than its
isomeric alcohols were separated and were isomeric alcohols.27
established human ovarian cancer cell lines pharmacophore toward the development of
(A2870, A2780-DDP, OV-4, SKOV3, PA-1, and anticancer drug synthesis.32
OVCAR3) as well as in a murine xenograft tumor
(A2780) model. The compound was comparably 3,5-Bis(benzylidene)-4-piperidones prepared
and significantly cytotoxic to A2780 cells. The were shown 100-9700 times greater the activity of
study revealed that (22) may be useful as a safe and N,N'-bis(2-chloroethyl)-N-nitrosourea towards
effective anticancer agent for ovarian cancer P388 leukemia cells. Molecular modification of the
therapy.28 compounds by forming two mono-benzylidene
compounds, a related acyclic derivative and an N-
acyl compound resulted in diminished but retained
high cytotoxicity.33 The increasing resistance of the
malaria parasites has enforced new strategies of
finding new drug targets. Experiments with the
antifungal drug ciclopiroxolamine, an α-
hydroxypyridone, and the plant amino acid L: -
mimosine, a 4-pyridone, resulted in an
antiplasmodial effect in vitro. Using mimosine as a
A series of 3,5-bis(arylidene)-4-piperidones lead structure, alkyl 4-oxo-piperidine 3-
(23) (DAP) compounds are considered as synthetic carboxylates were found to have the most efficient
analogues of curcumin for anticancer properties. antiplasmodial effects in vitro and in vivo.34
The studies were performed on the structure-
activity relationship of number of DAPs as potent A series of 3,5-bis(arylidene)-4-piperidone
antioxidant moieties. The anticancer efficacy of (DAP) compounds are the synthetic analogues of
(23) was tested by measuring their cytotoxicity to curcumin for anticancer properties. We performed
cancer cell lines A2780 and MCF-7 cell line. The structure-activity relationship studies by
results showed that all DAP compounds induced a synthesizing a number of DAPs N-alkylated or
significant loss of cell viability in the human cancer acylated with nitroxides or their amine precursors
cell lines tested.29 as potent antioxidant moieties. Both subtituents on
arylidene rings and on piperidone nitrogen (five- or
six-membered, 2- or 3-substituted or 3,4-
disubstituted isoindoline nitroxides) were varied.
The anticancer efficacy of the new DAP
compounds was tested by measuring their
cytotoxicity to cancer cell lines A2780 and MCF-7
and to the H9c2 cell line. The results showed that
all DAP compounds induced a significant loss of
cell viability in the human cancer cell lines tested;
however, only pyrroline appended nitroxides
showed limited toxicity toward noncancerous cell
lines. Computer docking simulations support the
N-Substituted-2-piperidones bearing 1,4- biological activity tested. These results suggest that
benzodioxan ring were prepared by aldol antioxidant-conjugated DAPs will be useful as a
condensation of the lithium enolate of N- safe and effective anticancer agent for cancer
substituted-2-piperidones with 1,4-benzodioxan-6- therapy.35
carbaldehyde were evaluated for their activity to
induce lateral roots in lettuce seedlings. Among the Dysregulated Notch signaling plays an
series; N-cinnamyl-3-[1-(1,4-benzodioxan-6-yl)-1- important role in the progression of cancer. Notch
hydroxymethyl]-2-piperidone had the highest signaling affects tumor growth and angiogenesis
activity.30 3,5-Diarylidene-4-piperidones were through the actions of its ligand Jagged-1. 3,5-
prepared principally as candidate cytotoxic agents. bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD)
The testing was done on 54 human tumor cell lines showed that it inhibits cancer cell growth and its
from eight neoplastic diseases. Selective toxicity effects on Notch signaling. Intraperitoneal
was demonstrated by some of the compounds, administration of DiFiD significantly suppressed
especially toward leukemia.31 A series of twenty growth of pancreatic cancer tumor xenografts. In
2,6-diarylpiperidin-4-one O-methyloximes vitro, DiFiD inhibited the proliferation of various
synthesized were evaluated for their in vitro human and mouse pancreatic cancer cells.36 Series
antiproliferative activity against human cervical of 2,6-diaryl-3-methyl-4-piperidones synthesized
carcinoma (HeLa) cell line. Preliminary SAR by Mannich reaction of ethyl-methyl ketone,
suggests some lead molecules are with a scope of substituted aromatic aldehydes and ammonium
further structural optimization of the piperidone acetate were converted to oximes and
thiosemicarbazone derivatives. The compounds
were screened for acute toxicity, analgesic, local precursors of pharmacologically active analogues
anaesthetic and antifungal activity. The study of GABA.41
revealed that 2-(4-methylphenyl)-3-methyl-6-(4-
chlorophenyl)-piperidin-4-one exhibited the highest Difluorodiarylidenyl piperidone (H-4073) and
analgesic and local anaesthetic activity. The oximes its N-hydroxypyrroline modification (HO-3867)
and thiosemicarbazones derivatives were were evaluated for their anticancer potency in
completely devoid of analgesic and local human ovarian cancer cell lines (A2870,
anaesthetic activity.37 A2780cDDP, OV-4, SKOV3, PA-1, and
OVCAR3) as well as in a murine xenograft tumor
The N-acyl-3,5-bis(arylidene)-4-piperidones (A2780) model. Results revealed that both
and related analogues stimulate a protein tyrosine compounds were comparably and significantly
kinase enzyme. Molecular modelling suggested cytotoxic to A2780 cells. However, HO-3867
that the compounds interact transiently with the showed a preferential toxicity toward ovarian
ATP binding site of fyn kinase thereby enhancing cancer cells while sparing healthy cells. In addition,
the catalytic phosphorylation of proteins.38 A series HO-3867 significantly inhibited the growth of the
of bis[3,5-bis(benzylidene)-4-oxo-1- ovarian xenografted tumors in a dosage-dependent
piperidinyl]amides display potent cytotoxic manner without any apparent toxicity. The study
properties towards a wide range of tumours. These suggested that HO-3867 may be useful as a safe
compounds have the following important and effective anticancer agent for ovarian cancer
properties. First, greater toxicity was demonstrated therapy.42
towards certain tumours than various non-
malignant cells. Second, various compounds in The compound 3,3,5,5-tetramethyl-4-
series are toxic to a number of human colon cancer piperidone (TMP), extracted from Marasmius
and leukaemic cells. Third, these compounds androsaceus was evaluated for antihypertensive
reverse P-gp mediated multidrug resistance.39 effect. Besides, the hemodynamic profiles and
pertinent mechanism of the compound were
A number of 3,5-diarylidene-4-piperidones explored. Acute and chronic antihypertensive
prepared principally as candidate cytotoxic agents effects of TMP were examined in spontaneous
in two screens. The first test system used an hypertensive rats (SHRs) and reno-hypertensive
average of 54 human tumor cell lines from eight rats. Anesthetized dogs were used to evaluate the
neoplastic diseases, namely leukemia, melanoma, hemodynamic effects of TMP. Moreover, the cat
colon, non-small-cell lung, small-cell lung, central nictitating membrane response was used to test the
nervous system, ovarian, and renal cancers. ganglionic blocking property of TMP. TMP
Selective toxicity was demonstrated by some of the notably reduced the blood pressure of SHR in 30
compounds, especially toward leukemia. The min. The results of hemodynamic study in
second screen used L1210 lymphoid leukemia anesthetized dogs showed that, except for the
cells. In general, the compounds were less reduction in blood pressure and left ventricular
cytotoxic than the reference drug melphalan in both work, no other changes were detected. The results
screens. Evaluation against the human tumor cell of heart rate variability analysis indicated an intact
lines revealed that 3,5-bis-[[4'- sympathetic-vagal balance after TMP treatment.43
(methylthio)phenyl]methylene]-1-methyl-4- A series of 3,5-bis(phenylmethylene)-1-(N-
piperidone methiodide had significant cytotoxicity, arylmaleamoyl)-4-piperidones synthesized were
and 3,5-bis(4-pyridylmethylene)-1-methyl-4- displayed potent cytotoxicity towards human Molt
piperidone methiodide was virtually inactive in 4/C8 and CEM T-lymphocytes as well as murine
both screens.40 P388 and L1210 leukemic cells. Molecular
modeling revealed certain interplanar and bond
1-Piperideine, 5-aminopentanoic acid, and its angles and interatomic distances which were
lactam, 2-piperidone, were identified as metabolites perceived to contribute to the observed bioactivity
of cadaverine in 10,000 g mouse liver supernatants as well as providing suggestions for future
to which diamine oxidase had been added. Both structural modifications of the piperidones.44
metabolites were also found when the cadaverine
metabolite 1-piperideine was incubated with the N-Morpholinoacetyl-2,6-diarylpiperidin-4-
preparation which suggested that 1-piperideine is ones (24) were prepared in search of new leads
an intermediate in the formation of 5- towards potent antimicrobial agents. The
aminopentanoic acid and 2-piperidone. compounds have been evaluated in vitro for their
Identification of the metabolites was based on gas antibacterial activity against S. aureus, E. coli, P.
chromatography-mass spectrometric analysis in aeruginosa and S. typhi; and antifungal activity
comparison to authentic standards. Mouse brain against C. albicans, A. niger and A. flavus.
homogenates converted 1-piperideine to 5- Structure-activity relationship results for these
aminopentanoic acid. The results suggest that the compounds have shown that these exerted excellent
metabolic fate of cadaverine may provide
antibacterial activity against all the bacterial 3. Chan Y, Balle J, Sparrow J.K, Boyd
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