Synthesis and biological evaluation of some novel thiazole substituted benzotriazole derivatives

DOI: 10.1016/j.bmcl.2012.03.094

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Bioorganic and Medicinal Chemistry Letters p. 3449 - 3454 (2012)

Update date:2022-08-03

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Authors:

Gaikwad, Nitin D.

Patil, Sachin V.

Bobade, Vivek D.

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Article abstract of DOI:10.1016/j.bmcl.2012.03.094

A series of novel hybrid molecules 4a-y containing thiazole and benzotriazole templates were designed and synthesized. The structures of the synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR and mass spectral data. All the

Full text of DOI:10.1016/j.bmcl.2012.03.094

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3449–3454

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: w ww.elsevier.com/locate/bmcl

Synthesis and biological evaluation of some novel thiazole substituted

benzotriazole derivatives

Nitin D. Gaikwad ^b, Sachin V. Patil ^a, Vivek D. Bobade ^a,

⇑

^aDepartment of Chemistry, H.P.T Arts & R.Y.K. Science College, Nashik 422005, India

^bDepartment of Chemistry, K.T.H.M. College, Nashik 422005, India

a r t i c l e i n f o

a b s t r a c t

Article history:

A series of novel hybrid molecules 4a–y containing thiazole and benzotriazole templates were designed

and synthesized. The structures of the synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR

and mass spectral data. All the synthesized compounds were tested for their antimicrobial activity (zone

of inhibition) against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. After that

minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs) and minimum

fungicidal concentrations (MFCs) of all the synthesized compounds were determined. The investigation

of antimicrobial screening data revealed that most of the tested compounds showed moderate to good

microbial inhibitions.

Received 4 October 2011

Revised 19 March 2012

Accepted 27 March 2012

Available online 1 April 2012

Keywords:

Thiazole

Benzotriazole

Hydrazone

MIC

MBC

MFC

The chemistry of carbon–nitrogen double bond of hydrazone is

becoming the backbone of condensation reaction in benzo-fused

N-heterocycles.¹Hydrazone containing azomethine (–NH–N@C)

constitutes an important class of compounds for new drug devel-

opment.²Many researchers have synthesized these compounds

as target structures and evaluated their biological activities. Hydra-

zones have been reported to possess, antimicrobial,³antitubercu-

lar,⁴anticonvulsant,⁵analgesic,⁶antiinﬂammatory,⁷antiplatelet,⁸

anticancer,⁹antiviral,¹⁰antitumoral,¹¹and antimalarial¹²activities.

One of the most common classes of antifungal agents is azoles.

For over a decade, azoles have been a mainstay of the antifungal

armamentarium. The triazole derivatives,^13–17are known to exhi-

bit various pharmacological properties. The most important use,

however, is as antimycotics in drugs such as ﬂuconazole, itraconaz-

ole and voriconazole¹⁸and so on, (Fig. 1) currently play a leading

role in the treatment of invasive fungal infections.¹⁹These anti-

fungal drugs act by competitive inhibition of cytochrome P450

super-family.²²In all cases CYP51 catalyzes a three-step reaction

of sterol 14 -demethylation. The 14 -methyl group is converted

to an alcohol, then to an aldehyde, and is removed as formic acid

in the ﬁnal step.²³Recent studies showed that typical azole inhib-

itors were able to ﬁt the putative active site of CYP51 by a combi-

nation of heme coordination, hydrogen bonding,

p–p stacking and

hydrophobic interactions.^24–26

Benzotriazole represent an overwhelming and rapid developing

ﬁeld in modern heterocyclic chemistry. From literature it is pre-

dictable that, benzotriazoles represent important pharmacophores,

and play a vital role as medicinal agents. A degree of respectability

has been bestowed for benzotriazole derivatives due to their wide

range of biological activities such as antiprotozoal agents²⁷(inhib-

itors of Acanthamoeba castellani), antimicrobial,²⁸antiinﬂamma-

tory,²⁹antitumor³⁰and etc. Several derivatives of benzotriazoles

are reported as agonists of peroxisome proliferator activated

receptors.³¹Synthesis and biological activity of benzotriazole anal-

ogous as inhibitors of the NT pase/helicase and of some related

ﬂavivade has been extensively investigated.³²

14a-demethylase (CYP51), a necessary enzyme in the biosynthesis

of ergosterol which is the primary membrane sterol in fungi.²⁰

CYP51 is a member of the cytochrome P450 super-family, which

is widely distributed in different biological kingdoms, being found

in animals, plants, fungi, yeast, lower eukaryotes and bacteria,²¹

and considered to be the most ancient member of the

Triazole and thiazole^33–37derivatives represent a major chemi-

cal group as biologically active agent. Triazoles, in particular,

substituted 1,2,4-triazoles and the open-chain thiosemicarbazide

counterparts of 1,2,4-triazole, are among the various heterocycles

that have received the much attention during the last two decades

as potential antimicrobial agents.^38–41Thiazole moiety has already

been reported for its antimicrobial activity.^42,43Thiazole ring is an

⇑

Corresponding author. Tel.: +91 9970499527; fax: +91 0253 2573097.

E-mail address: v_bobade31@rediffmail.com (V.D. Bobade).

http://dx.doi.org/10.1016/j.bmcl.2012.03.094

3450

N. D. Gaikwad et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3449–3454

Fluconazole

Posaconazole

CH₃

Itraconazole

Voriconazole

CH₃

R³

R⁴

R⁵

R³

R¹

R²

Ravuconazole

4a-y

Figure 1. Structures of the antifungal agent ﬂuconazole, posaconazole, voriconazole, itraconazole, ravuconazole and synthesized compounds 4a–y.

R³

R¹

R³

R¹

Et₃N

R²

Ethanol

2a-e

1a-e

Thiosemicarbazide

Ethanol

R⁴

R⁵

Ethanol

R⁵

NH₂

R⁴

R⁵

R³

R¹

R²

R³

R¹

R²

4a-y

R⁶

3a-e

Scheme 1. Synthetic route of 4a–y.

important pharmacophore⁴⁴and its coupling with other rings

could furnish new biologically active compounds. Thiazole con-

taining compounds exhibit a wide range of biological properties,

such as antitumor,⁴⁵anticonvulsant,⁴⁶cardiotonic,⁴⁷IMP dehydro-

genase inhibiton,⁴⁸analgesic,⁴⁹anticancer.⁵⁰

It was observed that, benzotriazole and thiazole rings present in

the same molecule could be convenient models for investigation of

their biological activity. Literature revealed that syntheses of such

thiazolyl-benzotriazole showed anti-convulsant and anti-inﬂam-

matory activity,⁵¹anti-tumoral activity.⁵²After extensive literature

search, it was observed that, till date enough efforts have not been

made to combine benzotriazole and thiazole moieties as a single

molecular scaffold and to study its biological activity. In continua-

tion with our earlier work,^53–55we herein report the synthesis of

new benzotriazole derivatives clubbed with thiazole moiety

(Scheme 1) with the aim of investigating their antimicrobial activity.

N. D. Gaikwad et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3449–3454

3451

condensation of 3a–e with appropriate phenacyl bromide resulted

in the formation of 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-(4-sub-

Compound

R¹

R²

R³

R⁴

R⁵

R⁶

stitutedphenyl)ethylidene)-2-(4-(substitutedphenyl)

thiazol-2-

CF₃

NO₂

CF₃

yl)hydrazine 4a–y as shown in Scheme 1. Analytical and spectral

data (IR, ¹H NMR, ¹³C NMR and EIMS) conﬁrmed the structures of

the new compounds.

The behavior of thiocarbamoyl functional group in thiosemicar-

bazone towards phenacyl bromide was investigated. Literature⁵⁷

reported three sets of experimental conditions used to the reaction

of thiosemicarbazone with phenacyl bromide using pyridine as

catalyst. In the literature⁵⁸it was reported that thiosemicarbazone

reacted with phenacyl bromide in absolute ethanol in the presence

of fused sodium acetate at room temperature. We treated the thio-

semicarbazones 3a–e with phenacyl bromide in anhydrous ethanol

under 70 °C for 15 min to give corresponding compounds in good

yields without using catalyst (Scheme 1).

NO₂

The structure of intermediates 3 were substantiated by IR, ¹H

NMR. IR spectra of compounds 3 revealed in each case, absorption

band in the region 3395–3215, 1613–1604 and 1276–1275 cm^À1

corresponding to N–H, C@N and C@S, respectively. The structure

of the title compounds have been conﬁrmed by elemental analysis

IR, ¹H NMR, ¹³C NMR and MS. The IR spectra of these compounds

show C@C/C@N absorption bands between 1610–1482 cm^À1and

showed a broad band at 3118–3104 cm^À1due to N–H group

absorption. In the NMR, title compounds exhibited broad singlet

between d 12.06–11.90 ppm, due to N–H protons, the presence of

multiplet signal at d 6.96–7.87 ppm was assigned to the aromatic

protons and thiazole-H, the methylene absorption bands appeared

as a singlet at d 5.71–5.79. In MS spectra, molecular ion peaks of all

title compounds were obtained from EI-MS, the presence of M+2

peaks are characteristics for the compound having chlorine and

bromine atoms.

CF₃

NO₂

CF₃

The synthetic route of compounds is outlined in Scheme 1. In the

present work substituted phenacyl bromides 1a–e and substituted

1-aryl-2-(1H-benzotriazole-1-yl) ethanones 2a–e were obtained by

literature method.⁵⁶The 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-

1-(4-substitutedphenyl)ethylidene)thiosemicarbazide 3a–e were

prepared by reacting 1-aryl-2-(1H-benzotriazole-1-yl) ethanones

2a–e with thiosemicarbazide in the presence of acetic acid. The

All the synthesized compounds were screened for their in vitro

antibacterial activity against the standard strains Bacillus subtilis

(2250), Staphylococcus aureus (2079), Escherichia coli (2109) and

Pseudomonas aeruginosa (2036) and for their antifungal activity

Table 1

Antimicrobial screening of synthesized compounds 4a–y (zone diameter of growth inhibition in mm)

Compounds

Microorganisms

S. aureus

E. coli

B. subtilis

P. aeruginosa

A. niger

C. albicans

20.12

25.88

20.85

—

19.23

24.68

27.88

—

23.44

—

22.15

26.48

—

22.58

—

24.29

—

15.04

—

17.58

—

18.85

—

11.80

19.14

—

14.31

11.32

—

16.44

—

19.83

21.22

—

13.18

—

20.72

16.73

—

15.63

—

19.11

21.44

—

16.25

17.52

20.08

18.20

15.25

13.63

—

17.56

15.25

—

21.08

20.18

14.74

18.71

17.44

21.33

20.98

18.01

—

13.71

16.76

—

18.09

—

12.25

—

17.32

14.28

19.02

18.44

—

22.81

14.86

24.14

16.92

25.14

13.76

—

17.23

—

20.27

—

15.28

—

21.12

18.66

21.84

—

18.68

—

17.54

14.96

—

18.68

—

17.76

—

17.88

16.81

19.66

—

11.74

22.03

13.14

16.41

Nystatin

Chloramphenicol

—

29.24

31.4

23.87

20.32

27.55

Chloramphenicol (128

lg/disc); Nystatin (128

lg/disc) were used as reference; synthesized compounds (128

lg/disc); NA = not applicable; (—) = inactive.

3452

N. D. Gaikwad et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3449–3454

Table 2

against Candida albicans (3471) and Aspergillus niger (545). All the

strains were obtained from microbial type culture collection

(MTCC) at the NCIM, Pune, India. For antibacterial activity solid

medium used for the study were Muller-Hinton agar (Hi media)

MHA and soybean casein digest agar (SCDA) and for antifungal

activity solid medium used for the study were Potato dextrose agar

(Hi media).

Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC)

results of 4a–y

Compounds

Microorganisms

E. coli B. subtilis

MIC MBC MIC MBC MIC MBC MIC

S. aureus

P. aeruginosa

MBC

—

128

—

128

—

128

—

128

—

128

—

128

—

128

—

128

—

128

—

128

—

128

—

256

—

256

128

—

128

—

256

—

128

—

128

—

The antibacterial activity of all the newly synthesized com-

pounds was done by the agar-well diffusion assay technique.^59,60

Twenty four-hour-old bacterial cultures of all test microorganisms

were used as inoculums, which was adjusted to 0.5 McFarland

standard, that is, 1.5 Â 10⁸CFU/mL. The stock solutions of all test

128

—

128

—

128

—

128

256

128

256

—

256

—

128

—

256

—

compounds (128 lg/mL) were prepared by dissolving 128 lg of

the test compound in DMSO (1 mL). Chloramphenicol and DMSO

were used as positive and negative controls, respectively. Twenty

milliliter of molten and cooled MHA and 320 lL of each test bacte-

—

128

—

128

—

128

—

128

—

128

—

256

—

256

—

rial culture were mixed (separate ﬂasks were used for each bacte-

rial culture) and poured in sterilized and labeled petri plates. The

wells of 6 mm were punched in the solidiﬁed petri plates, asepti-

cally. Fifty microlitres from stock solutions of all compounds as

well as controls was added to each well of labeled petri plates

and incubated at 35 °C for 24 h. The diameter of the zone of growth

inhibition around each well was measured after incubation using

vernier caliper (Table 1).

The minimum inhibitory concentration (MIC) of compounds

against Gram-positive and Gram-negative test bacteria was deter-

mined by the method of NCCLS.⁶¹All the test cultures were

streaked on SCDA and incubated overnight at 37 °C. Turbidity of

all the bacterial cultures was adjusted to 0.5 McFarland standard

by preparing bacterial suspension of 3–5 well isolated colonies of

the same morphological type selected from an agar plate culture.

The cultures were further diluted 10-fold to get an inoculums size

of 1.2 Â 10⁷CFU/mL. Stock solutions of 4 mg/mL of each compound

was prepared in DMSO and was appropriately diluted to get a ﬁnal

128

256

—

Chloramphenicol

Chloramphenicol (

ml) = minimum inhibitory concentration, that is, the lowest concentration of the

compound to inhibit the growth of bacteria completely; MBC ( g/ml) = minimum

bactericidal concentration, that is, the lowest concentration of the compound for

killing the bacteria completely.

lg/ml) were used as positive control; (—) = inactive; MIC (lg/

concentration of 256, 128, 64, 32, 16, 8, 4, 2, 1

g/mL. Standard

by cutting 6 mm diameter were spread individually with needle

and planted upon the chilled seeded medium. The culture plates

were then incubated for 24–72 h at 37 °C and inhibition zone

around each disc was measured from the centre of the discs. The

diameter of growth inhibition zone was calculated by vernier cal-

iper (Table 1).

For minimum inhibitory concentrations (MIC) of synthesized

compounds 4a–y were determined in the range of concentrations

from 256 to 1 lg/mL. The standardized micro broth dilution meth-

ods, were used according to the guidelines of Clinical and Labora-

tory Standards Institute (CLSI, formerly National Committee for

Clinical and Laboratory Standards NCCLS).⁶¹Table 3 summarizes

the minimum concentration of each derivative necessary to com-

pletely inhibit (MIC₉₀) the growth of two standardized opportunis-

tic pathogenic fungi including C. albicans and A. Niger. To obtain the

minimum fungicidal concentration (MFC), 0.1 mL volume was

taken from each tube and spread on agar plates. The number of

CFU was counted after 48 h of incubation at 35 °C. MFC was de-

ﬁned as the lowest drug concentration at which 99.9% of the inocu-

lums were killed. The minimum inhibitory concentration and

minimum fungicidal concentration are given in Table 3. The ratio

MFC/MIC was calculated in order to determine if the compound

had a fungistatic (MFC/MIC P 4) or fungicidal (MFC/MIC 6 4)

activity and the results have been summarized in Table 3.

antibiotic chloramphenicol were also diluted to get a ﬁnal concen-

tration in the same manner. Three hundred and twenty micro liters

of each dilution was added to 20 mL molten and cooled MHA (sep-

arate ﬂasks was taken for each dilution). After thorough mixing,

the medium was poured in sterilized petri plates. The test bacterial

cultures were spotted in a predeﬁned pattern by ascetically trans-

ferring 5 mL of each bacterial culture on the surface of solidiﬁed

agar plates and incubated at 35 °C for 24 h. The lowest concentra-

tion (highest dilution) required to arrest the growth of bacteria was

regarded as MIC. To obtain the minimum bacterial concentration

(MBC), 0.1 mL volume was taken from each tube and spread on

agar plates. The number of CFU was counted after 18–24 h of incu-

bation at 35 °C. MBC was deﬁned as the lowest drug concentration

at which 99.9% of the inoculums were killed. The minimum inhib-

itory concentration and minimum bactericidal concentration are

given in Table 2.

For the antifungal activity, Potato dextrose agar (Hi media)

medium was used. This sterilized hot medium (15 mL) was pipette

out into ﬂat petri plates. When it solidiﬁed 15 mL of warm seeded

agar was applied over it. The seeded agar was made by cooling the

medium to 40 °C and then adding spore suspension to seeded med-

ium. The spores were obtained from 10 days culture of C. albicans

and A. niger species. The ﬁnal inoculums size was adjusted to

1 Â 10⁶spore mL^À1. Nystatin and DMSO were used as positive

and negative controls, respectively.

Careful analysis of the MICs in Table 2 and 3 provides some lead

molecules with good antibacterial and antifungal activity. Of the

compounds 4a–y tested, compounds with electron-withdrawing

F, Cl, Br, CF₃, and NO₂at the phenyl ring expressed a moderate to

good activity against most of the tested pathogens, they inhibited

the Gram-positive and Gram-negative pathogens equally. Com-

Before the solidiﬁcation of agar, the plate was tilted to ensure

that coverage should be even. These petri plates were then put into

the refrigerator upside down to prevent condensation of moisture.

Concentration 128 lg/mL of the synthesized compounds were pre-

pared by dissolving the required quantity of compounds in DMSO,

pounds 4a–y required about 16–128

lg/mL against Gram-positive

sterilized Whatman ﬁlter paper number 541 discs were prepared

and Gram-negative bacteria as well as both the fungi species,

N. D. Gaikwad et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3449–3454

3453

Table 3

In conclusion, a series of new 4a–y were synthesized. The phar-

macological studies were undertaken to evaluate the effect of sub-

stituents for their antimicrobial activities. Most of the synthesized

compounds exhibited moderate to good activity towards Gram-po-

sitive and Gram-negative bacteria as well as both the fungi species.

The enhancement in antibacterial and antifungal activity can be

attributed to the presence of pharmacologically active F, Cl, Br

groups irrespective of their position in the molecule.

Minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC)

and fungicidal/fungistatic activity (MFC/MIC) of 4a–y

Compounds

Microorganisms

C. albicans A. niger

MIC MFC

A. niger

C. albicans

MIC

MFC

MFC/MIC

—

128

—

256

128

—

128

—

128

256

—

Acknowledgments

We thank UGC, New Delhi and Principal, K.T.H.M. College, Nas-

hik for providing laboratory facilities.

—

128

—

Supplementary data

—

128

—

Supplementary data associated with this article can be found, in

the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.03.094.

These data include MOL ﬁles and InChiKeys of the most important

compounds described in this article.

—

128

—

128

—

256

—

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128

256

128

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Nystatin

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P. aeruginusa (they are four and eightfold less potent than chloram-

phenicol). The MBC of few compounds was found to be the same as

MIC but in most of the compounds it was 2- or 4-folds higher than

the corresponding MIC results.

Table 2 also describes the MIC of synthesized compounds for

their antifungal activity. The introduction of F, Cl, Br, NO₂substit-

uents on phenyl ring exhibited moderate to good activity against C.

albicans and A. niger, whereas, except the 4m, 4o, 4r, 4w, 4x all

other compounds showed moderate to good activity against A. ni-

ger and C. albicans. Of the ﬂuoro and chloro substituted compounds

4a, 4b, 4f registered a excellent activity against A. niger at 16

g/mL, also compounds 4d, 4e, 4g, 4k, 4p, 4t, 4u recorded good

activity at 32 g/mL and 4h, 4j, 4l recorded moderate activity at

64 g/mL which is fourfold lower than standard Nystatin. In addi-

tion compounds 4a, 4b, 4f, 4g registered the MIC at 16 g/mL, 4d,

4e, 4h, 4l, 4n, 4s, 4u, 4v recorded at 32 g/mL and4c, 4i, 4q, 4t, 4x

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