Design and synthesis of antimicrobial active new molecular entities of N-substituted pipradol derivatives

Article abstract of DOI:10.14233/ajchem.2017.20588

Synthesis of antimicrobial 4-(hydroxyldiphenyl methyl)piperidin-1-yl)(substituted phenyl)methanone derivatives by using conventional chemical reactions to produces feasible and entirely new chemical entities (NCE’S) which were having a great potential microbial activities equivalent to fexofenidine used as a biological standard. This invention may help full for derive more potential pipradol molecules with peptide bond linkage.

Full text of DOI:10.14233/ajchem.2017.20588

Asian Journal of Chemistry; Vol. 29, No. 10 (2017), 2113-2115
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20588
Design and Synthesis of Antimicrobial Active New
Molecular Entities of N-Substituted Pipradol Derivatives
1,*
1
2
2
B. SRI RAMUDU , D. RAMACHANDRAN , S. VENKAT RAO , CH. MURALI KRISHNA ,
2
2
B. SATYA NARAYANA and KALLAM NAVEEN REDDY
1Acharya Nagarjuna University, Nagarjuna Nagar, Guntur-522 510, India
2Srigen Life Sciences Pvt. Ltd., Plot No. 34, 35, I.E. Rajiv Gandhi Nagar, IDA Kukatpally-500 037, India
*Corresponding author: E-mail: sriram.elm.chem@gmail.com
Received: 15 February 2017;
Accepted: 19 May 2017;
Published online: 31 August 2017;
AJC-18501
Synthesis of antimicrobial 4-(hydroxyldiphenyl methyl)piperidin-1-yl)(substituted phenyl)methanone derivatives by using conventional
chemical reactions to produces feasible and entirely new chemical entities (NCE’S) which were having a great potential microbial
activities equivalent to fexofenidine used as a biological standard. This invention may help full for derive more potential pipradol molecules
with peptide bond linkage.
Keywords: Pipradol derivatives, Antimicrobial, Peptide bond, Fexofenadine.
Aspergillus niger and Saccharomyces cerrevisiae with respect
to fexofenidine hydrochloride taken as a standard.
INTRODUCTION
In this millennium, the most important drug development
areas are antiviral, antifungal or antimicrobial, antidiabetes
mellitus, anticancerous, as per as our research budget is concern
here we developed some new pipradol derivatives by using
simple conventional and economic reagents to generate the
new chemical entities with the pipradol having a peptide (-HN-
C=O) bond linkage. Literature survey revealed that pipecolic
acid (piperidine-2-carboxylic acid) is a precursor of various
bioactive compounds such as thioridazine [1] (antituberculosis
agent), pipradol [2,3] (anticonvulsant agent) which are derived
from piperidine-4-carboxylic acid.
Few reports have been appeared on central stimulant activity
of various diaryl piperidines, diaryl piperidine methanol [4],
few reports available on optical isomers [5,6] and their activities
of pipradols [7]. Pipradols N-alkylation’s and their drug appli-
cations were reported [8-15], however, none of the literature is
available for N-acylation i.e., peptide bond formation with γ-
pipradol.
Herein the present work, we have developed some
contemporary pipradol with peptide linkage, having chemical
name of (4-(hydroxyldiphenyl methyl)piperidin-1-yl) (substituted
phenyl)methanone. These analogues synthesized from commer-
cially available raw material diphenyl(piperidin-4-yl)methanol
(azacyclonol), which is a basic scaffold in fexofenadine and
these molecular derivatives synthesized have more potential
towards antimicrobial activity [3] against Candida albicans,
EXPERIMENTAL
All the key raw materials, reagents and solvents were
purchased from Aldrich. Instruments used for their analytical
testing are 1H NMR (Bruker 400 MHZ), Mass (Bruker), HPLC
(Shimadzu, LC-20 solutions) and IR by Perkin Elmer.
Synthesis of diphenyl(piperidin-4-yl)methanol (4c): In
a 3 L round bottom flask equipped with mechanical stirrer
and a water bath the following materials are poured: magnesium
turnings (100 g, 4.16 mmol), tetrahydrofuran (650 mL), bromo
benzene (43.6 g, 0.277 mmol). The mixture is heated to reflux
while stirring and as soon as the reaction is started a solution
of brombenzene (608.4 g, 3.87 mmol) is slowly added at such
a rate so as to maintain reflux. When the addition is complete,
the mixture is refluxed until magnesium is almost completely
dissolved. Then isonipecotic acid (4a) (200 g) and toluene
(300 mL) are added to phenyl magnesium bromide (4b) (Grignard
reagent) kept at 50 °C. The mixture is refluxed at atmospheric
pressure for about 1 h. Then, the reaction is kept under pressure
with nitrogen (0.4 to 1.5 atm) and the mixture is heated again
between 105 and 120 °C. for 10 h.After this, the reaction mixture
is allowed to cool, the pressure of the reaction is slowly decreased
and the mixture is slowly poured into 4 L of cold water.Yield
415 g of the azacyclonol [16] compound 4c of the title
(Scheme-I).

2114 Ramudu et al.
Asian J. Chem.
Synthesis of (4-(hydroxydiphenylmethyl)piperidin-1-
yl)(4-bromophenyl)methanone (5c): 1H NMR: δ 7.4-7.5 m,
6H, δ 7.29-7.32 t, 4H, δ 7.2 m, 4H, δ 4.74 s,1H, δ 3.7 s,1H, δ
2.87 s,1H, δ 2.0 t, 2H, δ 2.2 s,1H, δ 1.27-1.58 m, 4H. Mass:
M: 450.37, M+H: 451.6.
HO
O
OH
MgBr
THF
2
0-5 °C
N
H
4a
Synthesis of (4-(hydroxydiphenylmethyl)piperidin-1-
N
H
1
yl)(4-methyl-3-nitrophenyl)-methanone (5d): H NMR:
4c
4b
δ 7.99 s, 1H, δ 7.51 m, 10H, δ 7.2 d, 2H, δ 3.4-4.9 m, 2H, δ
2.8 t, 2H, δ 2.6 s,3H, δ 1.4-1.9 m, 4H. Mass: M: 430.5M+H:
431.3.
Synthesis of (4-(hydroxydiphenylmethyl)piperidin-1-
yl)(2-methyl-3-nitrophenyl)methanone (5e): 1H NMR : δ 7.8
d,1H, δ 7.45 d2H, δ 7.40 t, 3H, δ 7.33 d, 4H, δ 7.2 m, 2H, δ
7.17 t2H, δ 4.85 t1H, δ 3.36 d1H, δ 3.02 m1H, δ 2.8 t1H, δ
2.65 m1H, δ 2.41 d3H, δ 2.1 s2H, δ 1.72 d1H, δ 1.53 s2H, δ
1.4 m3H, δ 1.29 m1H, Mass: M: 430.5, M+H: 431.
Synthesis of (4-(hydroxyl diphenyl methyl)piperidin-
1-yl)-(4-methylphenyl)methanone (5f): 1H NMR: δ 7.44 d,
1H, δ 7.29 m, 6H, δ 7.18 d, 4H, δ 4.77 s, 1H, δ 3.82 s, 1H, δ
2.26-3.03 m, 3H, δ 2.36 s, 3H, δ 1.25-1.70 m, 5H. Mass: M+:
385.5, M+H: 386.8.
Synthesis of (4-(hydroxyl diphenyl methyl)piperidin-
1-yl)(3, 5-dimethylphenyl)methanone (5g): 1H NMR: δ 7.45
d, 4H, δ 7.30 t, 4H, δ 7.19 t, 2H, δ 6.98 s,1H, δ 6.95 s, 2H, δ
4.76 s,1H, δ 2.88 bs, 2H, δ 2.69 t, 1H, δ 2.29 s,1H, δ 1.27 s,
6H, δ 2.11 t, 1H, δ 1.43 t, 3H. Mass: M+: 399.52, M+H: 400.5.
Cup-Plate method: The antimicrobial activity of synthe-
sized analogues was tested by cup and plate method [17],
Nutrient agar was poured onto the sterilized petri-dishes (20-
25 mL each pertri dish). The poured material was allowed to
set (1-1.5 h) and thereafter the “Cup-Plate method” (10 mm
diameter) were made by punching into the agar surface with a
sterile cork borer and scooping out the punched part of the
agar. Into these cups, the test compound solution was added
with the help of sterile syringe. The plates were incubated at
37 °C for 48 h and the results were noted. A solvent control
(10 % DMSO in methanol) was also run to not the activity of
the blank (solvent). The standard drug fexofenadine was also
screened under similar conditions for comparison.
Scheme-I
Synthetic method of acid chloride of substituted benzoic
acids (2b.a-2b.f): In a 100 mL round bottom flask equipped
with mechanical stirrer and a water bath, taken 2-methyl-3-
nitrobenzoic acid (15 g, 0.00 mmol), chloroform (200 mL)
and then freshly distilled thionyl chloride (30 mL) was added
drop wise at room temperature. The reaction mass stirred for
10 min at ambient temperature and slowly heated to 70 °C,
maintain the same temperature for 1-2 h. After completion of
the TLC removed the excess thionyl chloride and once stripped
off with chloroform to get desired substituted benzoyl chlorides.
Synthesis of (4-(hydroxydiphenylmethyl)piperidin-1-
yl)(2-methyl-3-nitrophenyl)methanone (5e): To a 250 mL
round bottom flask, diphenyl(piperidin-4-yl)methanol (12 g),
triethylamine (2 mL) in acetone (100 mL) under constant stirring
were added follwed by the addition of 2-methyl-3-nitrobenzoyl
chloride (15 g) dropwise at room temperature and then refluxed
for 3-4 h. After TLC complies stripped off the acetone and the
obtained crude product is subjected to column purification in a
mobile phase (1:9) methanol:chloroform. The yellow coloured
obtained product yield 15 g (Scheme-II). m.p.: 140-145 °C.
1H NMR: δ 7.8 d, 1H, δ 7.45 d, 2H, δ 7.40 t, 3H, δ 7.33 d, 4H,
δ 7.2 m, 2H, δ 7.17 t, 2H, δ 4.85 t, 1H, δ 3.36 d, 1H, δ 3.02 m,
1H, δ 2.8 t, 1H, δ 2.65 m, 1H, δ 2.41 d, 3H, δ 2.1 s, 2H, δ 1.72 d,
1H, δ 1.53 s, 2H, δ 1.4 m, 3H, δ 1.29 m, 1H. Mass: M: 430.5,
M+H: 431.
R
O
Cl
OH
OH
NH
N
O
a
RESULTS AND DISCUSSION
R
Four drugs has been synthesized using piperidine moiety
as a common scaffold and exhibiting their perfect drug activity
at various levels of absorbance, if you see none of the drug
was constructed with peptide bond (–CO-NH-) at secondary
amine junction of piperidine ring to form tertiary amine.
To increase the drug activity of piperidine tertiary amine
functional group, it is thought to construct a peptide bond
formation with secondary amine of piperidine by treating with
some substituted aromatic carbonyl chlorides in presence of a
base often to form some biologically active pipradol derivatives.
The synthesized analogues of (4-(hydroxyl diphenyl
methyl)piperidin-1-yl) (substituted phenyl)methanone from
commercially available diphenyl(piperidin-4-yl)methanol
(azacyclonol) were examined for its biological activity and
the obtained results were showing more potential towardsanti-
microbial activity against Candida albicans, Aspergillus niger
and Saccharomyces cerrevisiae (Table-1).
2a-g
4c
5a-g
a: Triethylamine or K2CO3, acetone or methylene chloride
R: -CH3, -F, -Cl, -Br, (-CH3)2, -NO2,
Scheme-II
And rest of the compounds also followed the same proce-
dure what we done for compound 5e, hence we incorporated
their spectral data for each compound as follows:
Synthesis of (4-(hydroxyl diphenyl methyl)piperidin-
1-yl)(2,4,5-triflourophenyl)methanone (5a): 1H NMR: δ 7.5
m, 4H, δ 7.35 m, 5 H, δ 7.22 m, 2 H, δ 609 m, 1 H, δ 4.74
dd,1H, δ 3.51 dd, 1H, δ 3.12 s,1H, δ 2.84 t,1H, δ 2.6 t,1H, δ
1.7 m,1H, δ 1.4 m, 3H. Mass: M: 425.44, M+H: 426.
Synthesis of (4-(hydroxyl diphenyl methyl)piperidin-
1-yl)(3, 5-dinitrophenyl)methanone (5b):1H NMR: δ9.05 s,1H,
δ 8.55 s, 2H, δ 7.45 t, 6H, δ 7.32 d, 4H, δ 3.65 s,1H, δ 3.20-2.7
m, 4H, δ 2.26 m, 1H, δ 1.27 t, 4H, Mass: M: 461.47, M+H: 462.1.

Vol. 29, No. 10 (2017)
Synthesis of Antimicrobial Active New Molecular Entities of N-Substituted Pipradol Derivatives 2115
TABLE-1
MICROBIOLOGY TESTING RESULTS; STD: FEXOFENADINE DRUG STANDARD;
5a, 5b, 5c, 5d, 5e, 5f, 5g ARE SYNTHESIZED DERIVATIVES
Microbiology - Cell cultures
Conc.
(µg/mL)
Std
5a
5b
5c
5d
5e
5f
5g
Aspergillums niger
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
10.2
10.4
10.5
10.5
10.4
10.6
10.8
10.8
10.1
10.2
10.2
10.2
10.2
10.4
10.4
10.5
10.5
10.1
10.2
10.2
10.3
10.3
10.3
10.4
10.5
10.5
10.1
10.1
10.1
10.1
10.2
10.4
10.4
10.5
10.0
10.1
10.0
10.1
10.1
10.1
10.1
10.1
10.3
10.1
10.1
10.1
10.1
10.1
10.3
10.4
10.4
10.4
10.0
10.0
10.0
10.0
10.0
10.2
10.2
10.4
10.6
09.9
10.1
10.1
10.2
10.1
10.4
10.4
10.4
10.7
10.5
Candida albicans
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
10.1
10.1
10.1
10.3
10.3
10.3
10.3
10.3
10.5
-
10.2
10.5
10.6
10.8
10.8
10.9
10.8
10.9
-
10.2
-
-
Saccharomyces cerevisiae
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
-
-
-
-
-
-
-
-
-
-
11.1
11.2
11.2
11.3
11.3
11.3
11.3
11.4
11.6
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
09.6
09.6
09.8
09.9
09.9
10.3
10.5
10.8
10.4
10.7
10.8
10.8
11.4
11.9
11.9
11.3
11.8
11.8
11.9
11.9
11.9
11.9
11.1
11.0
11.1
11.2
11.2
11.7
11.4
11.5
11.5
11.7
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Conclusion
A new attempt is made for synthesizing a potential 4-
(hydroxyldiphenyl methyl)piperidin-1-yl)(substituted phenyl)-
methanone derivatives as antimicrobial agent. Among the six
synthezied compounds, more or less all are gets positive range
of activity against fexofenadine, but compounds 5g, 5c and 5d
were seems to be more attractive and promising molecules for
extended research work, which can be use full to identify a new
drug product for drug therapy applications.
ACKNOWLEDGEMENTS
Our first and foremost thanks to CSIR for providing the
fellowship, then for Department of Chemistry of Acharya
Nagarjuna University and M/s Srigen Life Sciences Pvt. Ltd.
for providing the laboratory facility to do its part of the work.
13. W. Ronggeng, Z. Yougui and Z. Guanchao, Res. Chem. Intermed., 39,
2149 (2013);
https://doi.org/10.1007/s11164-012-0747-y.
14. Fine Spec. Chem., 19, 32 (2011).
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