Synthesis, spectral analysis and antibacterial evaluation of 5-substituted-1,3,4-oxadiazol-2-yl 4-(4-methylpiperidin-1-ylsulfonyl)benzyl sulfides

Article abstract of DOI:10.4067/S0717-97072017000100013

Owing to valuable biological activities of 1,3,4-oxadiazole, sulfamoyl and piperidine functionalities, some new 1-(4-{[(5-substituted-1,3,4-oxadiazol-2-yl) thio]methyl}benzene sulfonyl)-4-methylpiperidine (6a-o) derivatives have been introduced. The target molecules were synthesized from different aralkyl/aryl carboxylic acids, 1a-o, through a series of steps. First the compounds, 1a-o, were converted to heterocyclic 1,3,4-oxadiazole nucleophiles, 4a-o. Second an electrophile as 1-(4-bromomethylbenzenesulfonyl)-4-methylpiperidine (5) was synthesized from 4-methylpiperidine. Finally the target compounds, 6a-o, were prepared by reacting 4a-o with 5 in DMF and LiH. The final compounds were structurally elucidated by spectral data of IR, 1H-NMR and EI-MS. All the compounds were screened for their antibacterial evaluation and found to exhibit valuable results.

Full text of DOI:10.4067/S0717-97072017000100013

J. Chil. Chem. Soc., 62, Nº 1 (2017)
SYNTHESIS, SPECTRAL ANALYSIS AND ANTIBACTERIAL EVALUATION OF 5-SUBSTITUTED-1,3,4-
OXADIAZOL-2-YL 4-(4-METHYLPIPERIDIN-1-YLSULFONYL)BENZYL SULFIDES
AZIZ-UR-REHMANa,*, SAMREEN AHTZAZa, MUHAMMAD ATHAR ABBASIa, SABAHAT ZAHRA SIDDIQUIa,
SHAHID RASOOLa, IRSHAD AHMADb
aDepartment of Chemistry, Government College University, Lahore-54000, Pakistan.
bDepartment of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur-63100, Pakistan.
ABSTRACT
Owing to valuable biological activities of 1,3,4-oxadiazole, sulfamoyl and piperidine functionalities, some new 1-(4-{[(5-substituted-1,3,4-oxadiazol-2-yl)
thio]methyl}benzene sulfonyl)-4-methylpiperidine (6a-o) derivatives have been introduced. The target molecules were synthesized from different aralkyl/aryl
carboxylic acids, 1a-o, through a series of steps. First the compounds, 1a-o, were converted to heterocyclic 1,3,4-oxadiazole nucleophiles, 4a-o. Second an
electrophile as 1-(4-bromomethylbenzenesulfonyl)-4-methylpiperidine (5) was synthesized from 4-methylpiperidine. Finally the target compounds, 6a-o, were
prepared by reacting 4a-o with 5 in DMF and LiH. The final compounds were structurally elucidated by spectral data of IR, 1H-NMR and EI-MS. All the
compounds were screened for their antibacterial evaluation and found to exhibit valuable results.
Keywords: 1,3,4-oxadiazole, 4-methylpiperidine, antibacterial activity, sulfonamide, 1H-NMR, EI-MS.
refluxed for 3-4 hours. Thin layer chromatography was the technique used to
monitor the completion of reaction by using 1:4 ratio of n-hexane and ethyl
acetate as mobile phase. After maximum completion, reaction mixture was
treated with 10% aqueous Na CO3 (pH 9-10) to neutralize the reaction mixture
and to remove unreacted free2acid. To get the pure esters, solvent extraction of
neutralized reaction mixture was performed by 50 mL of CHCl3 in a separating
funnel for 3-4 times. After that CHCl layer was separated from the lower
density aqueous layer and was distilled3 by using rotary evaporator to acquire
ethyl esters.
1. INTRODUCTION
New diseases have been discovered and also the commercial drugs have
become ineffective against the old ones. So a large work has to be performed in
this regard in search of new more potent drug molecules. Organic synthesis along
with other fields of research is continuously being used for drug development
program and hence designing new drug candidates1,2
.
Oxadiazole is a class of heterocyclic organic compounds that is known
because of its magnificent therapeutic potential3. 1,3,4-Oxadiazole moieties
display an inclusive variety of biological and pharmacological activities, for
example, anti-cancer, anti-oxidant, anti-tubercular4-6. Besides anti-bacterial
and anti-fungal properties, they have other biological properties such as anti-
convulsant, anti-inflammatory and anti-anxiety7,8. Sulfonamides, antimicrobial
agents, are synthetically formed from sulfanilic acid9-11. They are highly
putative antibiotic due to their cost effectiveness and stable chemical activity12.
Correspondingly, they exhibit antibacterial, antiviral, diuretic, anti-carbonic
anhydrase and anti-thyroid activities13,14. The piperidine and its derivatives
have also acquired substantial prominence to medicinal chemistry because
of the wide variety of their biological and pharmaceutical properties15. Apart
from this, piperidine nucleus is playing fundamental role as agrochemicals,
anti-depressants, analgesics, anti-bacterial, anti-fungicidal, anti-histaminic,
2.3. Procedure for the synthesis of different aralkyl/aryl acid
hydrazides (3a-o)
The ethyl esters (0.15 mol; 2a-o) were taken in 250 mL round bottom flask.
About 30 mL of methanol was added to the flask and homogenized by stirring
at room temperature. Hydrazine hydrate (80%; 0.15 mol) was introduced to the
flask drop wise and the reaction apparatus was refluxed for 5-6 hrs. Reaction
progress was confirmed by thin layer chromatography. n-Hexane and ethyl
acetate (3:2). At the end of reaction, excess of solvent was evaporated and
residue was poured into the ice cold water. Precipitates of acid hydrazides were
filtered, washed with water and dried. Re-crystallization of acid hydrazides was
performed by using methanol.
2.4. Procedure for the synthesis of 5-substituted-1,3,4-oxadiazol-2-
thiols (4a-o)
anti-HIV and anti-cancer agents16,17
.
The aralkyl/aryl acid hydrazides (0.01 mol; 3a-o) were dissolved in 20 mL
absolute C2H OH in a 250 mL of round bottom flask. Solid KOH (0.02 mol)
and carbon d5isulphide (0.02 mol) were added to reaction flask. The reaction
contents were refluxed for 4-5 hrs with continuous stirring. H S was evolved
during the completion of reaction. Completion of reaction wa2s confirmed by
thin layer chromatography by using n-hexane and ethyl acetate (3:2) as mobile
phase to develop a chromatogram. After confirmation, cold distilled water was
added to the flask contents along with the addition of dilute HCl (pH 4-5).
Precipitates of title compounds were filtered, washed with distilled water
and dried. To obtain the pure products, precipitates were recrystallized from
methanol.
The valuable biological results of nominated functionalities prompted us
to synthesize some new molecules bearing all these functionalities together
in a single molecule and further to evaluate their pharmacological behavior
regarding antibacterial activity. In continuation of previous attempts by our
group in this regard18,19, the presented compounds with some new chemical
entities were synthesized and subjected to antibacterial screening against
certain strains of Gram-negative and Gram-positive bacteria.
2. EXPERIMENTAL
2.1. General
2.5.
Synthesis
of
1-(4-bromomethylbenzenesulfonyl)-4-
All the chemicals (Merck & Alfa Aesar) and analytical grade solvents
were purchased through local suppliers. Melting points were taken on Griffin
and George melting point apparatus by open capillary tube method. TLC
plate F256 20 x 20 cm coated with silica gel was used to detect the purity of
the synthesized compounds, developed by different ratios of n-Hexane and
EtOAc as solvent system. UV lamp was used to visualize the TLC. With the
help of KBr pellet method, IR spectrum was recorded by using Jasco-320-A
spectrophotometer. 1H-NMR spectra were recorded on Bruker spectrometers at
frequency 400 MHz, taken in deuterated chloroform, indicating chemical shifts
value in ppm and taking TMS as reference standard.
methylpiperidine (5)
4-Methylpiperidine (0.0126 mol; a) was taken in an iodine flask. Aqueous
sodium carbonate solution (15%), a weak base, was added to maintain a pH
of 9. Small amount methanol (2-3 mL) and 4-bromomethylbenzenesulfonyl
chloride (0.0126 mol; b) were added to the mixture pinch by pinch. The
mixture was shaken vigorously and set to stir for 1 hour till precipitation. White
precipitates of 1-(4-bromomethylbenzenesulfonyl)-4-methylpiperidine were
filtered, washed with distilled water and dried. The synthesized electrophile
was re-crystallized from methanol and used for further reaction.
2.6. General procedure for the S-substituted derivatives (6a-o)
2.2. Procedure for the synthesis of different ethyl esters (2a-o)
The different organic acid (0.02 mol; 1a-o) was taken in 200 mL round
bottom flask. 20 mL absolute ethanol (99%) was added to the flask and
stirred for ten minutes to homogenize the reaction contents. Later on, 2.5 mL
concentrated sulphuric acid, an activator, was added and reaction contents were
The molecules 4a-o (0.0006 mol) were homogenized in 5-10 mL of
N,N-dimethylformamide in a round bottom flask and then (0.0006 mol)
of lithium hydride was added along with stirring. After half hour stirring,
1-(4-bromomethylbenzenesulfonyl)-4-methylpiperidine (0.0006 mol) was
3370
e-mail: rehman@gcu.edu.pk; azizryk@yahoo.com

J. Chil. Chem. Soc., 62, Nº 1 (2017)
poured into homogeneous solution and further stirred for 4-6 hours. After
confirmation of reaction completion by Thin Layer Chromatography, ice cold
distilled water was introduced into reaction contents along with 2-3 drops of
aq. NaOH. The mixture was gently shaken and precipitates of title compounds
were acquired through filtration. Precipitates were washed with distilled water
and dried. All the compounds were re-crystallized from methanol.
(3.2%), 117 (98.6%), 91 (67.6%), 98 (87.3%).
2.7.6. 1-[4-({[5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzene sulfonyl]-4-methylpiperidine (6f)
Brown crystalline solid; M.P: 104-106 0C; Yield: 80%; M.F: C22H25N3O4S2;
M.W: 459.13; IR (KBr, υ , cm-1): 3052 (C-H str. of ar. ring), 1642 (C=N str.
of oxadiazole ring), 1534m(aCx =C ar. str.), 1332 (-SO2 str.), 1226, 1055 (C-O-C
bond str.), 618 (C-S bond str.); 1H-NMR (CDCl3, 400 MHz): δ (ppm) 7.85 (d, J
= 7.2 Hz, 1H, H-6ꞌ), 7.71 (d, J = 8.4 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.63 (d, J = 8.0 Hz,
2H, H-3ꞌꞌ & H-5ꞌꞌ), 7.47 (t, J = 7.2 Hz, 1H, H-5ꞌ), 6.50 (t, J = 8.0 Hz, 1H, H-4ꞌ),
6.60 (d, J = 8.0 Hz, 1H, H-3ꞌ), 4.56 (s, 2H, H-7ꞌꞌ), 3.92 (s, 3H, -OCH3), 3.71 (d,
J = 11.2 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.23 (t, J = 11.2 Hz, 2H, Hax-2ꞌꞌꞌ & Hax-6ꞌꞌ
ꞌ), 1.69 (d, J = 7.6 Hz, 2H, Heq-3ꞌꞌꞌ & Heq-5ꞌꞌꞌ), 1.37 (d, J = 12.4 Hz, 2H, Hax-3ꞌꞌꞌ
& Hax-5ꞌꞌꞌ), 1.12-0.99 (m, 1H, H-4ꞌꞌꞌ), 0.91 (d, J = 4.0 Hz, 3H, CH3-7ꞌꞌꞌ); EI-MS
m/z: 459 (5%)[M+], 297 (60.3%), 251 (87.9%), 207 (16.8%), 149 (3.2%), 113
(100%), 107 (67.6%), 98 (87.3%).
2.7. Physical and spectral data of synthesized compounds
2.7.1.
1-(4-{[(5-Phenyl-1,3,4-oxadiazol-2-yl)thio]methyl}
benzenesulfonyl)-4-methylpiperidine (6a)
White amorphous solid; M.P: 109-111 oC; Yield: 85%; M.F: C21H23N3O3S2;
M.W: 429.12; IR (KBr, υ , cm-1): 3030 (C-H str. of ar. ring), 1634 (C=N str.
of oxadiazole ring), 1524m(aCx =C ar. str.), 1330 (-SO2 str.), 1226, 1059 (C-O-C
1
bond str.), 701 (C-Cl bond str.), 616 (C-S bond str.); H-NMR (CDCl3, 400
MHz): δ (ppm) 7.98 (d, J = 7.2 Hz, 2H, H-2ꞌ & H-6ꞌ), 7.70 (d, J = 8.0 Hz, 2H,
H-2ꞌꞌ & H-6ꞌꞌ), 7.62 (d, J = 8.0 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 7.48 (m, 3H, H-3ꞌ to
H-5ꞌ), 4.50 (s, 2H, H-7ꞌꞌ), 3.70 (d, J = 10.8 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.25 (t,
J = 11.2 Hz, 2H, Hax-2ꞌꞌꞌ & H -6ꞌꞌꞌ), 1.55 (d, J = 9.2 Hz, 2H, Heq-3ꞌꞌꞌ & H -5ꞌꞌꞌ),
1.35 (d, J = 12.4 Hz, 2H, Hax-a3xꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.19-1.00 (m, 1H, H-4ꞌꞌꞌ), 0.9e0q (d, J
= 4.0 Hz, 3H, CH -7ꞌꞌꞌ); EI-MS: m/z 429 (4%)[M]+, 267 (62%), 251 (89%), 177
(18%), 119 (4%),3103 (100%), 98 (88%), 77 (69%).
2.7.7. 1-[4-({[5-(2-Naphthylmethyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzene sulfonyl]-4-methylpiperidine (6g)
White amorphous solid; M.P: 93-95 oC; Yield: 78%; M.F: C26H27N3O3S2;
M.W: 493.64; IR (KBr, υ , cm-1): 3036 (C-H str. of ar. ring), 1638 (C=N str.
of oxadiazole ring), 1529m(aCx =C ar. str.), 1336 (-SO2 str.), 1228, 1056 (C-O-C
bond str.), 619 (C-S bond str.); 1H-NMR (CDCl3, 400 MHz): δ (ppm) 8.08 (d, J
= 8.0 Hz, 1H, H-4ꞌ), 7.87 (dd, J = 8.4, 1.2 Hz, 1H, H-8ꞌ), 7.83 (dd, J = 8.0, 2.0
Hz, 1H, H-5ꞌ), 7.57 (d, J = 8.0 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.54 (dd, J = 7.6, 1.6 Hz,
1H, H-3ꞌ), 7.52 (dt, J = 8.8, 1.6 Hz, 1H, H-7ꞌ), 7.46-7.41 (m, 1H, H-6ꞌ), 7.42 (s,
1H, H-1ꞌ), 7.39 (d, J = 8.0 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 4.50 (s, 2H, H-7ꞌꞌ), 3.70 (d,
J = 11.2 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.25 (t, J = 11.2 Hz, 2H, Hax-2ꞌꞌꞌ & Hax-6ꞌꞌ
ꞌ), 1.57 (d, J = 8.8 Hz, 2H, Heq-3ꞌꞌꞌ & Heq-5ꞌꞌꞌ), 1.39 (d, J = 12.4 Hz, 2H, Hax-3ꞌꞌꞌ
& Hax-5ꞌꞌꞌ), 1.13-1.08 (m, 1H, H-4ꞌꞌꞌ), 0.93 (d, J = 4.0 Hz, 3H, CH3-7ꞌꞌꞌ); EI-MS
m/z: 493 (6%)[M]+, 332 (70%), 251 (78%), 241 (27%), 183 (4%), 167 (100%),
141 (78%), 98 (77%).
2.7.2.
1-[4-({[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6b)
Light pink amorphous solid; M.P: 90-92 oC; Yield: 76%; M.F:
C21H ClN3O3S ; M.W: 463.08; IR (KBr, υmax, cm-1): 3031 (C-H str. of ar. ring),
16352(2C=N str.2of oxadiazole ring), 1523 (C=C ar. str.), 1329 (-SO2 str.), 1227,
1
1059 (C-O-C bond str.), 704 (C-Cl bond str.), 615 (C-S bond str.); H-NMR
(CDCl3, 400 MHz): δ (ppm) 7.90 (d, J = 7.2 Hz, 1H, H-6ꞌ), 7.72 (d, J = 8.0 Hz,
2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.61 (d, J = 7.6 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 7.53 (d, J = 7.6 Hz,
1H, H-3ꞌ), 7.45 (t, J = 7.6 Hz, 1H, H-4ꞌ), 7.38 (t, J = 7.6 Hz, 1H, H-5ꞌ), 4.50 (s,
2H, H-7ꞌꞌ), 3.75 (d, J = 9.6 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.25 (d, J = 10.8 Hz, 2H,
Hax-2ꞌꞌꞌ & Hax-6ꞌꞌꞌ), 1.55 (d, J = 8.8 Hz, 2H, H -3ꞌꞌꞌ & Heq-5ꞌꞌꞌ), 1.35 (d, J = 12.4
Hz, 2H, Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.17-1.05 (m, 1He,qH-4ꞌꞌꞌ), 0.90 (d, J = 4.0 Hz, 3H,
CH3-7ꞌꞌꞌ); EI-MS m/z: 463 (4%)[M+], 302 (67.3%), 251 (77.9%), 212 (17.8%),
153 (26.8%), 137 (4.2%), 116 (100%), 98 (88.8%).
2.7.8. 1-[4-({[5-(2,4-Dichlorophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzene sulfonyl]-4-methylpiperidine (6h)
White amorphous solid; M.P: 109-111 oC; Yield: 80%; M.F:
C21H21Cl2N3O3S2; M.W: 497.04; IR (KBr, υmax, cm-1): 3051 (C-H str. of ar.
ring), 1653 (C=N str. of oxadiazole ring), 1532 (C=C ar. str.), 1367 (-SO2
str.), 1237, 1065 (C-O-C bond str.), 624 (C-S bond str.); 1H-NMR (CDCl , 400
MHz): δ (ppm) 7.85 (d, J = 8.8 Hz, 1H, H-6ꞌ), 7.72 (d, J = 8.0 Hz, 2H, H3-2ꞌꞌ &
H-6ꞌꞌ), 7.61 (d J = 8.0 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 7.42 (s, 1H, H-3ꞌ), 7.37 (d, J =
8.0 Hz, 1H, H-5ꞌ), 4.53 (s, 2H, H-7ꞌꞌ), 3.72 (d, J = 10.8 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌ
ꞌꞌ), 2.27 (t, J = 11.2 Hz, 2H, H -2ꞌꞌꞌ & Hax-6ꞌꞌꞌ), 1.55 (d, J = 8.8 Hz, 2H, H -3ꞌꞌꞌ
& Heq-5ꞌꞌꞌ), 1.32 (d, J = 12.4 Hazx, 2H, Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.14-1.06 (m, 1H,eHq -4ꞌ
ꞌꞌ), 0.94 (d, J = 4.0 Hz, 3H, CH -7ꞌꞌꞌ); EI-MS m/z: 497 (6%)[M+], 334 (70.3%),
251 (77.9%), 244 (26.8%), 1863(26.8%), 171 (4.2%), 145 (100%), 98 (88.3%).
2.7.3.
1-[4-({[5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6c)
White amorphous solid; M.P: 107-109 oC; Yield: 72%; M.F:
C21H ClN3O3S ; M.W: 463.08; IR (KBr, υmax, cm-1): 3031 (C-H str. of ar. ring),
16352(2C=N str.2of oxadiazole ring), 1523 (C=C ar. str.), 1327 (-SO2 str.), 1227,
1
1059 (C-O-C bond str.), 708 (C-Cl bond str.), 615 (C-S bond str.); H-NMR
(CDCl3, 400 MHz): δ (ppm) 7.95 (s, 1H, H-2ꞌ), 7.85 (d, J= 7.6 Hz, 1H, H-6ꞌ),
7.72 (d, J = 7.6 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.61 (d J = 7.6 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ),
7.48 (d, J = 7.6 Hz, 1H, H-4ꞌ), 7.42 (t, J = 7.6 Hz, 1H, H-5ꞌ), 4.51 (s, 2H, H-7ꞌ
ꞌ), 3.76 (d, J = 10.4 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.23 (t, J = 10.4, Hz, 2H, H -2ꞌꞌ
ꞌ & Hax-6ꞌꞌꞌ), 1.67 (d, J = 7.6 Hz, 2H, H -3ꞌꞌꞌ&Heq-5ꞌꞌꞌ), 1.31 (d, J = 12.4 Hz,a2x H,
Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.16-1.00 (m, 1H, eHq -4ꞌꞌꞌ), 0.93 (d, J = 4.0 Hz, 3H, CH3-7ꞌ
ꞌꞌ); EI-MS m/z: 463 (3%)[M+], 302 (60.3%), 251 (100%), 212 (16.8%), 153
(16.8%), 137 (3.2%), 116 (88%), 98 (87.3%).
2.7.9.
1-[4-({[5-(2-Nitrophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6i)
Dark brown amorphous solid; M.P: 59-61 oC; Yield: 80%; M.F:
C21H N4O5S ; M.W: 474.10; IR (KBr, υ , cm-1): 3037 (C-H str. of ar. ring),
16392(2C=N s2tr. of oxadiazole ring), 1522m(aCx =C ar. str.), 1342 (-SO2 str.), 1232,
1
2.7.4.
1-(4-{[(5-Benzyl-1,3,4-oxadiazol-2-yl)thio]methyl}
1051 (C-O-C bond str.), 621 (C-S bond str.); H-NMR (CDCl3, 400 MHz): δ
benzenesulfonyl)-4-methylpiperidine (6d)
(ppm) 8.02 (d, J = 7.2 Hz, 1H, H-3ꞌ), 7.90 (d, J = 7.2 Hz, 1H, H-6ꞌ), 7.79-7.73
(m, 2H, H-4ꞌ & H-5ꞌ), 7.72 (d, J = 8.0 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.60 (d, J = 8.0 Hz,
2H, H-3ꞌꞌ & H-5ꞌꞌ), 4.52 (s, 1H, H-7ꞌꞌ), 3.71 (d, J = 11.2 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌ
ꞌꞌ), 2.25 (t, J = 11.2 Hz, 2H, H -2ꞌꞌꞌ & Hax-6ꞌꞌꞌ), 1.55 (d, J = 8.8 Hz, 2H, H -3ꞌꞌꞌ
& Heq-5ꞌꞌꞌ), 1.35 (d, J = 12.4 Hazx, 2H, Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.10-0.97 (m, 1H,eHq -4ꞌ
ꞌꞌ), 0.90 (d, J = 4.0 Hz, 3H, CH3-7ꞌꞌꞌ); EI-MS m/z: 474 (5%)[M+], 312 (43.0%),
251 (87.4%), 222 (1.9%), 164 (2.3%), 148 (2.7%), 98 (100%), 122 (9.6%).
Light brown amorphous solid; M.P: 63-65 oC; Yield: 83%; M.F:
C22H N3O3S ; M.W: 443.13; IR (KBr, υ , cm-1): 3043 (C-H str. of ar. ring),
16372(5C=N s2tr. of oxadiazole ring), 1529m(aCx =C ar. str.), 1349 (-SO2 str.), 1228,
1
1051 (C-O-C bond str.), 619 (C-S bond str.); H-NMR (CDCl3, 400 MHz): δ
(ppm) 7.65 (d, J = 8.0 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.50 (d J = 8.0 Hz, 2H, H-3ꞌꞌ &
H-5ꞌꞌ), 7.35-7.19 (m, 5H, H-2ꞌ to H-6ꞌ), 4.53 (s, 2H, H-7ꞌꞌ), 4.21 (s, 2H, H-7ꞌ),
3.71 (d, J = 10.8 Hz, 2H, H -2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.18 (t, J = 11.2 Hz, 2H, Hax-2ꞌꞌꞌ &
Hax-6ꞌꞌꞌ), 1.59 (d, J = 7.6 Hz,e2q H, Heq-3ꞌꞌꞌ&Heq-5ꞌꞌꞌ), 1.33 (d, J = 12.4 Hz, 2H, Hax-
3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.17-1.02 (m, 1H, H-4ꞌꞌꞌ), 0.95 (d, J = 4.0 Hz, 3H, CH3-7ꞌꞌꞌ); EI-
MS m/z: 443 (8%)[M+], 281 (69.3%), 252 (88.9%), 192 (38.1%), 191 (36.8%),
162 (23.3%), 133 (3.4%), 117 (100%), 91 (60.6%), 98 (85.3%).
2.7.10.
1-[4-({[5-(3-Nitrophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6j)
Orange amorphous solid; M.P: 88-90 oC; Yield: 79%; M.F: C21H22N4O5S2;
M.W: 474.10; IR (KBr, υ , cm-1): 3030 (C-H str. of ar. ring), 1637 (C=N str.
of oxadiazole ring), 1525m(aCx =C ar. str.), 1327 (-SO2 str.), 1223, 1059 (C-O-C
bond str.), 616 (C-S bond str.); 1H-NMR (CDCl3, 400 MHz): δ (ppm) 8.34 (d,
J = 8.8 Hz, 1H, H-4ꞌ), 8.15 (d, J = 8.4 Hz, 1H, H-6ꞌ), 7.91-7.87 (m, 1H, H-5ꞌ),
7.73 (d, J = 7.2 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.70 (s, 1H, H-2ꞌ), 7.62 (d, J = 7.6 Hz,
2H, H-3ꞌꞌ & H-5ꞌꞌ), 4.50 (s, 1H, H-7ꞌꞌ), 3.71 (d, J = 11.2 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌ
ꞌꞌ), 2.24 (t, J = 11.2 Hz, 2H, H -2ꞌꞌꞌ & Hax-6ꞌꞌꞌ), 1.54 (d, J = 8.8 Hz, 2H, H -3ꞌꞌꞌ
& Heq-5ꞌꞌꞌ), 1.36 (d, J = 12.4 Hazx, 2H, Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.13-1.04 (m, 1H,eHq -4ꞌ
ꞌꞌ), 0.97 (d, J = 4.0 Hz, 3H, CH -7ꞌꞌꞌ); EI-MS m/z: 474 [M+](5%), 313 (44.0%),
252 (22.9%), 223 (1.8%), 222 3(1.6%), 164 (2.2%), 162 (4.2%), 148 (10.9%),
122 (9.5%), 98 (100%).
2.7.5.
1-[4-({[5-(4-Methylphenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6e)
White amorphous solid; M.P: 83-85 oC; Yield: 80%; M.F: C22H25N3O3S2;
M.W: 443.58; IR (KBr, υ , cm-1): 3043 (C-H str. of ar. ring), 1640 (C=N str.
of oxadiazole ring), 1537m(aCx =C ar. str.), 1359 (-SO2 str.), 1232, 1064 (C-O-C
bond str.), 623 (C-S bond str.); 1H-NMR (CDCl3, 400 MHz): δ (ppm) 7.84 (d,
J = 8.4 Hz, 2H, H-2ꞌ & H-6ꞌ), 7.70 (d, J = 8.4 Hz, 2H, H-3ꞌ & H-5ꞌ), 7.61 (d,
J = 8.0 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.28 (d, J = 7.6 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 4.51 (s,
2H, H-7ꞌꞌ), 3.77 (t, J = 10.8 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.27-2.22 (m, 2H, H -2ꞌ
ꞌꞌ & Hax-6ꞌꞌꞌ), 1.62 (d, J = 7.6 Hz, 2H, Heq-3ꞌꞌꞌ&H -5ꞌꞌꞌ), 1.38 (d, J = 12.4 Hz, a2xH,
Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.21-1.11 (m, 1H, H-4ꞌꞌꞌ), 0e.q97 (d, J = 4.0 Hz, 3H, CH3-7ꞌ
ꞌꞌ); EI-MS m/z: 443 (4%)[M+], 281 (60.3%), 251 (100%), 191 (16.8%), 133
2.7.11.
1-[4-({[5-(4-Nitrophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6k)
Yellowamorphoussolid;M.P:159-161oC;Yield:82%;M.F:C21H22N4O5S2;
3371

J. Chil. Chem. Soc., 62, Nº 1 (2017)
1
M.W: 474.10; IR (KBr, υ , cm-1): 3031 (C-H str. of ar. ring), 1635 (C=N str.
of oxadiazole ring), 1523m(aCx =C ar. str.), 1327 (-SO2 str.), 1227, 1059 (C-O-C
bond str.), 615 (C-S bond str.); 1H-NMR (CDCl3, 400 MHz): δ (ppm) 8.35 (d,
J = 8.8 Hz, 2H, H-3ꞌ & H-5ꞌ), 8.15 (d, J = 8.8 Hz, 2H, H-2ꞌ & H-6ꞌ), 7.71 (d,
J = 8.0 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.63 (d, J = 8.0 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 4.62 (s,
1H, H-7ꞌꞌ), 3.74 (d, J = 10.8 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.25 (t, J = 10.8 Hz, 2H,
Hax-2ꞌꞌꞌ & Hax-6ꞌꞌꞌ), 1.65 (d, J = 9.2 Hz, 2H, H -3ꞌꞌꞌ & Heq-5ꞌꞌꞌ), 1.30 (d, J = 10.8
Hz, 2H, Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.09-0.96 (m, 1He,qH-4ꞌꞌꞌ), 0.91 (d, J = 4.0 Hz, 3H,
CH3-7ꞌꞌꞌ); EI-MS m/z: 474 (2%)[M+], 313 (44.0%), 251 (87.4%), 223 (2.1%),
164 (2.5%), 148 (2.5%), 98 (100%), 122 (9.9%).
1059 (C-O-C bond str.), 616 (C-S bond str.); H-NMR (CDCl , 400 MHz):
δ (ppm) 9.05 (s, 1H, H-4ꞌ), 8.92 (s, 1H, H-6ꞌ), 7.80 (d, J = 7.6 3Hz, 2H, H-2ꞌ
ꞌ & H-6ꞌꞌ), 7.65 (d, J = 7.6 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 4.52 (s, 1H, H-7ꞌꞌ), 3.7 (d,
J = 10.8 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.25 (t, J = 11.2 Hz, 2H, Hax-2ꞌꞌꞌ & Hax-6ꞌꞌ
ꞌ), 1.55 (d, J = 9.2 Hz, 2H, Heq-3ꞌꞌꞌ & Heq-5ꞌꞌꞌ), 1.35 (d, J = 12.4 Hz, 2H, Hax-3ꞌꞌꞌ
& Hax-5ꞌꞌꞌ), 1.17-1.08 (m, 1H, H-4ꞌꞌꞌ), 0.90 (d, J = 4.0 Hz, 3H, CH3-7ꞌꞌꞌ); EI-MS
m/z: 553 (4%)[M]+, 267 (62%), 251 (89%), 177 (18%), 119 (4%), 103 (100%),
98 (88%), 77 (69%).
2.7.15.
1-[4-({[5-(3-Pyridinyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6o)
2.7.12. 1-[4-({[5-(3-Aminophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6l)
Dark brown amorphous solid; M.P: 102-104 oC; Yield: 80%; M.F:
C20H N4O3S ; M.W: 430.11; IR (KBr, υ , cm-1): 3036 (C-H str. of ar. ring),
16392(2C=N s2tr. of oxadiazole ring), 1528m(aCx =C ar. str.), 1339 (-SO2 str.), 1234,
Half white amorphous solid; M.P: 100-102 oC; Yield: 75%; M.F:
C21H N4O3S ; M.W: 444.13; IR (KBr, υ , cm-1): 3045 (C-H str. of ar. ring),
16422(4C=N s2tr. of oxadiazole ring), 1531m(aCx =C ar. str.), 1338 (-SO2 str.), 1233,
1
1056 (C-O-C bond str.), 621 (C-S bond str.); H-NMR (CDCl , 400 MHz): δ
(ppm) 9.20 (s, 1H, H-2ꞌ), 8.77 (br.s, 1H, H-6ꞌ), 8.36 (d, J = 7.63Hz, 1H, H-4ꞌ),
7.72 (d, J = 8.0 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ), 7.60 (d, J = 8.0 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ),
7.54 (br.s, 1H, H-5ꞌ), 4.53 (s, 1H, H-7ꞌꞌ), 3.71 (d, J = 11.2 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-
6ꞌꞌꞌ), 2.25 (t, J = 11.2 Hz, 2H, H -2ꞌꞌꞌ & H -6ꞌꞌꞌ), 1.55 (d, J = 8.8 Hz, 2H, H -3ꞌꞌꞌ
& Heq-5ꞌꞌꞌ), 1.35 (d, J = 12.4 Hza,x2H, Hax-a3xꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.12-1.05 (m, 1H,eHq -4ꞌ
ꞌꞌ), 0.92 (d, J = 4.0 Hz, 3H, CH -7ꞌꞌꞌ); EI-MS m/z: 430 (3%)[M+], 268 (60.3%),
251 (87.9%), 178 (16.8%), 1203(3.2%), 104 (100%), 98 (87.3%), 78 (67.6%).
2.8. Antibacterial activity assay
1
1064 (C-O-C bond str.), 618 (C-S bond str.); H-NMR (CDCl , 400 MHz): δ
(ppm) 7.96 (d, J = 7.2 Hz, 1H, H-6ꞌ), 7.69 (d, J = 8.0 Hz, 2H,3H-2ꞌꞌ & H-6ꞌꞌ),
7.62 (d, J = 8.0 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 7.53 (t, J = 9.1 Hz, 1H, H-5ꞌ), 7.53 (s,
1H, H-2ꞌ), 7.48 (t, J = 8.4 Hz, 1H, H-4ꞌ), 4.55 (s, 1H, H-7ꞌꞌ), 3.72 (t, J = 10.8
Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ), 2.23-2.17 (m, 2H, Hax-2ꞌꞌꞌ & Hax-6ꞌꞌꞌ), 1.68-1.63 (m,
2H, Heq-3ꞌꞌꞌ & Heq-5ꞌꞌꞌ), 1.35 (d, J = 12.4 Hz, 2H, Hax-3ꞌꞌꞌ & Hax-5ꞌꞌꞌ), 1.14-1.05
(m, 1H, H-4ꞌꞌꞌ), 0.90 (d, J = 4.0 Hz, 3H, CH -7ꞌꞌꞌ); EI-MS m/z: 445 (6%)[M]+,
282 (59%), 251 (87%), 192 (16%), 134 (5%),3118 (100%), 98 (89%), 92 (70%).
2.7.13. 1-[4-({[5-(3,5-Dinitrophenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzene sulfonyl]-4-methylpiperidine (6m)
The antibacterial activity was performed using sterile 96-wells microplates
under aseptic environments. The method is based on the principle that microbial
cell number increases as the microbial growth proceeds in a log phase of growth
Light brown amorphous solid; M.P: 69-71 oC; Yield: 83%; M.F:
C21H N5O7S ; M.W: 519.09; IR (KBr, υ , cm-1): 3042 (C-H str. of ar. ring),
16362(1C=N s2tr. of oxadiazole ring), 1526m(aCx =C ar. str.), 1336 (-SO2 str.), 1229,
which results in increased absorbance of broth medium20,21
.
2.9. Statistical analysis
All the calculations were accomplished after performing the experiment
thrice and then analyzing statistically by Microsoft Excel 2010.
1
1062 (C-O-C bond str.), 617 (C-S bond str.); H-NMR (CDCl3, 400 MHz): δ
(ppm) 9.14 (s, 1H, H-4ꞌ), 9.10 (s, 2H, H-2ꞌ & H-6ꞌ), 7.73 (d, J = 7.2 Hz, 2H,
H-2ꞌꞌ & H-6ꞌꞌ), 7.60 (d, J = 7.2 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ), 4.52 (s, 1H, H-7ꞌꞌ), 3.71
(d, J = 11.2 Hz, 2H, H -2ꞌꞌꞌ & H -6ꞌꞌꞌ), 2.25 (t, J = 11.2 Hz, 2H, Hax-2ꞌꞌꞌ & Hax-6ꞌ
3. RESULTS AND DISCUSSION
ꞌꞌ), 1.55 (d, J = 8.8 Hze,q2H, H -e3qꞌꞌꞌ & H -5ꞌꞌꞌ), 1.34 (d, J = 12.4 Hz, 2H, H -3ꞌꞌ
Stimulated by significance of piperidine and 1,3,4-oxadiazole on the
pharmaceutical and biological grounds, the synthesis of 1-(4-{[(5-substituted-
1,3,4-oxadiazol-2-yl)thio]methyl}benzenesulfonyl)-4-methylpiperidine (6a-o)
was carried out by the protocol elaborated in scheme-1. The different aralkyl/
aryl groups are listed in Table-1. The detailed procedures are explicated in
experimental section. The results for antibacterial activity are demonstrated as
% inhibition and MIC (Minimum Inhibitory Concentration) values in Table-2
and Table-3, respectively.
ax
ꞌ & Hax-5ꞌꞌꞌ), 1.11-1.03 (m, 1He,qH-4ꞌꞌꞌ), 0e.q94 (d, J = 4.0 Hz, 3H, CH3-7ꞌꞌꞌ); EIMS
m/z: 519 (4%)[M+], 357 (70.3%), 267 (26.8%), 251 (86.9%), 209 (15.8%), 193
(4.2%), 167 (100%), 98 (67.3%).
2.7.14.
1-[4-({[5-(2-Chloro-3,5-dinitrophenyl)-1,3,4-oxadiazol-2-yl]
thio}methyl) benzenesulfonyl]-4-methylpiperidine (6n)
Dark brown amorphous solid; M.P: 98-100 oC; Yield: 85%; M.F:
C21H ClN5O7S ; M.W: 553.54; IR (KBr, υmax, cm-1): 3030 (C-H str. of ar. ring),
16342(0C=N str.2of oxadiazole ring), 1524 (C=C ar. str.), 1330 (-SO2 str.), 1226,
Scheme-1: Outline for the synthesis of 1-(4-{[(5-substituted-1,3,4-oxadiazol-2-yl)thio]
methyl}benzenesulfonyl)-4-methylpiperidine (6a-o). Reagents & conditions: (I) EtOH, H2SO4,
reflux for 3-4 hrs (II) MeOH, N H , reflux for 5-6 hrs (III) EtOH, KOH, CS , reflux for 4-5 hrs (IV)
4-bromomethylbenzenesulfonyl2ch4loride (b), 5% Na2CO3 soln, H2O, stir for 21 hr (V) LiH, DMF, stir
for 4-6 hrs.
3372

J. Chil. Chem. Soc., 62, Nº 1 (2017)
Table-1: Different aralkyl/aryl groups.
Compd.
R
Compd.
6f
R
Compd.
6k
R
OCH
3
2'
2'
2'
6a
6'
4'
6'
4'
6'
O N
2
4'
Cl
CH
H N
2
2
8'
2'
2'
2'
2'
6b
6c
6g
6h
6l
6'
6'
4'
4'
4'
6'
4'
Cl
O N
2
Cl
2'
6'
2'
6m
6'
4'
6'
4'
NO
Cl
Cl
2
NO
2
O N
2
CH
2
2'
NO
2'
2'
2'
6d
6e
6i
6j
6n
6o
6'
6'
4'
4'
6'
4'
2
O N
2
4'
2'
2'
6'
6'
6'
4'
4'
H C
3
N
Table-2: % Inhibition results for antibacterial activity of synthesized compounds.
% INHIBITION
P. aeroginosa (-)
41.13±1.75
59.63±0.36
60.50±0.11
59.75±0.43
56.00±0.30
62.13±0.55
40.63±1.15
49.50±0.35
64.88±1.05
57.38±0.15
58.50±0.20
65.13±0.30
61.08±0.75
67.88±1.10
61.23±0.38
92.34±0.35
Compound
S. typhi (-)
73.43±1.11
72.71±0.50
68.71±0.22
65.14±1.39
72.57±0.28
59.57±1.09
39.29±0.33
65.14±0.61
65.29±0.39
69.29±0.72
65.71±1.50
56.57±0.17
63.57±0.26
74.14±0.11
62.13±0.66
92.87±0.91
E. coli (-)
75.34±0.20
71.37±1.40
75.33±0.89
73.10±0.47
73.25±0.55
78.44±0.27
65.11±0.60
70.33±0.25
78.65±1.75
30.78±0.50
76.54±0.20
71.87±1.35
61.62±0.82
67.22±0.70
68.56±1.22
92.27±0.64
B. subtilis (+)
78.75±0.80
65.75±0.75
65.88±0.70
72.13±0.75
61.88±1.00
61.00±0.30
38.38±0.55
69.75±0.75
75.43±0.25
76.00±0.20
81.43±0.55
74.14±0.65
68.19±0.39
73.00±0.40
74.25±0.79
91.63±0.05
S. aureus (+)
82.71±0.70
70.43±0.35
71.86±0.50
68.86±1.00
71.86±0.30
65.43±0.60
72.14±0.80
71.14±0.95
53.25±0.35
65.50±0.10
60.75±0.90
64.25±0.15
61.27±1.37
59.38±1.05
75.28±0.42
90.57±0.35
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
Ciprofloxacin
3373

J. Chil. Chem. Soc., 62, Nº 1 (2017)
Table-3: MIC results for antibacterial activity of synthesized compounds
MIC (μmol/L)
P. aeroginosa (-)
-
Compound
S. typhi (-)
10.32±0.64
10.63±0.08
11.211±0.14
12.49±0.53
10.75±0.94
17.65±0.72
-
E. coli (-)
10.84±0.29
10.33±0.36
10.21±0.65
11.16±0.40
10.18±0.49
9.43±0.15
12.61±0.17
12.56±0.79
10.38±0.81
-
B. subtilis (+)
10.55±0.94
12.64±0.60
12.57±0.29
11.84±0.18
15.28±0.09
15.73±0.22
-
S. aureus (+)
9.84±0.30
6a
6b
16.42±0.47
14.53±0.10
15.75±0.23
17.38±0.12
14.98±0.32
-
10.48±0.49
12.48±0.27
12.85±0.84
10.74±0.11
12.42±0.16
10.87±0.10
10.76±0.10
18.74±0.55
12.74±0.48
15.38±0.33
12.76±0.90
13.12±0.81
16.98±0.64
10.77±0.51
7.00±1.54
6c
6d
6e
6f
6g
6h
10.27±0.68
12.87±0.47
11.39±0.82
12.47±0.71
19.21±0.68
11.72±0.31
10.52±0.18
11.23±0.67
7.83±0.78
-
10.37±0.17
10.29±0.09
9.79±0.53
9.21±0.94
10.16±0.65
12.16±0.85
10.36±0.33
10.04±0.63
7.22±0.67
6i
12.58±0.38
14.29±0.05
16.31±0.94
14.29±0.30
14.76±0.29
12.40±0.54
14.62±0.91
7.98±0.89
6j
6k
10.29±0.05
11.85±0.96
14.06±0.66
12.36±0.98
12.09±0.43
8.01±0.12
6l
6m
6n
6o
Ciprofloxacin
Figure-1: Proposed mass fragmentation pattern of 1-(4-{[(5-benzyl-1,3,4-oxadiazol-2-yl)thio]methyl}benzenesulfonyl)-4-
methylpiperidine (6d)
3374

J. Chil. Chem. Soc., 62, Nº 1 (2017)
3.1. Chemistry
compounds were obtained against certain strains of Gram-positive and Gram-
negative bacteria with reference to ciprofloxacin. The MIC values declared
the most of the compounds good antibacterial agents and hence these can be
further subjected to in vivo study along with cytotoxic study. Thus the series
of molecules can be considered by the pharmacological industries as new drug
candidates for the drug discovery pathway.
The target molecules, 1-(4-{[(5-substituted-1,3,4-oxadiazol-2-yl)thio]
methyl}benzenesulfonyl)-4-methylpiperidine (6a-o), have been synthesized
with reasonable yields from simple aralkyl/aryl carboxylic acids through a
series of steps. First step is simple ethyl esterification, second one is about
nucleophilic substitution of ethoxy of ester by hydrazine on stirring or
refluxing, third one is the intermolecular cyclization of carbohydrazide into
heterocyclic 1,3,4-oxadiazole. Solid KOH was used in this step to provide
the basic media that facilitated the cyclization process. After addition of
excess water, the pH was adjusted to low acidic one (pH = 5-6) to acquire the
product because of salt formation as potassium thioxide. Highly acidic pH has
negative effect on yield because of further salt formation. The electrophile,
1-(4-bromomethylbenzenesulfonyl)-4-methylpiperidine (5) was synthesized
by a facile method in a basic aqueous medium. The precipitates of electrophile
were also acquired after adjusting pH to 5-6 and also too low pH was obviated.
The last step comprised of the reaction of the synthesized electrophile and the
nucleophilic 1,3,4-oxadiazol-2-thiols in a aprotic polar solvent along with an
activator. All the compounds were structurally corroborated through spectral
studies including IR, 1H-NMR and EIMS, given in experimental section.
Compound 6d was synthesized as light brown amorphous solid having
yield 83 % and melting point 63-65 oC. Molecular formula was erected on the
basis of EI-MS with molecular ion peak at m/z 443, forwarding to molecular
formula as C22H25N3O3S2 which was also confirmed through protons in
5. ACKNOWLEDGEMENT
The Higher Education Commission (HEC) of Pakistan is highly
acknowledged by the authors for financial support regarding purchasing of
chemicals and spectral study.
6. REFERENCES
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1
integration curves of its H-NMR spectrum. The IR spectrum supported the
main functionalities by absorption bands at 3043 (for aromatic C-H), 1637
(for oxadiazole C=N), 1529 (for aromatic C=C), 1349 (for S=O of sulfamoyl
group), 1228, 1051 (for oxadiazole C-O-C) and 619 (for thiol C-S). In 1H-NMR
spectrum, two signals were assigned to benzyl group: one multiplet at δ 7.35-
7.19 (m, 5H, H-2ꞌ to H-6ꞌ) and one singlet at δ 4.21 (s, 2H, H-7ꞌ). Nine signals
were allocated to the 1-(4-Bromomethylbenzenesulfonyl)-4-methylpiperidine:
two doublets in aromatic region at δ 7.65 (d, J = 8.0 Hz, 2H, H-2ꞌꞌ & H-6ꞌꞌ) and
7.50 (d J = 8.0 Hz, 2H, H-3ꞌꞌ & H-5ꞌꞌ); one singlet at δ 4.53 (s, 1H, H-7ꞌꞌ); four
doublets in aliphatic region at δ 3.71 (d, J = 10.8 Hz, 2H, Heq-2ꞌꞌꞌ & Heq-6ꞌꞌꞌ),
1.59 (d, J = 7.6 Hz, 2H, H -3ꞌꞌꞌ & H -5ꞌꞌꞌ), 1.33 (d, J = 12.4 Hz, 2H, Hax-3ꞌꞌꞌ &
Hax-5ꞌꞌꞌ) and 0.95 (d, J = 4.e0q Hz, 3H,eqCH3-7ꞌꞌꞌ); one triplet at δ 2.18 (t, J = 11.2
Hz, 2H, H -2ꞌꞌꞌ & Hax-6ꞌꞌꞌ); and one multiplet at δ 1.17-1.02 (m, 1H, H-4ꞌꞌꞌ). The
afore menatxioned data structurally confirmed the formation of new derivative
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as
1-(4-{[(5-benzyl-1,3,4-oxadiazol-2-yl)thio]methyl}benzenesulfonyl)-4-
methylpiperidine. The proposed mass fragmentation pattern of 6d is sketched
out in Figure-1. Likewise the structures of other compounds were elucidated.
3.2. Antibacterial Activity
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All the compounds were screened against S. typhi (-), E. coli (-), P.
aeruginosa (-), B. subtilis (+) and S. aureus (+). The results are mentioned
in Table 2 and Table 3. The most of synthesized compounds demonstrated
valuable results against almost all the strains. S. typhi (-), E. coli (-) and S. aureus
(+) were better inhibited by all the compounds except a few. The whole series
remained the least active or inactive at all against P. aeruginosa (-). B. subtilis
(+) was moderately inhibited by the most ones and excellently by a few. The
phenyl substituted compound, 6a, remained efficient inhibitor against all the
strains except P. aeruginosa (-). The molecules bearing chlorophenyl groups,
6b & 6c, possessed excellent potential against all the strains except moderate
against P. aeruginosa (-). Compound, 1-[4-({[5-(2,4-Dichlorophenyl)-
1,3,4-oxadiazol-2-yl]thio}methyl)benzenesulfonyl]-4-methylpiperidine (6h)
exhibited excellent inhibitory potential against S. typhi (-), B. subtilis (+) and S.
aureus (+) with MIC values of 10.27±0.68, 10.37±0.17 and 10.76±0.10 μmol/L
relative to ciprofloxacin, a reference standard with MIC values of 7.83±0.78,
7.22±0.67 and 7.00±1.54 μmol/L respectively but against E. coli (-), the
inhibitory potential was not appreciable. It remained inactive at all against
P. aeruginosa (-). The better activity of this molecule might be attributed to
the presence of dichlorophenyl ring attached to bioactive oxadiazole ring.
Compound, 1-[4-({[5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]thio}methyl)
benzenesulfonyl]-4-methylpiperidine (6f) demonstrated excellent inhibitory
potential against E. coli (-) with MIC of 9.43±0.15 μmol/L relative to reference
standard with MIC of 8.01±0.12 μmol/L but moderately low activities against
the remaining bacterial strains. The compound 6g bearing naphthyl group
demonstrated the least activity. The nitro substituted phenyl ring bearing
compounds, 6i to 6j, remained notably efficient against E. coli (-) and excellent
inhibitor of B. subtilis (+).
4. CONCLUSION
All the compounds were obtained in good yields and structurally
corroborated by the spectral data. The results of antibacterial activity of these
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