Synthesis and pharmacological evaluation of a novel series of 2-((2-aryl thiazol-4-yl)methyl)-5-(alkyl/alkylnitrile thio)-1,3,4-oxadiazole derivatives as possible antifungal agents

Article abstract of DOI:10.1002/jhet.1910

In the present investigation, a novel series of 2-[(2-arylthiazol-4-yl)methyl]-5-(alkyl/alkylnitrile thio)-1,3,4-oxadiazole derivatives were synthesized by cyclo-condensation of 2-(2-substituted thiazol-4-yl)aceto hydrazide with carbon disulfide followed by S-alkylation with alkyl halide in dry acetone. All the newly synthesized compounds were characterized by spectral (IR, ¹H NMR, ¹³C NMR, mass, and elemental analysis) methods. The title compounds were screened for in vitro antifungal activity and most of the synthesized compounds show moderate to good antifungal activity.

Full text of DOI:10.1002/jhet.1910

November 2014 Synthesis and Pharmacological Evaluation of a Novel Series of 2-((2-Aryl
thiazol-4-yl)methyl)-5-(alkyl/alkylnitrile thio)-1,3,4-oxadiazole Derivatives
as Possible Antifungal Agents
1893
a
b
b
a
*
Shivaji H. Shelke, Pravin C. Mhaske, Sridhar Kumar Kasam, and Vivek D. Bobade
aDepartment of Chemistry, H. P. T. Arts and R. Y. K. Science College, College Road, Nashik 422005, India
bDepartment of Chemistry, Sir Parshurambhau College, Tilak Road, Pune 411030, India
*
E-mail: v_bobade31@rediffmail.com
Received August 10, 2012
DOI 10.1002/jhet.1910
Published online 21 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
O
N
N
R1
OEt
N
O
S
N
S
S
R
R
1 a-c
4 a-l; 5a-c
In the present investigation, a novel series of 2-[(2-arylthiazol-4-yl)methyl]-5-(alkyl/alkylnitrile thio)-
1,3,4-oxadiazole derivatives were synthesized by cyclo-condensation of 2-(2-substituted thiazol-4-yl)aceto
hydrazide with carbon disulfide followed by S-alkylation with alkyl halide in dry acetone. All the newly syn-
thesized compounds were characterized by spectral (IR, 1H NMR, 13C NMR, mass, and elemental analysis)
methods. The title compounds were screened for in vitro antifungal activity and most of the synthesized
compounds show moderate to good antifungal activity.
J. Heterocyclic Chem., 51, 1893 (2014).
INTRODUCTION
alkyl/alkylnitrile thio-1,3,4-oxadiazole by the condensation
of 2-(2-arylthiazol-4-yl)acetohydrazide with carbon disulfide
followed by nucleopholic substitution with alkyl halide.
Five-member heterocycles are privileged structures with
utility in synthetic and medicinal chemistries. The heterocyclic
compounds hold a special place among pharmaceutically
active products and development of simple and efficient
synthesis of compounds incorporating multi heterocyclic rings
has given a new dimension to the drug discovery. Thiazole
and oxadiazoles are an important class of five-member
heterocyclic compounds, which have been the subject of great
interest because of its wide range of biological activities.
Thiazole compounds have attracted continuing interest
over the years because of their varied biological activities
[1–10]. The presence of oxadiazole nucleus in diverse types
of compounds proves its importance in the field of medicinal
chemistry. Oxadiazole possesses a wide spectrum of biolog-
ical activities such as antimicrobial [11–15], anti-tubercular
[16–19], anti-inflammatory [20–24], antiviral [25,26],
tyrosianse inhibitor activity [27], EGFR PTK inhibitor
[28], anticancer [29,30], anticonvulsant [31,32], and proto-
porphyrinogen oxidase inhibitor [33] activities.
Concurring with previous reports, 2-(4-isopropylthiazol-2-
yl)-5-substituted-1,3,4-oxadiazoles [34], 2,3-dihydrothiazoline
substituted 1,3,4-oxadiazole [35] 1,2,4-triazolo [1,5-a]-
pyrimidine substituted-1,3,4-oxadiazoles [36], thiazole
substituted-1,3,4-oxadiazoles [37], 5-dithiazolyl-2-R-1,3,4-
Δ4-oxadiazoline [38] derivatives have shown antimicrobial,
antitumor, and antifungal activities. In view of these obser-
vations, it was thought to synthesize new thiazole-based 2-
RESULTS AND DISCUSSION
The synthetic route of the compounds 4a–l and 5a–c is
outlined in Figure 1. Ethyl 2-(2-aryl thiazol-4-yl)acetate
1a–c was prepared by cyclo-condensation of substituted
thioamides with ethyl 4-chloro-3-oxobutanoate in dry
ethanol. Ester 1a–c on nucleopholic substitution reaction
with hydrazine hydrate gave 2-(2-aryl thiazol-4-yl)aceto-
hydrazide 2a–c. Carbazide 2a–c on reaction with carbon
disulphide and KOH in dry methanol furnished 5-((2-aryl
thiazol-4-yl)methyl)-1,3,4-oxadiazole-2-thiol 3a–c. Thiol
3a–c on nucleopholic substitution reaction with alkyl
halide/chloroacetonitrile in dry acetone furnished target com-
pounds 2-((2-aryl thiazol-4-yl)methyl)-5-(alkyl thio)-1,3,4-
oxadiazole 4a–l and 2-(5-((2-aryl thiazol-4-yl)methyl)-
1,3,4-oxadiazol-2-ylthio)acetonitrile 5a–c in good yield.
The structure of compounds 4a–l and 5a–c were con-
firmed by spectral method. The IR spectrum of 4a–l -
displayed absorption bands between 3128 and 2852 cmÀ1
corresponding to C–H, 1599–1481 cmÀ1 corresponding
to C═C and C═N and 1245–933 cmÀ1 corresponding to
1
C–O stretching frequency. The H NMR spectrum of 4e
in CDCl3 displayed a triplet at d 1.47 and a quartet at d
3.26 that corresponds to S–CH2CH3 functionality, singlet
at d 4.43 integrating for two protons was assigned to
© 2014 HeteroCorporation

1894
S. H. Shelke, P. C. Mhaske, S. K. Kasam, and V. D. Bobade
Vol 51
O
N
O
O
NHNH2
N
OEt
N
SH
N
N
N2H4
CS2, KOH
MeOH, reflux
Cl
S
S
S
MeOH, reflux
R
R
3 a-c
R
1 a-c
2 a-c
R1-X, TEA,
CN
Dry acetone
TEA
Dry acetone
N
N
N
O
N
R1
O
S
N
S
N
CN
S
S
R
R
5 a-c
4 a-l
Figure 1. Synthetic scheme for compounds 4a-l and 5a-c.
methylene protons of thiazole–CH2–oxadiazole. A singlet
that appeared at d 7.25 was attributed to thiazole proton,
whereas the aromatic protons resonated at d 7.34–7.95.
It was noteworthy that the thiazole proton appeared down-
field (d 7.73) in DMSO-d6 solvent. The 13C NMR
spectrum of 4e showed three peaks in the aliphatic region
that corresponds to S–CH2CH3 and methylene carbon of
thiazole–CH2–oxadiazole. The aromatic, thiazole, and
oxadiazole carbons appeared between d116.8 and 168.7.
The LCMS spectrum of 4e showed (M + H)+ peak at
338.1. The physical properties and yield of synthesized
compounds 4a–l and 5a–c are reported in Table 1.
MIC screening results of synthesized compounds 4a–l and
5a–c are given in Table 2.
Careful analysis of the MICs in Table 2 provides some
lead molecules with good antifungal activity. Of the
compounds 4a–l tested, compounds with S–CH(CH3)2
expressed a moderate to good antifungal activity against
all of the tested pathogens. It was observed that in com-
pounds 4a, 4b, and 4c, the phenyl group at two-position
of thiazole ring and R1 = –C2H5, n-C3H7 and –CH(CH3)2,
respectively, showed good to moderate activity against most
of the fungi species with MIC values 3.125–12.5 mg/mL.
Introduction of the chlorine at three-position of the phenyl
ring of thiazole nucleus, compounds 4g (R1 = –CH(CH3)2)
and 4h (R1 = n-C7H15) inhibited the growth of all the
tested species, where as compounds 4e (R1 = –C2H5) and
4f (R1 = n-C3H7 ) registered a moderate to good activity
against A. niger and A. flavus. If the 3-chloro phenyl group
is replaced by 4-chloro phenyl group, compound 4k
(R1 = –CH(CH3)2) recorded good activity against C. albicans,
C. tropicalis, and A. niger with MICs (3.125–6.25 mg/mL)
and compound 4j (R1 = n-C3H7 ) showed good activity
against A. niger (MIC 3.125 mg/mL) and moderate
activity against A. flavus (MIC 12.5 mg/mL). Compound 5c
(R= 4–Cl and R1 = –CH2CN) recorded good activity
against C. albicans, C. tropicalis, and A. niger with MICs
(3.125–12.5 mg/mL) and compound 5b (R = 3–Cl and
R1 =–CH2CN) registered the MIC at 6.25 mg/mL against
A. flavus. Thus, it is concluded that compound 4g registered
the MIC at 3.125 mg/mL against C. tropicalis, compounds
4b, 4j, 4k, and 5c showed significant activity at MIC
3.125 mg/mL against A. niger, and compounds 4a and 4c
recorded excellent activity at MIC 3.125 mg/mL against
A. flavus.
Antifungal testing.
All the synthesized compounds
were quantitatively evaluated for their in vitro antifungal
activity against Candida albicans, Candida tropicalis,
Aspergillus niger and Aspergillus flavus. Fluconazole was
used as positive control and DMSO as negative control.
The minimum inhibitory concentration (MIC) value is
defined as the lowest concentration of the antifungal agent
exhibiting no fungal growth. The in vitro antimicrobial
Table 1
The physical properties and yield of synthesized compounds 4a–l and 5a–c.
Compound
R
R1
MPa
Yielda
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
5a
5b
5c
H
H
H
H
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
C2H5
86–88
74–76
66–67
72–74
68–70
86–88
68–70
68–70
75–77
80–81
64–66
78–80
65–66
70–72
84–86
80
76
69
82
84
79
66
78
80
76
65
80
75
73
70
n-C3H7
i-C3H7
n-C7H15
C2H5
n-C3H7
i-C3H7
n-C7H15
C2H5
n-C3H7
i-C3H7
n-C7H15
CH2CN
CH2CN
CH2CN
CONCLUSIONS
In summary, the antifungal screening result showed that 2-
[(2-R-1,3-thiazol-4-yl)methyl]-5-(R1-thio)-1,3,4-oxadiazoles
4a (R = C6H5, R1 = C2H5), 4b (R = C6H5, R1 = n-C3H7), 4c
(R = C6H5, R1 = –CH(CH3)2, 4g (R = 3-ClC6H4, R1 = –CH
3-Cl
4-Cl
aIsolated yield.
aꢀ
C.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2014
Synthesis and Pharmacological Evaluation of a Novel Series of 2-((2-Aryl thiazol-4-yl)
methyl)-5-(alkyl/alkylnitrile thio)-1,3,4-oxadiazole
1895
Table 2
Antifungal activity of 2-[(2-aryl-1,3-thiazol-4-yl)methyl]-5-(alkylthio)-1,3,4-oxadiazole 4a–l and 2-[5-((2-aryl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-
2-ylthio]acetonitrile 5a–c.
MIC mg/mL (mM)
Compound
MW
Candida albicans
Candida tropicalis
Aspergillus niger
Aspergillus flavus
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
5a
5b
5c
303.40
317.43
317.43
373.54
337.85
351.87
351.87
407.98
337.85
351.87
351.87
407.98
314.39
348.83
348.83
12.5 (41.20)
6.25 (19.69)
12.5 (39.37)
25 (66.93)
50 (133.74)
>100
6.25 (17.76)
12.5 (30.63)
25 (66.87)
25 (71.05)
6.25 (17.76)
25 (61.27)
25 (79.51)
50 (143.33)
6.25 (17.91)
1.56 (5.09)
12.5 (41.20)
12.5 (39.37)
12.5 (39.37)
>100
50 (164.80)
3.125 (9.84)
6.25 (19.69)
25 (66.93)
25 (66.87)
12.5 (35.52)
6.25 (17.76)
6.25 (15.31)
>100
3.125 (8.88)
3.125 (8.88)
25 (61.27)
25 (79.51)
25 (71.68)
3.25 (8.96)
1.56 (5.09)
3.125 (10.54)
25 (78.75)
3.125 (9.84)
50 (133.85)
12.5 (33.43)
6.25 (17.76)
12.5 (35.52)
12.5 (30.63)
50 (133.74)
12.5 (35.52)
25 (71.05)
50 (122.55)
50 (159.03)
6.25 (17.91)
25 (71.68)
>100
25 (71.05)
3.125 (8.88)
25 (61.25)
50 (133.74)
50 (142.09)
6.25 (17.76)
>100
25 (79.51)
25 (71.68)
12.5 (35.83)
3.125 (10.18)
Fluconazole
3.125 (10.18)
(CH3)2, 4h (R = 4-ClC6H4, R1 = n-C7H15), 4k (R = 4-
ClC6H4, R1 = –CH(CH3)2 and 5c (R = 4-ClC6H4, R1 =
CH2CN) displayed good antifungal activity at a level of
MIC from 3.125 to 12.5 mg/mL against most of the strains.
It is also concluded that the S–CH(CH3)2 group is more effec-
tive against all tested strains. The results also reveal that com-
pounds with R1 = alkyl, phenyl or 3-chlorophenyl group at 2
position of thiazole ring show good activity against most of
the tested species as compared with 4-chlorophenyl group.
was evaporated under reduced pressure; residue was
dissolved in ethyl acetate and extracted with 5% HCl.
Organic layer was washed with water and distilled on
rotary evaporator to furnish target compounds. All the
compounds were purified by column chromatography
using ethyl acetate: hexane (9:1) as eluent.
2-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(ethylthio)-1,3,4-
oxadiazole 4a. IR: 3120, 2931, 2854, 1599, 1516, 1481,
1417, 1381, 1244, 1151, 1074, 976, 933 785, 688 cmÀ1; 1H
NMR (300 MHz, CDCl3): d 1.46 (t, J = 7.2 Hz, 3H),3.25
(q, J = 7.2 Hz, 2H), 4.42 (s, 2H), 7.18 (s, 1H), 7.40–7.44
(m, 3H), 7.89–7.94 (m, 2H); 13C NMR (75 MHz, CDCl3): d
14.5, 26.8, 29.6, 116.5, 126.6, 128.8, 130.0, 133.2, 149.1,
164.3, 164.8, 169.0; LCMS: 304.1 (M + H)+. Anal. Calcd.
for C14H13N3OS2: C, 55.42; H, 4.32; N, 13.85. Found: C,
EXPERIMENTAL
Melting points were determined in an open capillary on
Veego melting point apparatus (Mumbai, India) and are
uncorrected. All reactions were monitored by thin layer chro-
matography on 0.25 mm E. Merck silica gel plates (F-254)
using UV light or iodine vapors as the visualizing methods.
Infrared (IR) spectra (cmÀ1) were recorded in KBr on a
Shimadzu Model FTIR-435 spectrophotometer (Kyoto,
Japan). 1H NMR and 13C NMR spectra were recorded
in CDCl3 and DMSO-d6 solution on a Varian Mercury
YH-300 spectrometer (Darmstadt, Germany) operating at
300 MHz for 1H or 75 MHz for 13C respectively. Chemical
shifts are expressed relative to tetramethylsilane and are
reported as d (ppm). LCMS measurements were made on a
Jeol-JMS-DX 303 mass spectrometer (Tokyo, Japan). The
elemental analysis was performed on FLASH EA 1112
analyzer (Thermo Scientific, Cambridge, UK) and results
55.46; H, 4.28; N, 13.79.
2-[(2-Phenyl-1,3-thiazol-4-yl)methyl]-5-(propylthio)-1,3,4-
oxadiazole 4b. IR: 3118, 2930, 2850, 1594, 1518, 1483,
1
1420, 1379, 1240, 1149, 1074, 975, 938, 688cmÀ1; H
NMR (300MHz, CDCl3): d 1.44 (t, J = 7.2 Hz, 3H),1.83
(m, 2H), 3.21 (t, J = 7.2 Hz, 2H), 4.42 (s, 2H), 7.18 (s, 1H),
7.42–7.44 (m, 3H), 7.91–7.94 (m, 2H); 13C NMR
(100MHz, DMSO-d6): d 13.2, 22.5, 28.0, 34.3, 116.1,
126.5, 129.0, 130.1, 133.2, 149.0, 164.2, 164.7, 168.9;
LCMS: 318.1 (M+ H)+. Anal. Calcd. for C15H15N3OS2: C,
56.76; H, 4.76; N, 13.24. Found: C, 56.68; H, 4.71; N, 13.18.
2-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(2-propylthio)-1,3,4-
oxadiazole 4c. IR: 3122, 2933, 2850, 1597, 1518, 1483,
1417, 1382, 1245, 1150, 1075, 977, 785, 685cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.47 (d, J = 6.8 Hz, 6H),
3.84–3.93 (m, 1H), 4.42 (s, 2H), 7.17 (s, 1H), 7.41–7.43
(m, 3H), 7.91–7.93 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 23.2, 28.2, 38.8, 116.1, 126.4, 128.9, 130.1, 133.2,
149.2, 164.4, 164.8, 169.0; LCMS: 318.1 (M+ H)+. Anal.
were found within the Æ0.4% of theoretical values.
General procedure for synthesis of compounds 4a–l. The
solution of thiol 3a–c (10 mmol), triethyl amine (11 mmol),
and alkyl halide (11 mmol) in dry acetone was refluxed for
1 h. After completion of the reaction (TLC), the solvent
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1896
S. H. Shelke, P. C. Mhaske, S. K. Kasam, and V. D. Bobade
Vol 51
2-[(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(ethylthio)-
1,3,4-oxadiazole 4i.
Calcd. for C15H15N3OS2: C, 56.76; H, 4.76; N, 13.24.
Found: C, 56.62; H, 4.70; N, 13.16.
IR: 3120, 2931, 2854, 1599, 1516,
1481, 1417, 1381, 1244, 1151, 1074, 976, 933
785, 688 cmÀ1 1H NMR(300 MHz, CDCl3): d 1.47
2-[(2-phenyl-1,3-thiazol-4-yl)methyl]-5-(heptylthio)-1,3,4-
oxadiazole 4d. IR: 3120, 2931, 2854, 1599, 1516, 1481,
;
1417, 1381, 1244, 1151, 1074, 976, 933 785, 688 cmÀ1
;
(t, J= 7.6 Hz, 3H), 3.25 (q, J = 7.6 Hz, 2H), 4.42 (s, 2H),7.21
(s,1H), 7.40(d, J= 8Hz, 2H), 7.86 (d, J=8Hz,2H);13C NMR
(75 MHz, CDCl3): d 14.5, 26.9, 28.1, 116.1, 126.4, 129.0,
130.1, 133.3, 149.1, 164.3, 164.8, 169.0; LCMS: 338.0
(M + H)+ Anal. Calcd. for C14H12ClN3OS2: C, 49.77;
H, 3.58; N, 12.44. Found: C, 49.72; H, 3.61; N, 12.39.
2-[(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(propylthio)-
1H NMR(400MHz, DMSO-d6): d 0.83 (t, J = 7.2 Hz, 3H),
1.20–1.32 (m, 8H), 1.67 (quint, 2H), 3.19 (t, J = 7.2 Hz,
2H), 4.46 (s, 2H), 7.48–7.56 (m, 3H), 7.65 (s, 1H), 7.90
(m, 2H); 13C NMR (100 MHz, DMSO-d6): d 13.8, 21.9,
27.3, 27.7, 29.9, 28.9, 31.0, 31.9, 116.0, 126.5, 128.8,
130.0, 133.1, 149.2, 164.3, 164.8, 168.9; LCMS: 374.0
(M + H)+. Anal. Calcd. for C19H23N3OS2 C, 61.09; H,
1,3,4-oxadiazole 4j.
IR: 3128, 2964, 2933, 1589, 1491,
1454, 1406, 1246, 1145, 1087, 1008, 840, 783 cmÀ1; H
NMR (400MHz, DMSO-d6): d 0.94 (t, J = 7.2 Hz, 3H),
1.65–1.77 (m, 2H), 3.18 (t, J=7.2Hz, 2H), 4.47 (s, 2H), ,
7.55 (d, J= 8.4 Hz, 2H), 7.69 (s, 1H), 7.91 (d, J=8.4Hz,
2H); 13C NMR (100 MHz, DMSO-d6): d 12.7, 22.3, 27.3,
33.8, 118.2, 127.7, 129.2, 131.5, 134.8, 149.6, 163.7, 165.2,
165.9; LCMS: 352.0 (M + H)+. Anal. Calcd. for
C15H14ClN3OS2: C, 51.20; H, 4.01; N, 11.94. Found: C,
1
6.21; N, 11.25. Found: C, 61.14; H, 6.18; N, 11.20.
2-[(2-(3-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(ethylthio)-
1,3,4-oxadiazole 4e.
IR: 3091, 2962, 2870, 1579, 1518,
1483, 1408, 1238, 1193, 1151, 1008, 964, 802, 765 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.47 (t, J = 7.6 Hz, 3H),
3.26 (q, J =7.6Hz, 2H), 4.43 (s, 2H),7.25 (s, 1H), 7.34–7.41
(m, 2H), 7.78–7.81 (m, 1H), 7.95 (s, 1H); 13C NMR
(75 MHz, CDCl3): d 14.6, 26.9, 28.1, 116.8, 124.7, 126.4,
130.1, 134.7, 135.0, 149.4, 164.9, 166.8, 168.7; LCMS:
338.1 (M + H)+. Anal. Calcd. for C14H12ClN3OS2: C, 49.77;
51.17; H, 4.02; N, 11.90.
2-[(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(isopropylthio)-
1,3,4-oxadiazole 4k. IR: 3122, 2933, 2850, 1597, 1518,
H, 3.58; N, 12.44. Found: C, 49.80; H, 3.55; N, 12.39.
2-[(2-(3-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(propylthio)-
1483, 1417, 1382, 1245, 1150, 1075, 977, 785, 685cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.47 (d, J = 7.2 Hz, 6H),
3.85–3.94 (m, 1H), 4.42 (s, 2H),7.20 (s, 1H), 7.40 (d,
J = 8.6 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d 23.2, 28.2, 38.8, 116.1, 126.4, 128.9,
130.1, 133.2, 149.2, 164.4, 164.8, 169.0; LCMS: 352.1
(M + H)+. Anal. Calcd. for C15H14ClN3OS2: C, 51.20; H,
1,3,4-oxadiazole 4f.
IR: 3091, 2962, 2870, 1579, 1518,
1483, 1408, 1238, 1193, 1151, 1008, 964, 802, 765 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 1.02 (t, J = 6.9 Hz, 3H),
1.40–1.88 (m, 2H), 3.19 (t, J = 7.2 Hz, 2H), 4.39 (s, 2H),
7.21 (s, 1H), 7.31–7.38 (m, 2H), 7.74–7.77 (m, 1H), 7.92
(m, 1H);13C NMR (75 MHz, CDCl3): d 13.1, 22.6, 28.1,
34.3, 116.7, 124.6, 126.4, 130.0, 130.1, 134.8, 134.9,
149.5, 164.7, 165.0, 166.6; LCMS: 352.1 (M + H)+. Anal.
Calcd. for C15H14ClN3OS2: C, 51.20; H, 4.01; N, 11.94.
4.01; N, 11.94. Found: C, 51.17; H, 4.00; N, 11.90.
2-[(2-(4-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(heptylthio)-
1,3,4-oxadiazole 4l.
IR: 3124, 2926, 2852, 1589, 1516,
1489, 1419, 1381, 1247, 1149, 1095, 1006, 972, 837 781,
688 cmÀ1 1H NMR (400 MHz, DMSO-d6):
0.82
Found: C, 51.15; H, 3.97; N, 11.89.
2-[(2-(3-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(isopropylthio)-
;
d
1,3,4-oxadiazole 4g. IR: 3091, 2962, 2870, 1579, 1518,
(t, J=7.2Hz, 3H), 1.20–1.33 (m, 8H), 1.65 (quint, 2H), 3.16
(t, J= 7.2 Hz, 2H), 4.46 (s, 2H),7.54 (d, J= 8.4 Hz, 2H), 7.69
(s, 1H), 7.90 (d, J= 8.4 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6): d 13.8, 21.9, 27.3, 27.7, 28.0, 28.9, 31.0, 31.9,
118.1, 127.8, 129.2, 131.5, 134.8, 149.7, 163.7, 165.1, 165.9;
LCMS: 408.1 (M + H)+. Anal. Calcd. for C19H22ClN3OS2: C,
1483, 1408, 1238, 1193, 1151, 1008, 964, 802, 765 cmÀ1
;
1H NMR (300MHz, CDCl3): d 1.42 (d, J = 7.2 Hz, 6H),
3.88–3.92 (m, 1H), 4.43 (s, 1H), 7.24 (s, 1H), 7.33–7.39 (m,
2H), 7.77–7.79 (m, 1H), 7.94 (m, 1H); 13C NMR (75MHz,
CDCl3): d 23.1, 28.2, 38.8, 116.8, 124.7, 126.5, 130.0,
130.2, 134.8, 134.9, 149.4, 164.7, 165.1, 167.1; LCMS:
352.0 (M + H)+. Anal. Calcd. for C15H14ClN3OS2: C, 51.20;
55.93; H, 5.44; N, 10.30. Found: C, 55.88; H, 5.45; N, 10.33.
2-[5-((2-Phenyl-1,3-thiazol-4-yl)methyl)-1,3,4-oxadiazol-2-
ylthio]acetonitrile 5a.
3115, 2977, 2930, 2248, 1584,
H, 4.01; N, 11.94. Found: C, 51.14; H, 3.98; N, 11.89.
2-[(2-(3-Chlorophenyl)-1,3-thiazol-4-yl)methyl]-5-(heptylthio)-
1,3,4-oxadiazole 4h. IR: 3120, 2931, 2854, 1599, 1516, 1481,
1489, 1477, 1430, 1379, 1240, 1139, 1008, 960, 830,
1
cmÀ1; H NMR (300 MHz, CDCl3): d 4.42 (s, 2H), 4.51 (s,
1
1417, 1381, 1244, 1151, 1074, 976, 933 785, 688 cmÀ1; H
2H), 7.18 (s, 1H), 7.40–7.44 (m, 3H), 7.89–7.94 (m, 2H);
13C NMR (75MHz, CDCl3): d 17.6, 28.2,, 116.6, 126.6,
128.8, 130.1, 133.2, 149.1, 164.3, 164.7, 169.0; LCMS:
315.1 (M + H)+. Anal. Calcd. for C14H10N4OS2: C, 53.49; H,
3.21; N, 17.82. Found: C, 53.46; H, 3.24; N, 17.78.
2-[5-((2-(3-Chlorophenyl)-1,3-thiazol-4-yl)methyl)-1,3,4-
oxadiazol-2-ylthio]acetonitrile 5b. 3110, 2979, 2932, 2249,
NMR (400 MHz, DMSO-d6): d 0.82 (t, J=7.2Hz, 3H),
1.19–1.23 (m, 8H), 1.67 (m, 2H), 3.18 (t, J= 7.6 Hz, 2H),
4.46 (s, 2H),7.52–7.54 (m, 2H), 7.73(s, 1H), 7.84 (m, 1H),
7.90 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d 13.8, 21.9,
27.2, 27.6, 27.9, 28.9, 30.9, 31.9, 118.5, 124.8, 125.3, 130.0,
131.2, 133.9, 134.5, 149.7, 163.7, 165,1, 165.4; LCMS:
408.1 (M + H)+. Anal. Calcd. for C19H22ClN3OS2: C, 55.93;
H, 5.44; N, 10.30. Found: C, 55.99; H, 5.40; N, 10.27.
1588, 1490, 1485, 1433, 1390, 1245, 1176, 1140, 1006,
960, 715, cmÀ1 1H NMR (300MHz, CDCl3): d 4.43
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2014
Synthesis and Pharmacological Evaluation of a Novel Series of 2-((2-Aryl thiazol-4-yl)
methyl)-5-(alkyl/alkylnitrile thio)-1,3,4-oxadiazole
1897
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(s, 2H), 4.51 (s, 2H), 7.25 (s, 1H), 7.34–7.41 (m, 2H), 7.78–
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1589, 1491, 1485, 1433, 1396, 1244, 1176, 1139, 1008,
1
960, 717, cmÀ1; H NMR (300 MHz, DMSO-d6): d 4.43
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48.17; H, 2.57; N, 16.02.
Antifungal activity. All the strains were obtained from
microbial type culture collection at the NCIM, Pune, India.
For the antifungal activity, Sabouraud dextrose broth medium
was used. The spores were obtained from 10 days culture of C.
albicans, C. tropicalis, A. niger, and A. flavus species. The
twofold dilution technique [39–42] was followed to
determine the MIC of the synthesized compounds. The test
compounds were dissolved in dimethyl sulfoxide (DMSO)
and then diluted with culture medium (Mueller Hinton agar
medium) at the required final concentration in between 0.2
and 100 mg/mL. A plate containing only the culture medium
and DMSO in the same dilution was used as negative
control. The MIC values were recorded after incubation at
37 ꢀC for a period of 24 h, the turbidity produced in each
tube was recorded by using a UV–visible spectrometer. The
lowest concentration of the test substance that completely
inhibited the growth of the microorganism was reported as
MIC expressed in terms of mg/mL.
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Acknowledgments. The authors would like to express their
sincere thanks to Department of Chemistry, Pune University,
IIT, Mumbai for providing spectral analysis and CSIR, New
Delhi for financial assistance.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet