Synthesis and antimicrobial studies of 5-n-alkyl-1,3,4-oxadiazole-2-thiol derivatives from fatty acids

Article abstract of DOI:10.14233/ajchem.2017.20665

The novel 5-N-alkyl-1,3,4-oxadiazole-2-thiol derivatives have been synthesized by esterification of fatty acid followed by reaction the ester with hydrazine hydrate. The acid hydrazide was converted to 1,3,4-oxadiazole by ring closure mechanism. The synthesized compounds have been characterized by physical (melting point and TLC) and spectral (IR, 1H NMR and mass) data. All the compounds were screened for their antimicrobial activity. The compounds 3F₁ & 3F₄ showed good inhibition activity against all four types of bacteria; while compound 3F₂ & 3F₃ shown moderate activity.

Full text of DOI:10.14233/ajchem.2017.20665

Asian Journal of Chemistry; Vol. 29, No. 11 (2017), 2369-2371
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20665
Synthesis and Antimicrobial Studies of 5-N-alkyl-1,3,4-oxadiazole-2-thiol
Derivatives from Fatty Acids
*
B. NAGA SUDHA , N. YELLA SUBBAIAH, A.M. SRIKANTH, C. VENKATA RAMANA REDDY, M. SNEHA LATHA and P. VIJAYA LAKSHMI
Department of Pharmaceutical Chemistry, C.E.S. College of Pharmacy, Kurnool-518 218, India
*Corresponding author: E-mail: sudulumpharm@yahoo.com
Received: 22 March 2017;
Accepted: 15 June 2017;
Published online: 29 September 2017;
AJC-18552
The novel 5-N-alkyl-1,3,4-oxadiazole-2-thiol derivatives have been synthesized by esterification of fatty acid followed by reaction the
ester with hydrazine hydrate. The acid hydrazide was converted to 1,3,4-oxadiazole by ring closure mechanism. The synthesized compounds
have been characterized by physical (melting point and TLC) and spectral (IR, 1H NMR and mass) data. All the compounds were screened
for their antimicrobial activity. The compounds 3F1 & 3F4 showed good inhibition activity against all four types of bacteria; while
compound 3F2 & 3F3 shown moderate activity.
Keywords: 1,3,4-Oxadiazole, Fatty acids, Acid hydrazides, Anti-microbial activity.
1H NMR spectra were recorded on BRUKER (400 MHz) in
DMSO-d6 using TMS as an internal standard. Mass spectra
were recorded in apex mass spectrophotometer. The purity of
INTRODUCTION
The macronutrient groups are dietary fats, lipids that include
fatty acids, triglycerides, cholesterol, essential fatty acids, linoleic
the compounds for checked in silica gel-G precoated plates
and α-linoleic acid. Fats are a key factor for the maintenance
caloric balance and to the body weight. Specific fatty acids are
by using n-hexane and ethyl acetate (1:1) as the eluent and
observed in UV-chamber.
also serves as precursor for numerous biological functions. Fat
soluble vitamins (i.e., vitamin A, D, E, K) and carotenoids are
Synthesis of acid esters (1F1-1F4): Fatty acid (10 g), in
35 mL of methanol and concentrated sulphuric acid was added
engaged in pathways that influence inflammation, coagulation
through sides of the walls. The resulting mixture was allowed
and gene expression which are transported by fats [1].
1,3,4-Oxadiazole are an important class of heterocyclic
to reflux for 5 h, the contents were allowed to cool on water
bath. To this, 5 % sodium bicarbonate was added and the resulting
compounds with a wide range of pharmaceutical and biological
mixture was filtered and recrystalized from methanol.
activity [2-4]. Their synthesis and transformations have been
of interest for a long time.This interesting group of compounds
Synthesis of acid hydrazide (2F1-2F4):Dissolved the esters
of substituted fatty acids (0.01 mol), in 4 mL of hydrazine
possesses diverse biological activity such as antimicrobial [5,6],
hydrate was added drop wise with stirring. The resulting mixture
anti-inflammatory [7], antitubercular [8], anticonvulsant [9],
was allowed to reflux for 4 h. The reaction mixture was cooled
anti-cancer [10], anti-HIV [11], hypoglycemic [12] and
to room temperature and diluted with water. It was filtered,
genotoxic [13,14] activities.
washed thoroughly with water. The product was purified by
In view of above mentioned pharmacological importance
recrystallization from methanol.
of fatty acids and 1,3,4-oxadiazole our ongoing efforts to synthe-
size a novel derivatives of5-N-alkyl-1,3,4-oxadiazole-2-thiol
Synthesis of 5-N-alkyl-1,3, 4-oxadiazole-2-thiol (3F1-
3F4): Potassium hydroxide (0.01 mol) was dissolved in
absolute ethanol (50 mL). To the above solution, acid hydazide
(3F1-F4) and evaluated them for their potential as antimicrobial
agents.
(2) and carbon disulfide (0.01 mol) was added. The reaction
mixture was refluxed on water bath for 38 h until hydrogen
sulphide ceased completely. The reaction mixture was cooled
EXPERIMENTAL
Melting point taken in open capillary tubes using Arson
digital melting point apparatus and were uncorrected. IR
spectra were recorded on BRUKERAlpha FTIR spectrometer,
to room temperature. On acidification with dil. hydrochloric
acid, the precipitate was obtained which was filtered, washed
thoroughly with water and recrystallized from ethanol.

2370 Sudha et al.
Asian J. Chem.
5-(Heptadec-8-1-yl)-1,3,4-oxadiazole-2-thiol (3F1):
by using four types microorganisms like E. coli, P. aeruginosa
(Gram-positive), S. aureus, B. subtilis (Gram-negative) at 50,
100 µg mL-1 concentrations respectively, in the nutrient agar
media by measuring the zone of inhibition in mm.The solution
of required concentrations (50, 100 µg mL-1) of test compounds
were prepared by dissolving the compounds in DMSO. Strepto-
mycin was used as standard.
Yield: 30 %; m.p.: 174-179 °C; IR (KBr, νmax, cm-1): 2937
(C-H stretching long alkyl chain), 1477 (C-O-C stretching),
1595 (C=C stretching), 1716 (C=N stretching), 2384 (C-SH
stretching); 1H NMR δ: 0.87-0.88 (t, 3H, terminal CH3), 1.20-
1.41 (m, 20H, -CH2-), 1.45-1.48 (d, 2H, -CH2-), 1.94-1.97 (d,
4H, allylic protons), 2.14-2.18 (t, 2H, -CH2-), 5.30-5.35 (d,
2H, CH=CH); MS m/z : 340 (M+2).
RESULTS AND DISCUSSION
5-Pentadecyl-1,3,4-oxadiazole-2-thiol (3F2):Yield (%):
45 %; m.p.: 174.17 °C; IR (KBr, νmax, cm-1): 2935 (C-H stretching,
long alkyl chain), 1168 (C-O-C stretching), 1623 (C=N stretching),
As depicted in Scheme-I, in addition to 1,3,4-oxadiazoles
we have synthesized 5-N-alkyl-1,3,4-oxadiazole-2-thiol (3F1-3F4)
through a three step reaction and acid ester of fatty acid (1)
has been synthesized from fatty acid and methanol in the presence
of conc. H2SO4 by esterification. In step 2, the formed ester of
fatty acid was hydrazinolyzed to give acid hydrazides (2),
which later cyclize to form a title compounds i.e. 5-N-alkyl-
1,3,4-oxadiazole-2-thiol (3F1-3F4) by reacting with CS2 and
KOH in ethanol. This procedure afforded various1,3,4-oxadiazoles
in moderate yields. The infrared spectra of the substituted 5-N-
alkyl-1,3,4-oxadiazole-2-thiol (3F1) showed characteristic absor-
ption bands, one of the which appearing at 2936 cm-1 was strong
alkyl chain C-H which are all final compounds (3F1-3F4) shown
1200-1100 cm-1 C-O-C, 1600-1500 cm-1 C=N and 2354 cm-1
SH Group. Similarly, 1H NMR spectra of synthesized compounds
(3F1-3F4) showed multiplet signals at δ 1.12-1.26 ppm due to
methylene protons. The terminal CH3 protons appeared as
triplet at δ 0.82-0.85 ppm. The SH proton as a singlet at δ 14.22
ppm. A triplet at δ 5.30-5.35 ppm integrating for 2 olefinic
proton (CH=CH) was attributed to the C9_C10 proton of 3F1,
doublet at 1.94-2.01 ppm for four allylic protons was attributed
to C8-C11 protons of 3F1.
1
1064 (C-O stretching), 2383 (C-SH stretching); H NMR δ:
0.82-0.85 (t, 3H, terminal CH3), 1.22-1.25 (m, 25H, -CH2-), 1.57-
1.64 (m, 2H, -CH2-), 2.66-2.69 (t, 2H, -CH2-), 14.25 (s, 1H, SH);
MS m/z : 312 (M+).
5-Heptadecyl-1,3,4-oxadaizole-2-thiol (3F3):Yield (%):
52 %; m.p.: 80-85 °C; IR (KBr, νmax, cm-1): 2935 (C-H stret-
ching), 1168 (C-O-C stretching), 1622 (C=N stretching), 1063
1
(C-O stretching), 2383 (C-SH, stretching); H NMR δ: 0.85
(t, 3H, terminal CH3), 1.22-1.25 (m, 28H, -CH2-), 1.57-1.64 (m,
2H, -CH2-), 2.65-2.69 (t, 2H, -CH2-), 14.25 (s, 1H, SH); MS
m/z: 341 (M+1).
5-Undecyl-1,3,4-oxadiazole-2-thiol (3F4):Yield (%): 48 %;
m.p.: 79-82 °C; IR (KBr, νmax, cm-1): 2936 (C-H stretching),
1177 (C-O-C stretching), 1517 (C=N stretching), 1065 (C-O
stretching), 2384 (C-SH stretching); 1H NMR δ: 0.82-0.85 (t,
3H, terminal CH3), 1.15-1.26 (m, 17H, -CH2-), 1.57-1.64 (m,
2H, -CH2-), 2.66-2.70 (t, 2H, -CH2-), 14.25 (s, 1H, SH); MS
m/z: 256 (M+).
Antimicrobial activity: The antimicrobial activity of title
compounds determined in vitro by using disc diffusion method
TABLE-1
ANTIMICROBIAL ACTIVITY OF 5-N-ALKYL-1,3,4-OXADIAZOLE-2-THIOL (3F1-F4)
Zone of inhibition
Compound code
Conc. (µg/mL)
Gram-positive organisms
Gram-negative organisms
B. subtilis
S. aureus
E. coli
P. aeurignosa
50
100
50
20
25
10
17
N
10
15
9
24
27
10
12
10
15
14
20
28
–
12
18
N
9
3F1
3F2
3F3
3F4
100
50
14
N
N
N
N
25
–
N
12
N
8
100
50
9
22
27
22
–
100
50
Streptomycin
Control
21
–
N = No inhibition
N
N
CH3OH
Conc. H2SO4
C2H5OH
KOH/CS2
R-COOH
R-COOCH3
R-CONHNH2
R
SH
NH2NH2 . H2O
O
1
2
3F1-3F4
R= 3F1 = Oleic acid
3F2 = Palmitic acid
3F3 = Stearic acid
3F4 = Lauric acid
Scheme-I: Conventional synthetic route for 5-N-alkyl-1,3,4-oxadiazole-2-thiol

Vol. 29, No. 11 (2017)
Synthesis and Antimicrobial Studies of 5-N-alkyl-1,3,4-oxadiazole-2-thiol Derivatives 2371
The results of the antimicrobial study of the newly synthe-
sized compounds was reported as zone of inhibition against
E. coli, P. aeruginosa (Gram-positive), S. aureus, B. subtilis
(Gram-negative) (Table-1). All the synthesized compounds
have shown significant antimicrobial activity. The compound
3F1 and 3F4 showed maximum activity at both 50 and 100 µg/
mL concentrations whereas compounds 3F2 and 3F3 showed
moderate activity. The results revealed that fatty acid moiety
is a satisfactory backbone for significant antimicrobial activity
and the presence of unsaturated double bonds in the structure
of fatty acid is also responsible for the good activity. Thus by
hybridization of 1,3,4-oxadiazole ring enhance the activity.
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