Synthesis and antibacterial activity of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones

DOI: 10.1016/j.bmcl.2004.12.039

Source and publish data:

Bioorganic and Medicinal Chemistry Letters p. 1023 - 1025 (2005)

Update date:2022-08-03

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Authors:

Tehranchian, Sara

Akbarzadeh, Tahmineh

Fazeli, Mohammad Reza

Jamalifar, Hossein

Shafiee, Abbas

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Article abstract of DOI:10.1016/j.bmcl.2004.12.039

A series of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3- methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones were synthesized and tested to demonstrate in vitro antimicrobial activity. Some of these compounds exhibited a good activity against Staphylococcus aureus, S. epidermidis and Bacillus subtilis.

Full text of DOI:10.1016/j.bmcl.2004.12.039

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1023–1025

Synthesis and antibacterial activity of 1-[1,2,4-triazol-3-yl]

and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydro-

benzo[c]thiophen-4(5H)ones

Sara Tehranchian,^aTahmineh Akbarzadeh,^aMohammad Reza Fazeli,^b

Hossein Jamalifar^band Abbas Shaﬁee^a,*

^aDepartment of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,

Tehran University of Medical Sciences, Tehran, Iran

^bDepartment of Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Received 20 September 2004; revised 12 December 2004; accepted 14 December 2004

Available online 12 January 2005

Abstract—A series of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones were

synthesized and tested to demonstrate in vitro antimicrobial activity. Some of these compounds exhibited a good activity against

Staphylococcus aureus, S. epidermidis and Bacillus subtilis.

A dramatic increase in antibiotic resistance specially

among Gram positive bacteria triggered a clear need

for the discovery of new antimicrobials rather than ana-

logs of the existing ones.¹Traditionally, small molecules

have been a reliable source for discovering novel biologi-

cally active compounds. Here, we focused mainly on

benzo[c]thiophene as our basic structure and investiga-

tion of its combination with other heterocycles. Studies

on thiophene-like compounds have served as a feasible

ﬁeld of research in the perusal for biologically active

compounds.^2–5In this regard structures similar to

benzo[c]thiophene had interesting antibacterial and anti-

fungal properties. The importance of sulfur in fused ring

system, as well as the signiﬁcance of the ketone function

group in 4-position has been determined,⁶hence we were

to deﬁne the eﬀect of 1-substitution in benzo[c]thiophene

ring on the antibacterial and antifungal eﬀects of these

compounds.

considerable activity against Gram negative and Gram

positive bacteria as well as some strains of fungi.^11–14

By considering these active heterocycles with potential

antimicrobial eﬀects, a new series of 1-[1,2,4-triazol-3-

yl] and 1-[1,3,4-thiadiazol-2-yl]-6,7-dihydrobenzo[c]thio-

phen-4(5H)ones were synthesized and their antimicro-

bial properties was evaluated.

The synthesis of 1,2,4-triazole and 1,3,4-thiadiazole

derivatives is outlined in Scheme 1. Compound 1 was

prepared by a known procedure.¹⁵Reaction of corre-

sponding ester group of compound 1 with hydrazine

hydrate gave 3-methylthio-6,7-dihydrobenzo[c]thio-

phen-4(5H)ones-1-carboxylic acid hydrazide (2), which

was used as the key intermediate for the preparation

of ﬁnal compounds. Treatment of compound 2 with

diﬀerent isothiocyanates in alkaline aqueous phase gave

corresponding thiosemicarbazides 3a–g. Cyclizations of

compounds 3a–g were accomplished in aqueous media

to give the corresponding 1,2,4-triazole-5-thiones 4a–g.

Reaction of compound 4 with methyl iodide in alkaline

media under the ultrasonic condition produced S-

methyl derivatives 5a–g.

Substituted 1,2,4-triazoles and 1,3,4-thiadiazoles are

associated with immense biological activities.^7–10Anti-

bacterial activity data of these structures showed their

Keywords: 1,2,4-Triazole; 1,3,4-Thiadiazole; 6,7-Dihydrobenzo[c]thio-

phen-4(5H)ones; Antibacterial activity.

Cyclization of compounds 3a–g with concd sulfuric acid

aﬀorded compounds 6a–e. Reﬂuxing of 1-cyano-3-

methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)one (7)

Corresponding author. Tel.: +98 21 6406757; fax: +98 21 6461178;

e-mail: ashaﬁee@ams.ac.ir

doi:10.1016/j.bmcl.2004.12.039

1024

S. Tehranchian et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1023–1025

SMe

H₂SO₄

CO₂Et

CONHNH₂

CONHNHCSNHR

3a-g

6a-c

NHR

NaHCO₃

SMe

MeI

SMe

5a-g

4a-g

SMe

F₃CCOOH

NH₂NHCSNH₂

NH₂

a: R = Me

b: R = Et

c: R= n-Bu

d: R=cyclohexyl

e: R= C₆H₄NO₂(₄)

f: R= C₆H₄OMe(₄)

g: R= C₆H₄F(₄)

Scheme 1.

Table 1. Antimicrobial activities of compounds 4–6 and 8 (zone of inhibition in mm)

Compound

S. aureus

S. epidermidis

B. cereus

B. subtilis

P. aeruginosa

E. coli

C. albicans

A. niger

—

NT^d

—

Genta.^a

Nitrof.^b

Amph. B^c

^aGentamycin.

^bNitrofurantoin.

^cAmphotricin B.

^dNot tested.

S. Tehranchian et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1023–1025

1025

Table 2. Minimum inhibitory concentration (MIC, lg/mL) of selected

compounds against certain bacterial strains^a

Derivatives 6a, 6b and 6e showed signiﬁcantacitviyt

against B. subtilis (MIC = 1–2 lg/mL) and compound

6e had the same potency as nitrofurantoin against B.

subtilis.

Compound

S. aureus

S. epidermidis

B. subtilis

NT^b

Acknowledgements

This work was supported by grants from the research

council of Tehran University of Medical Sciences and

Iran Chapter of TWAS.

Nitrofurantoin

Gentamycin

^aDisc diﬀusion method used to determine the MICs.¹⁷

^bNot tested.

References and notes

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Compounds 4–6 and 8 were screened for their antimi-

crobial activity by using cup–plate agar method at a

concentration of 300 lg/disc against Staphylococcus aur-

eus ATCC 29737, S. epidermidis ATCC 12229, Bacillus

cereus ATCC 1274, B. subtilis ATCC 12711, Pseudomo-

nas aeruginosa ATCC 9027, Escherichia coli ATCC

8739, Candida albicans ATCC 10231, Aspergilus niger

ATCC 16404 (Table 1).¹⁶The preliminary results of

antimicrobial activities indicated that some of the com-

pounds exhibited a moderate to good activity against

Gram positive strains, however none of the compounds

exerted a signiﬁcant eﬀect against the Gram negative

strains or fungi. Presence of bulky group of n-butyl or

p-nitrophenyl at 4-position of 1,2,4-triazole in com-

pounds 4 and 5 produced active compounds against

Gram positive strains. Although, S-methylation of

1,2,4-triazole-3-thiones 4c,e resulted in broader activity

of the obtained compounds 5c,e againstmore bacetrial

strains but it did not cause to make more potent deriva-

tives. 5-Amino-1,3,4-thiadiazole 8 showed no antimi-

crobial activity.

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In addition substitution of amino group of 8 resulted to

compounds 6a–e with antifungal activity and high po-

tency against B. subtilis. Determination of the minimum

inhibitory concentration (MIC) values of the potent

derivatives against certain bacterial strains (Table 2)

indicates that compound 4e was the most active deriva-

tive against S. aureus (MIC = 2 lg/mL), its activity was

equal to nitrofurantion, compounds 4c and 5c were the

mostpotentcompounds against S. epidermidis and their

activities were equal to gentamycin (MIC = 1 lg/mL).

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