Synthesis of new S-derivatives of clubbed triazolyl thiazole as anti-Mycobacterium tuberculosis agents

Bioorganic & Medicinal Chemistry 15 (2007) 3997–4008

Synthesis of new S-derivatives of clubbed triazolyl thiazole

as anti-Mycobacterium tuberculosis agents

Mahendra Ramesh Shiradkar,^a,*Kiran Kumar Murahari,^bHanimi Reddy Gangadasu,^b

Tatikonda Suresh,^bChakravarthy Akula Kalyan,^aDolly Panchal,^cRanjit Kaur,^d

Prashant Burange,^cJyoti Ghogare,^cVinod Mokale^cand Mayuresh Raut^c

^aDr. Reddy’s Laboratories, 7-1-27, Ameerpet, Hyderabad 500016, India

^bSanmar Speciality Chemicals, 38, Old Mahabalipuram Road, Chennai 600086, India

^cAISSMS College of Pharmacy, Kennedy Road, Pune 411001, India

^dSt. Johns College of Pharmacy, Vijayanagar, Bangalore 560040, India

Received 6 March 2007; revised 2 April 2007; accepted 3 April 2007

Available online 6 April 2007

Abstract—In the present study, a series of N-{4-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-1,3-thiazol-2-yl}-2-substituted-

amide (1a–d) derivatives were synthesized in good yields and characterized by IR, ¹H NMR, mass spectral and elemental analyses.

The compounds were evaluated for their preliminary in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli,

Pseudomonas aeruginosa and Salmonella typhosa and then were screened for antitubercular activity against Mycobacterium tubercu-

losis H37 Rv strain by broth microdilution assay method. The antibacterial data of the tested compounds indicated that most of the

synthesized compounds showed better activity against bacteria compared to reference drugs. The in vitro antitubercular activity

reports of tested compounds against M. tuberculosis strain H37 Rv showed moderate to better activity.

1. Introduction

the open-chain thiosemicarbazide counterparts of

1,2,4-triazole, are among the various heterocycles that

have received the most attention during the last two dec-

ades as potential antimicrobial agents.^11–14Substitutions

including thio,¹⁵alkylthio and alkenylthio¹⁶derivatives

have been carried out primarily at the 3-position of

the 1,2,4-triazole ring, as potential antimicrobial and

antimycobacterial agents will overcome the above-men-

tioned resistance problems. Thiazole moiety has already

been reported for its antimicrobial activity.^17,18Thus in

continuation of our in-house e to establish probable

pharmacological activities of triazole^19–23we herein re-

port the synthesis of new 1,2,4-triazole derivatives

clubbed with thiazole moiety. The synthesized com-

pounds were also tested for their antimicrobial activity.

Tuberculosis is a contagious disease with comparatively

high mortality worldwide. The statistics shows that

around three million people throughout the world die

annually from tuberculosis^1,2and there are around eight

million new cases each year, out of which developing

countries shows major share.³In addition, about a third

of the world’s population harbours a dormant Mycobac-

terium tuberculosis infection, representing a signiﬁcant

reservoir of disease for the future.

The azole antitubercular may be regarded as a new class

providing truly eﬀective drugs, which are reported to in-

hibit bacteria by blocking the biosynthesis of certain

bacterial lipids and/or by additional mechanisms.^4,5Tri-

azole and thiazole derivatives^6–10represent a novel

emerging major chemical group as antimicrobial agent.

Triazoles, in particular, substituted-1,2,4-triazoles and

In recent years, environmentally benign synthetic meth-

ods have received considerable attention and solvent-

free protocols are reported.^24–26A fast, highly eﬃcient

and eco-friendly solvent-free chemical transformation,

for the synthesis of title compounds, under microwave

irradiation, using acidic alumina is designed. The main

advantages of the synthetic approach presented here

are considerable rate enhancement in comparison with

Keywords: Thiazole; Triazole; Antimicrobial; Antimycobacterial.

*

Corresponding author. Tel.: +91 9989263660; fax: +91

4023731955; e-mail: rrshiradkar@rediﬀmail.com

doi:10.1016/j.bmc.2007.04.003

3998

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

Table 1. First antituberculosis screening of compounds 1a–d, 2a–h, 3a–h, 4a–h, 5a–h, 6a–h, 7a–x, 8a–h and 9a–h

Compound

R

R⁰

Ar

MIC^a

GI (%)^b

1a

1b

1c

1d

2a

2b

2c

2d

2e

2f

NHCOCH₂Cl

NHCOCH₃

NHCOC₆H₅

—

<6.25

—

96

—

96

100

96

—

96

100

96

—

96

—

96

100

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

–4-Cl–C₆H₄

–3-NO₂–C₆H₄

–4-Cl–C₆H₄

–3-NO₂–C₆H₄

–4-Cl–C₆H₄

–3-NO₂–C₆H₄

–4-Cl–C₆H₄

–3-NO₂–C₆H₄

–4-Cl–C₆H₄

–3-NO₂–C₆H₄

–4-Cl–C₆H₄

–3-NO₂–C₆H₄

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

2g

2h

3a

3b

3c

3d

3e

3f

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

3g

3h

4a

4b

4c

4d

4e

4f

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

4g

4h

5a

5b

5c

5d

5e

5f

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

5g

5h

6a

6b

6c

6d

6e

6f

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

6g

6h

7a

7b

7c

7d

7e

7f

NHCOC₆H₅

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

CH₃

C₆H₅

CH₂Cl

CH₃

C₆H₅

NHCOC₆H₅

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

7g

7h

7i

NHCOC₆H₅

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

7j

7k

7l

NHCOC₆H₅

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

7m

7n

7o

7p

7q

7r

7s

7t

NHCOC₆H₅

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

NHCOC₆H₅

NHCH₂CH₂COOH

^aMIC in (lg/mL^ꢀ1). MIC of rifampin: 0.015–0.125 mg mL^ꢀ1versus M. tuberculosis H37Rv (97% inhibition).

^bGrowth inhibition of virulent H37Rv strain of M. tuberculosis.

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

3999

Table 2. First antituberculosis screening of synthesized compounds 1a–d, 2a–h, 3a–h, 4a–h, 5a–h, 6a–h, 7a–x, 8a–h and 9a–h

Compound

R

R⁰

Ar

MIC^a

GI (%)^b

7u

7v

7w

7x

8a

8b

8c

8d

8e

8f

NHCOCH₂Cl

NHCOCH₃

NHCOC₆H₅

CH₂Cl

—

–3-NO₂–C₆H₄

–4-Cl–C₆H₄

<6.25

—

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

96

—

–4-Cl–C₆H₄

96

100

96

—

NHCOC₆H₅

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

–3-NO₂–C₆H₄

–4-Cl–C₆H₄

—

8g

8h

9a

9b

9c

9d

9e

9f

NHCOC₆H₅

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

–4-Cl–C₆H₄

NHCOC₆H₅

NHCH₂CH₂COOH

NHCOCH₂Cl

NHCOCH₃

—

–3-NO₂–C₆H₄

—

9g

9h

NHCOC₆H₅

NHCH₂CH₂COOH

—

^aMIC in (lg/mL^ꢀ1). MIC of rifampin: 0.015–0.125 mg mL^ꢀ1versus M. tuberculosis H37Rv (97% inhibition).

^bGrowth inhibition of virulent H37Rv strain of M. tuberculosis.

a thermal reaction, improved isolated yields of products

and cleaner and environmentally safer reactions. Thus,

this communication reports synthesis of the title com-

pounds using MAOS.

2. Results and discussion

2.1. Synthesis

Compounds 1a–d were synthesized as per the literature.²⁷

Compounds 1a–d, adsorbed on acidic alumina (alumin-

ium oxide, acidic, Brockmann I, ꢁ150 mesh, 58 A CA-

˚

MAG 506-C-I, surface area 155 m²/g, pH 6.0), when

treated with substituted (4-chloro or 3-nitro)benzoyl

chloride at 0 ꢁC to give 2a–h. The transformed com-

pounds 2a–h on treatment with diiodomethane in the

presence of strong alkali, that is, sodium hydroxide gave

3a–h. Title compounds 2a–h were treated with chloro-

acetonitrile, which on neutralization with sodium carbon-

ate gave precipitates of compounds 4a–h. Compounds

2a–h, when treated with methyl bromoacetate in basic

condition, produced 5a–h. Chemical transformation of

5a–h to 6a–h was achieved by treating it with hydrazine

hydrate. While compounds 6a–h, on treatment with

appropriate acid chlorides, furnished 7a–x. Schiﬀ bases,

the condensation products of 8a–h, were synthesized by

treating 6a–h with benzaldehyde and conﬁrmed by ab-

sence of triplet of NH of hydrazide. Compounds 6a–h

were converted to thiocarbazate salts by treatment with

carbon disulﬁde and potassium hydroxide, which on

treatment with hydrazine hydrate gave 9a–h. The NMR

spectra conﬁrmed formation of triazole derivative from

hydrazide, which shows presence of sulfhydryl proton at

d value 12.5. It was observed that there is remarkable loss

of product (32% yield) in the second step for the conver-

sion of 6a–h to 9a–h when performed in conventional

method, while reaction involving MORE method gave

good yield (70–82%).

Table 3. Second level antituberculosis screening

SN

MIC^a(lM)

1b

1c

2a

2b

2c

2d

2e

2f

3.13

6.25

3.13

6.25

3.13

1.56

0.78

0.39

1.56

2g

2h

4a

4b

4c

4d

6a

6b

6c

6e

6f

6g

8a

8b

8c

8d

8e

8f

2.2. Antitubercular activity

8g

8h

The results of the in vitro evaluation of antituberculosis

activity are reported in Tables 1–3. During the prelimin-

^aActual minimum inhibitory concentration (MABA assay).

4000

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

ary screening four compounds (1a–d) were tested (Table

1) for their antimycobacterial activity, the compounds

1b and 1c have exhibited 96% inhibition at this concen-

tration, while other compounds exhibited less than 90%

inhibition at the same concentration.

3. Conclusion

The antimycobacterial screening of the novel series has

demonstrated emergence of potent derivatives that have

highly electronegative part at sulfhydryl group. Speciﬁ-

cally compounds (8f and 8g), that is, Schiﬀ bases, prob-

ably due to their ability to increase the penetration in the

bacterial cell have shown the best of all. Due to the bet-

ter activity against the mycobacteria, compounds (8f

and 8g) were the best choice for the preparations of

new derivatives in order to improve its eﬀectiveness on

intracellular mycobacteria (macrophage) or in infected

animal. Finally it can be concluded that an ideal antimy-

cobacterial agent with minimal toxicity and potential

activity can be designed using above-said compounds

as lead molecules. The said inhibitor can be synthesized

using MAOS so as to get the beneﬁts of this novel

technique.

Thus, we have considered 1 as a lead molecule and

subsequent structural modiﬁcations were carried out

as two of the substitutions were active. As a ﬁrst step

towards lead optimization, amino group was pro-

tected to the corresponding compounds (2a–h) where-

in all the alterations made have shown promising

activity proving that the modiﬁcations are towards

synthesis of a pharmacophore. The next structural

modiﬁcation made was a dimeric product, 3a–h, but

these changes also resulted in a substantial loss of

biological activity. This loss may indicate retardation

in the intracellular transport of highly complex

molecule.

Compounds 4a–h have shown more than 90% of inhibi-

tion, which were obtained by S-alkylation with acetoni-

trile. As the cytotoxicity studies were performed for all

the active compounds and none of them were found to

be cytotoxic, it may be noted that cyano group may

not have any role in increase in the activity. Thus look-

ing at the activity, it was decided to modify the structure

at SH group. In order to optimize the sulfhydryl compo-

nent, compounds 5a–h were synthesized and investi-

gated, which revealed loss of activity. A further

modiﬁcation of compounds 5a–h produced compounds

6a–h. The results of the antimycobacterial activity are

quite interesting because all of these compounds have

shown inhibition above 96%. Compounds 6a–h were se-

lected for further studies as they have a free amino

group, which opened an area for further modiﬁcation

at this point. Compounds 7a–x were obtained by treat-

ment with acid chlorides, which ultimately showed de-

creased antimycobacterial activity. Furthermore,

compounds 6a–h was converted to Schiﬀ bases with

benzaldehyde, and on investigation all 8a–h have shown

more than 95% inhibition. More interestingly, com-

pounds 8f and 8g were the only ones, which have shown

good activity in secondary screening. Compounds 9a–h

were found to be inactive.

4. Experimental

4.1. General

The melting points were recorded on electrothermal

apparatus and are uncorrected. H NMR spectra were

1

recorded on a Bruker Avance 300 MHz instrument

using CDCl₃as solvent using TMS as internal standard;

the chemical shifts (d) are reported in ppm and coupling

constants (J) are given in Hz. Signal multiplicities are

represented by s (singlet), d (doublet), t (triplet), ds

(double singlet), dd (double doublet), m (multiplet)

and br s (broad singlet). Mass spectra were recorded

on a Finning LCQ mass spectrometer. Microwave irra-

diation was carried out in Raga Scientiﬁc Microwave

Systems, Model RG31L at 2450 MHz. Elemental analy-

ses were performed on a Heracus CHN-Rapid Analyser.

Analyses indicated by the symbols of the elements of

functions were within /0.4% of the theoretical values.

The purity of the compounds was checked on Merck

precoated silica gel 60 F-254.

4.2. Preparation of N-{4-[(4-amino-5-sulfanyl-4H-1,2,4-tria-

zol-3-yl)methyl]-1,3-thiazol-2-yl}-2-chloro acetamide (1a), N-

{4-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-1,3-

thiazol-2-yl}-acetamide (1b), N-{4-[(4-amino-5-sulfanyl-4H-

1,2,4-triazol-3-yl)methyl]-1,3-thiazol-2-yl}-benzamide (1c), 3-

{N-(4-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-

1,3-thiazol-2-yl}-amino)}-propanoic acid (1d)

All the compounds that were active in the ﬁrst level

screening were then tested to determine the actual min-

imum inhibitory concentration (MIC), wherein, com-

pounds 8f and 8g have been proven to be the most

active, with MIC values ranging from 0.39 to 0.78.

Above titled compounds were prepared as per the liter-

ature.²⁷The method of synthesis for compounds 2a–d,

3a–d, 4a–d, 5a–d, 6a–d, 7a–l, 8a–d and 9a–d was as per

the reported method.²⁸Synthetic routes of the newly

synthesized compounds are depicted in Scheme 1.

2.3. Antimicrobial activity

From the antibacterial screening it was observed that all

the compounds exhibited activity against all the organ-

isms employed. Looking at the structure–activity rela-

tionship, marked inhibition in bacteria was observed

in the compounds 8e, 8f and 8g, whereas 1b, 1c, 1d,

3c, 3h, 4b, 4c, 4d, 4e, 4g, 5d, 5e, 6c, 6d, 6e, 7f, 7m, 7n,

7r, 7x and 9h have shown moderate activity and others

showed least activity.

4.3. General preparation of N-[3-({2-[(substituted)amino]-

1,3-thiazol-4-yl}methyl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]-

3-nitrobenzamide (2e–h)

The triazole (1a–d) (0.01 mol) in 20 mL of 10% NaOH

was treated dropwise with an equimolar amount of the

3-nitrobenzoyl chloride at 0 ꢁC, which was stirred for

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

4001

N

S

CH₂

SH

O

SH

N

CH₂I₂

KI

N

ArCOCl

NaOH

N

HN

O

HN

NH₂

R

S

Ar

1a-d

Ar

2a-h

ClCH₂CN

Na₂CO₃

BrCH₂COOCH₃

NaOH

N

S

CN

N

3a-h

N

HN

O

R

S

SCH₂COOCH₃

N

Ar

4a-h

HN

O

R

S

Ar

5a-h

NH₂NH₂H₂O

ETHANOL

N

SCH₂CONHNH₂

O

N

HN

R

S

6a-h

Ar

C₆H₅CHO

CS₂/KOH, N₂H_4.H₂O

N

SCH₂CONHN=CHC₆H₅

O

R'COCl

N

HN

N

S

N

SH

N

R

N

HN

O

N

R

Ar

NH₂

S

Ar

8a-h

SCH₂CONHNHCOR'

O

N

9a-h

HN

R

S

Ar

7a-x

Scheme 1.

30–45 min. At the end of stirring a precipitate was ob-

served. The precipitate was then ﬁltered, washed thor-

oughly with water and crystallized.

4.3.2. N-[3-({2-[Acetyl-amino]-1,3-thiazol-4-yl}methyl)-5-

sulfanyl-4H-1,2,4-triazol-4-yl]-3-nitrobenzamide (2f).

Yield 77%; buﬀ white powder; mp 250–252 ꢁC; ¹H

NMR (300 MHz, CDCl₃), d (ppm): 2.12 (s, 3H, CH₃),

3.48 (s, 2H, CH₂), 4.27 (s, 4H, CH₂), 6.11 (s, 1H, thia-

zole CH), 7.26–7.41 (m, 4H, ArH), 8.12 (s, 2H, NH),

12.53 (s, 1H, SH); MS (%) 419 (M⁺, 100), 312 (29.6),

251 (9.8), 223 (15.1), 211 (10.8), 107 (14.7), 087 (10.1),

82 (7.6); Anal. calcd for C₁₅H₁₃N₇O₄S₂: C, 42.95; H,

3.12; N, 23.38. Found: C, 42.77; H, 3.23; N, 23.47.

4.3.1.

N-[3-({2-[(2-Chloroacetyl)amino]-1,3-thiazol-4-

yl}methyl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]-3-nitrobenza-

mide (2e). Yield 71%; yellow powder; mp 241–243 ꢁC;

¹H NMR (300 MHz, CDCl₃), d (ppm): 3.74 (s, 2H,

CH₂), 4.13 (s, 2H, CH₂), 6.21 (s, 1H, thiazole CH),

7.12–7.36 (m, 4H, ArH), 8.06 (s, 2H, NH), 12.31 (s,

1H, SH); MS (%) 453 (M⁺, 100), 323 (33.8), 309

(17.4), 248 (14.7), 247 (29.8), 233 (9.8), 220 (10.8), 180

(10.1), 095 (15.1), 86 (9.3); Anal. calcd for

C₁₅H₁₂ClN₇O₄S₂: C, 39.69; H, 2.66; N, 21.60. Found:

C, 39.84; H, 2.79; N, 21.85.

4.3.3. N-[3-({2-[Benzoyl-amino]-1,3-thiazol-4-yl}methyl)-

5-sulfanyl-4H-1,2,4-triazol-4-yl]-3-nitrobenzamide (2g).

1

Yield 76%; yellow powder; mp 280–282 ꢁC; H NMR

(300 MHz, CDCl₃), d (ppm): 3.32 (s, 2H, CH₂), 4.18

4002

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

(s, 2H, CH₂), 6.17 (s, 1H, thiazole CH), 7.21–7.86 (m,

9H, ArH), 8.13 (s, 2H, NH), 12.13 (s, 1H, SH); MS

(%) 481 (M⁺, 80), 306 (28), 292 (8.4), 251 (20), 214

(100), 195 (15), 154 (7), 106 (65); Anal. calcd for

C₂₀H₁₅N₇O₄S₂: C, 49.89; H, 3.14; N, 20.36. Found: C,

49.74; H, 3.29; N, 20.51.

274–276 ꢁC; ¹H NMR (300 MHz, CDCl₃), d (ppm): 3.73

(s, 4H, CH₂), 4.43 (s, 2H, CH₂), 6.27 (s, 2H, thiazole

CH), 7.13–7.80 (m, 19H, ArH), 8.16 (s, 4H, NH); MS

(%) 930 (M⁺, 14.1), 724 (15.7), 616 (14.3), 601 (100),

542 (23.5), 465 (3.9) 421 (13.2), 312 (5.8), 279 (7.2),

263 (11.0), 257 (11.7), 256(35.8), 216 (32.8), 91 (22), 83

(27.1), 69 (29.6); Anal. calcd for C₄₁H₃₀N₁₄O₈S₄: C,

50.51; H, 3.10; N, 20.11. Found: C, 50.68; H, 3.35; N,

20.38.

4.3.4. 3-{N-[(4-[(4-(3-Nitrobenzoylamino)-5-sulfanyl-4H-

1,2,4-triazol-3-yl)methyl]-1,3-thiazol-2-yl}-aminopropa-

noic acid (2h). Yield 69%; yellow powder; mp 271–

1

273 ꢁC; H NMR (300 MHz, CDCl₃), d (ppm): 2.46–

4.4.4. 3-[4-(4-(3-Nitrobenzoylamino)-5-[([4-(3-nitrobenzoyla-

mino)-5-(2-[(2-carboxy-ethyl)amino]-1,3-thiazol-4-ylmethyl)-

4H-1,2,4-triazol-3-yl]sulfanylmethyl)sulfanyl]-4H-1,2,4-

triazol-3-ylmethyl)-1,3-thiazol-2-yl]amino propanoic acid

(3h). Yield 89%; yellow powder; mp 255–257 ꢁC; ¹H

NMR (300 MHz, CDCl₃), d (ppm): 2.21–2.30 (t, 4H,

CH₂, J = 4.5 Hz), 3.28–3.35 (q, 4H, CH₂, J = 7.4 Hz),

3.76 (s, 4H, CH₂), 4.01–4.12 (t, 2H, NH, J = 7.9 Hz),

4.63 (s, 2H, CH₂), 6.2–6 (s, 2H, thiazole CH), 7.32–

7.76 (m, 9H, ArH), 8.21 (s, 4H, NH), 10.65 (br s, 2H,

OH); MS (%) 866 (M⁺,13.6), 791 (100), 725 (40.9), 693

(6), 578 (7.3), 512 (4.1), 472 (13.6), 371 (5), 356 (3.4),

283 (13.7), 269 (6.4), 155 (14.4); Anal. calcd for

C₃₅H₃₀N₁₄O₁₂S₄: C, 43.47; H, 3.13; N, 20.28. Found:

C, 43.54; H, 3.27; N, 20.41.

2.51 (t, 2H, CH₂, J = 4.3 Hz), 3.33–3.39 (q, 2H, CH₂,

J = 7.6 Hz), 4.01–4.11 (t, 1H, NH, J = 8.1), 4.32 (s,

2H, CH₂), 6.27 (s, 1H, thiazole CH), 7.43–7.62 (m,

4H, ArH), 8.16 (s, 1H, NH), 10.43 (br s, 1H, OH),

12.43 (s, 1H, SH); MS (%) 449 (M⁺, 100), 323 (14),

309 (17.1), 280 (6), 134 (35.9); Anal. calcd for

C₁₆H₁₅N₇O₅S₂: C, 42.76; H, 3.36; N, 21.81. Found: C,

42.58; H, 3.17; N, 21.56.

4.4. General preparation of N,N⁰-(methylenebis{sulfane-

dial-[5-({2-[(substituted)amino]-1,3-thiazol-4-yl}methyl)-

4H-1,2,4-triazole-3,4-dial]})-di-3-nitrobenzamide (3e–h)

The triazole (2e–h) (0.01 mol), diiodomethane (0.01 mol)

and 5.6 g (0.01 mol) potassium hydroxide were dissolved

in 20 mL of dichloromethane. To the said mixture acidic

alumina (20 g) was added. Dichloromethane was evapo-

rated in vacuo, and mixture was kept inside the alumina

bath and irradiated for 5–6 min at the power level of

300 W. The mixture was cooled. The solid thus sepa-

rated was dissolved in hot ethanol and ﬁltered. After

cooling, the ﬁltrate gave the product as crystals.

4.5. General preparation of N-{3-({2-[(substituted)amino]-

1,3-thiazol-4-yl}methyl)-5-[(cyanomethyl)sulfanyl]-4H-

1,2,4-triazol-4-yl}-3-nitrobenzamide (4e–h)

The triazole (2e–h) (0.01 mol) was mixed with 1.2 mL

(0.02 mol) of chloroacetonitrile and dissolved in 25 mL

of water. Neutralization with sodium carbonate gave a

precipitate. The precipitate was ﬁltered, washed with

cold water (2 · 20 mL) and crystallized.

4.4.1. N,N⁰-(Methylenebis{sulfanedial-[5-({2-[(chloroace-

tyl)amino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-triazole-3,4-

dial]})-di-3-nitrobenzamide (3e). Yield 84%; yellow pow-

4.5.1. N-{3-({2-[(Chloroacetyl)amino]-1,3-thiazol-4-yl}-

methyl)-5-[(cyanomethyl)sulfanyl]-4H-1,2,4-triazol-4-yl}-

3-nitrobenzamide (4e). Yield 86%; yellow powder; mp 241–

1

der; mp 278–280 ꢁC; H NMR (300 MHz, CDCl₃), d

(ppm): 3.34 (s, 4H, CH₂), 4.19 (s, 4H, CH₂), 4.58 (s,

2H, CH₂), 6.27 (s, 2H, thiazole CH), 7.13–7.62 (m,

9H, ArH), 7.84 (s, 4H, NH); MS (%) 874 (M⁺, 7.1),

679 (27.5), 622 (5.5), 607 (100), 516 (3.4), 484 (4.7) 453

(8.2), 347(9.6), 234 (10.3), 185(13.8), 146(8.7), 123

(13.2), 104 (10.5), 87 (26.8), 78 (40); Anal. calcd for

C₃₁H₂₄Cl₂N₁₄O₈S₄: C, 40.48; H, 2.63; N, 21.32. Found:

C, 40.62; H, 2.47; N, 21.52.

1

243 ꢁC; H NMR (300 MHz, CDCl₃), d (ppm): 3.74 (s,

2H, CH₂), 4.17 (s, 2H, CH₂), 4.32 (s, 2H, CH₂), 6.26 (s,

2H, thiazole CH), 7.11–7.32 (m, 4H, ArH), 8.24 (s, 2H,

NH); MS (%) 493 (M⁺, 100), 384 (21.9), 369 (20.6), 272

(34.2), 270 (40.8), 256 (17.9), 83 (28.9), 69 (16.1), 55

(11.3); Anal. calcd for C₁₇H₁₃ClN₈O₄S₂: C, 41.42; H,

2.66; N, 22.73. Found: C, 41.63; H, 2.71; N, 22.64.

4.4.2. N,N⁰-(Methylenebis{sulfanedial-[5-({2-[(acetyl)ami-

no]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-triazole-3,4-dial]})-

di-3-nitrobenzamide (3f). Yield 77%; yellow powder; mp

262–264 ꢁC¹H NMR (300 MHz, CDCl₃), d (ppm): 2.70

(s, 6H, CH₃), 4.34 (s, 4H, CH₂), 4.64 (s, 2H, CH₂),

5.93 (s, 2H, thiazole CH), 7.21–7.55 (m, 9H, ArH),

8.15 (s, 4H, NH); MS (%) 806 (M⁺, 35.9), 709 (11.1),

659 (13.2), 667 (23.6), 619 (100), 541 (3.6), 454 (3.7)

419 (9.8), 307 (8.2), 277 (8.1), 254 (11.9), 241 (15.4),

223(35.8), 216 (24.9), 91 (23.8), 83 (54.2), 69 (25.7);

Anal. calcd for C₃₁H₂₆N₁₄O₈S₄: C, 43.76; H, 3.08; N,

23.05. Found: C, 43.88; H, 3.24; N, 23.16.

4.5.2. N-{3-({2-[(Acetyl)amino]-1,3-thiazol-4-yl}methyl)-

5-[(cyanomethyl)sulfanyl]-4H-1,2,4-triazol-4-yl}-3-nitrob-

enzamide (4f). Yield 82%; yellow powder; mp 264–266 ꢁC;

¹H NMR (300 MHz, CDCl₃), d (ppm): 2.31 (s, 3H,

COCH₃), 3.62 (s, 2H, CH₂), 4.04 (s, 2H, CH₂), 6.18 (s,

1H, thiazole CH), 7.17–7.39 (m, 4H, ArH), 7.91 (s, 2H,

NH); MS (%) 458 (M⁺, 100), 384 (21.9), 369 (20.6), 272

(34.2), 270 (40.8), 256 (17.9), 83 (28.9), 69 (16.1), 55

(11.3); Anal. calcd for C₁₇H₁₄N₈O₄S₂: C, 44.54; H, 3.08;

N, 24.44. Found: C, 44.73; H, 3.19; N, 24.62.

4.5.3. N-{3-({2-[(Benzoyl)amino]-1,3-thiazol-4-yl}methyl)-

5-[(cyanomethyl)sulfanyl]-4H-1,2,4-triazol-4-yl}-3-nitrob-

enzamide (4g). Yield 81%; yellow powder; mp 267–

4.4.3.

N,N⁰-(Methylenebis{sulfanedial-[5-({2-[(benzoyl)-

1

amino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-triazole-3,4-dial]})-

di-3-nitrobenzamide (3g). Yield 79%; yellow powder; mp

269 ꢁC; H NMR (300 MHz, CDCl₃), d (ppm): 3.73 (s,

2H, CH₂), 4.14 (s, 2H, CH₂), 6.24 (s, 1H, Thiazole

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

4003

CH), 7.41–7.83 (m, 9H, ArH), 8.24 (s, 2H, NH); MS (%)

520 (M⁺, 93.3), 430 (10.9), 419 (4.1), 356 (31), 273 (46),

272 (100), 271 (14.3), 256 (9.3), 228 (4.4), 217 (3.2), 189

(3.6), 124 (8.9), 109 (5.8), 81 (4.5), 53 (3); Anal. calcd for

C₂₂H₁₆N₈O₄S₂: C, 50.76; H, 3.10; N, 21.53. Found: C,

50.81; H, 3.26; N, 21.44.

CH of thiazole), 6.93–7.51 (m, 9H, ArH), 8.22 (br, 2H,

NH); MS (%) 553 (69.9, M⁺), 356 (54), 354 (43), 248 (100),

233 (39), 232 (15); Anal. calcd for C₂₃H₁₉N₇O₆S₂: C,

49.90; H, 3.46; N, 17.71. Found: C, 49.79; H, 3.33; N, 17.86.

4.6.4. 3-{N-[4-(4-(3-Nitrobenzoylamino)-5-[(2-methoxy-

2-oxoethyl)sulfanyl]-4H-1,2,4-triazol-3-ylmethyl)-1,3-

thiazol-2-yl]amino} propanoic acid (5h). Yield 79%; yel-

low microcrystals; mp above 300 ꢁC; ¹H NMR (300

MHz, CDCl₃), d (ppm): 2.30–2.41 (q, 2H, CH₂, J =

4.0 Hz), 3.18–3.23 (t, 2H, CH₂, J = 7.3 Hz), 3.46 (s,

3H, OCH₃), 3.61 (s, 2H, CH₂), 3.93 (s, 2H, SCH₂),

4.11–4.18 (t, 1H, NH, J = 7.9 Hz), 6.26 (s, 1H, CH of

thiazole), 7.25–7.61 (m, 4H, ArH), 8.29 (br, 1H, NH),

11.13 (br, 1H, OH); MS (%) 521 (M⁺, 100), 379 (67),

309 (41), 272 (58),131 (16), 120 (60), 117 (44), 94 (27),

91(48), 84 (81); Anal. calcd for C₁₉H₁₉N₇O₇S₂: C,

43.76; H, 3.67; N, 18.80. Found: C, 43.57; H, 3.86; N, 18.91.

4.5.4. 3-{N-[4-(4-(3-nitrobenzoylamino)-5-[(cyanometh-

yl)sulfanyl]-4H-1,2,4-triazol-3-ylmethyl)-1,3-thiazol-2-

yl]amino} propanoic acid (4h). Yield 78%; yellow powder;

1

mp 275–277 ꢁC; H NMR (300 MHz, CDCl₃), d (ppm):

2.43–2.48 (t, 2H, CH₂, J = 4.1 Hz), 3.31–3.37 (q, 2H,

CH₂, J = 7.3 Hz), 3.84 (s, 2H, CH₂), 4.11–4.18 (t, 1H,

NH, J = 7.8 Hz), 4.34 (s, 2H, CH₂), 6.26 (s, 1H, Thiazole

CH), 7.22–7.43 (m, 4H, ArH), 8.25 (s, 1H, NH), 10.84 (br

s, 1H, OH); MS (%) 488 (M⁺, 56.8), 362 (100) 351 (6.9),

349 (16), 348 (12.8), 347 (26.8), 337 (9.7), 331 (12.4), 323

(9.7), 256 (8.8); Anal. calcd for C₁₈H₁₆N₈O₅S₂: C, 44.26;

H, 3.30; N, 22.94. Found: C, 44.42; H, 3.49; N, 22.77.

4.7. General preparation of N-{3-({2-[(substituted)amino]-

1,3-thiazol-4-yl}methyl)-5-[(2-hydrazino-2-oxoethyl)sul-

fanyl]-4H-1,2,4-triazol-4-yl}-3-nitrobenzamide (6e–h)

4.6. General preparation of methyl{[4-(3-nitrobenzoyla-

mino)-5-({2-[(chloroacetyl) amino]-1,3-thiazol-4-yl}methyl)-

4H-1,2,4-triazol-3-yl]sulfanyl} acetate (5e–h)

A solution of (5e–h) (0.01 mol) with 5 mL (0.01 mol)

hydrazine hydrate (98%) was prepared in 10 mL etha-

nol. To this, acidic alumina (10 g) was added. Ethanol

then was evaporated in vacuo, and mixture was kept in-

side the alumina bath and irradiated for 5–6 min at the

power level of 300 W. The mixture was cooled and the

product was extracted with ether. Ether was distilled

oﬀ and product thus obtained was crystallized from n-

hexane-carbon tetrachloride mixture.

A solution of triazole (2e–h) (0.01 mol), 0.4 g (0.01 mol)

of sodium hydroxide and methyl bromoacetate 1.53 g

(0.01 mol) was prepared. To this, acidic alumina was

added in 1:5 equivalent of triazole. The reaction mixture

was mixed, and mixture was kept inside the alumina

bath and irradiated for 4–5 min at the power level of

300 W. The mixture was cooled and poured on ice.

The solid thus separated was extracted with hot ethanol,

ﬁltered. After cooling, ﬁltrate gave almost pure product.

4.7.1.

N-{3-({2-[(Chloroacetyl)amino]-1,3-thiazol-4-yl}-

4.6.1. Methyl{[4-(3-nitrobenzoylamino)-5-({2-[(chloroace-

tyl)amino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-triazol-3-yl]sul-

fanyl} acetate (5e). Yield 82%; yellow microcrystals; mp

259–251 ꢁC; ¹H NMR (300 MHz, CDCl₃), d (ppm): 2.11

(s, 3H, OCH₃), 3.81 (s, 2H, CH₂), 3.89 (s, 2H, SCH₂),

4.28 (s, 2H, CH₂Cl), 6.32 (s, 1H, CH of thiazole), 7.20-

7.46 (m, 4H, ArH), 8.32 (br, 2H, NH); MS (%) 526 (M⁺,

100), 417 (14), 386 (12.3), 385 (11.3), 373 (7.2), 316 (7.7),

279 (79), 278 (10), 363 (8.2), 262 (19.5), 248 (7.7), 234

(7.9), 222 (10.5), 220 (5.7), 250 (31.6); Anal. calcd for

C₁₈H₁₆ClN₇O₆S₂: C, 41.11; H, 3.06; N, 18.64. Found:

C, 41.28; H, 3.18; N, 18.79.

methyl)-5-[(2-hydrazino-2-oxoethyl)sulfanyl]-4H-1,2,4-

triazol-4-yl}-3-nitrobenzamide (6e). Yield 83%; beige pow-

der; mp 245–247 ꢁC; H NMR (300 MHz, CDCl₃), d

(ppm): 2.13 (d, 2H, NH₂, J = 6.5 Hz), 3.64 (s, 2H, CH₂Cl),

3.94 (s, 2H, SCH₂), 4.07–4.15 (t, 1H, NH, J = 4.3 Hz),

6.65 (s, 1H, CH of thiazole), 7.22–7.48 (m, 4H, ArH),

8.21 (br, 2H, NH); MS (%) 526 (65, M⁺), 419 (69), 386

(145), 356 (61), 328 (78), 311 (8.4), 269 (24), 235 (100),

201 (13), 184 (18), 156 (53), 124 (25), 89 (49); Anal. calcd

for C₁₇H₁₆N₉O₅S₂: C, 38.82; H, 3.07; N, 73.97. Found: C,

38.96; H, 3.24; N, 74.11.

1

4.7.2. N-{3-({2-[(Acetyl)amino]-1,3-thiazol-4-yl}methyl)-

5-[(2-hydrazino-2-oxoethyl)sulfanyl]-4H-1,2,4-triazol-4-

yl}-3-nitrobenzamide (6f). Yield 82%; beige powder; mp

250–252 ꢁC; ¹H NMR (300 MHz, CDCl₃), d (ppm):

2.16 (d, 2H, NH₂, J = 6.5 Hz), 2.32 (s, 3H, CH₃), 3.67

(s, 2H, CH₂), 3.81 (s, 2H, SCH₂), 4.15–4.31 (t, 1H,

NH, J = 4.5 Hz), 6.69 (s, 1H, CH of thiazole), 7.45–

7.71 (m, 4H, ArH), 8.12 (br, 2H, NH); MS (%) 492

(78, M⁺), 390 (72), 321 (26.3), 247 (6.3), 215 (18.3),

174 (65.3), 136 (25), 88 (100), 69 (14.3); Anal. calcd for

C₁₇H₁₇N₉O₅S₂: C, 41.54; H, 3.49; N, 25.65. Found: C,

41.67; H, 3.31; N, 25.87.

4.6.2. Methyl{[4-(3-nitrobenzoylamino)-5-({2-[(acetyl)a-

mino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-triazol-3-yl]sul-

fanyl} acetate (5f). Yield 78%; yellow microcrystals; mp

261–263 ꢁC; ¹H NMR (300 MHz, CDCl₃), d (ppm): 2.17

(s, 3H, OCH₃), 3.52 (s, 3H, COCH₃), 3.74 (s, 2H, CH₂),

3.92 (s, 2H, SCH₂), 6.46 (s, 1H, CH of thiazole), 7.17–

7.38 (m, 4H, ArH), 8.13 (br, 2H, NH); MS (%) 492 (M⁺,

9), 387 (31), 337 (1), 323 (2), 309 (1), 273 (100), 272 (8);

Anal. calcd for C₁₈H₁₇N₇O₆S₂: C, 43.99; H, 3.49; N,

19.95. Found: C, 43.78; H, 3.63; N, 19.74.

4.6.3.

Methyl{[4-(3-nitrobenzoylamino)-5-({2-[(benzoyl)-

amino]-1,3-thiazol-4-yl} methyl)-4H-1,2,4-triazol-3-yl]sulfa-

nyl} acetate (5g). Yield 75%; yellow microcrystals; mp 226–

228 ꢁC; ¹H NMR (300 MHz, CDCl₃), d (ppm): 3.32 (s, 3H,

OCH₃), 3.62 (s, 2H, CH₂), 3.83 (s, 2H, SCH₂), 6.25 (s, 1H,

4.7.3. N-{3-({2-[(Benzoyl)amino]-1,3-thiazol-4-yl}methyl)-

5-[(2-hydrazino-2-oxoethyl)sulfanyl]-4H-1,2,4-triazol-4-yl}-

3-nitrobenzamide (6g). Yield 71%; beige powder; mp

222–224 ꢁC; ¹H NMR (300 MHz, CDCl₃), d (ppm):

4004

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

2.11 (d, 2H, NH₂, J = 6.5 Hz), 3.38 (s, 2H, CH₂), 3.76 (s,

2H, SCH₂), 4.12–4.39 (t, 1H, NH, J = 4.1 Hz), 6.11 (s,

1H, CH of thiazole), 7.13–7.68 (m, 9H, ArH), 8.10 (br,

2H, NH); MS (%) 553 (89, M⁺), 486 (31), 421 (60),

378 (14.3), 352 (45), 305 (24), 241 (73), 208 (56), 174

(66), 146 (100), 109 (18), 88 (15); Anal. calcd for

C₂₂H₁₉N₉O₅S₂: C, 47.73; H, 3.46; N, 22.77. Found: C,

47.86; H, 3.64; N, 22.90.

533 (97, M⁺), 408 (62), 398 (17.2), 359 (9.1), 327 (74),

297 (54), 241 (8.3), 223 (100), 174 (24), 146 (27); Anal.

calcd for C₁₉H₁₉N₉O₆S₂: C, 42.77; H, 3.59; N, 23.63.

Found: C, 42.94; H, 3.75; N, 23.84.

4.8.3. N-[3-{[2-(2-Acetylhydrazino)-2-oxoethyl]sulfanyl}-

5-({2-[(benzoyl)amino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-

triazol-4-yl]-3-nitrobenzamide (7o). Yield 82%; yellow

microcrystals; mp 226–231 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 2.03 (s, 3H, CH₃), 3.21 (s, 2H, CH₂),

4.7.4. 3-{N-[4-(4-(3-Nitrobenzoylamino)-5-[(2-hydrazino-

2-oxoethyl)sulfanyl]-4H-1,2,4-triazol-3-ylmethyl)-1,3-

thiazol-2-yl]amino}propanoic acid (6h). Yield 84%; beige

3.45 (s, 2H, SCH₂), 4.24–4.31 (dd, 2H, J_NH–NH

=

4.30 Hz, J_NH–NH= 4.70 Hz), 6.76 (s, 1H, thiazole CH),

7.31–7.87 (m, 9H, ArH), 8.42 (s, 2H, NH); MS (%)

595 (11, M⁺), 507 (56), 467 (35), 423 (16), 374 (52),

329 (47), 276 (74), 223 (100), 164 (35), 151 (08); Anal.

calcd for C₂₄H₂₁N₉O₆S₂: C, 48.40; H, 3.55; N, 21.16.

Found: C, 48.63; H, 3.72; N, 21.30.

1

powder; mp 243–245 ꢁC; H NMR (300 MHz, CDCl₃),

d (ppm): 2.13 (d, 2H, NH₂, J = 6.1 Hz), 2.27–2.31 (q,

2H, CH₂, J = 4.2 Hz), 3.16–3.27 (t, 2H, CH₂,

J = 7.1 Hz), 3.46 (s, 2H, CH₂), 3.84 (s, 2H, SCH₂),

4.23–4.45 (t, 2H, NH, J = 4.1 Hz, J = 8.1 Hz), 6.14 (s,

1H, CH of thiazole), 7.34–7.61 (m, 4H, ArH), 8.03 (br,

1H, NH), 11.09 (br, 1H, OH); MS (%) 521 (93.3, M⁺),

435 (32), 389 (22), 334 (56.4), 306 (28), 247 (64), 217

(100), 147 (83), 108 (71), 79 (10.2); Anal. calcd for

C₁₈H₁₉N₉O₆S₂: C, 41.45; H, 3.67; N, 24.77. Found: C,

41.63; H, 3.74; N, 24.91.

4.8.4. 3-[N-(4-[5-[2-(2-Acetylhydrazino)-2-oxoethyl]sulfa-

nyl-4-(-3-nitrobenzoylamino)-4H-1,2,4-triazol-3-yl]methyl-

1,3-thiazol-2-yl)amino]propanoic acid (7p). Yield 87%;

yellow microcrystals; mp 239–242 ꢁC; ¹H NMR

(300 MHz, CDCl₃), d (ppm): 2.11 (s, 3H, CH₃), 2.31–

2.37 (q, 2H, CH₂, J = 4.7 Hz), 3.20–3.26 (t, 2H, CH₂,

J = 7.3 Hz), 3.53 (s, 2H, CH₂), 3.79 (s, 2H, SCH₂),

4.12-4.20 (dd, 2H, J_NH–NH= 4.4 Hz, J_NH–NH= 4.6 Hz),

6.39 (s, 1H, thiazole CH), 7.11–7.42 (m, 4H, ArH), 8.27

(s, 2H, NH) 11.13 (br, 1H, OH); MS (%) 563 (64, M⁺),

476 (33), 438 (19), 387 (43), 341 (51), 317 (21), 264 (36),

224(100), 151 (16), 138 (67); Anal. calcd for

C₂₀H₂₁N₉O₇S₂: C, 42.62; H, 3.76; N, 22.37. Found: C,

42.76; H, 3.83; N, 22.54.

4.8. General preparation of N-[3-{[2-(substituted-hydra-

zino)-2-oxoethyl]sulfanyl}-5-({2-[(substituted)amino]-1,3-

thiazol-4-yl}methyl)-4H-1,2,4-triazol-4-yl]-3-nitro-benz-

amide (7m–x)

To a solution of (6e–h) (0.01 mol) in dichloromethane

(excess amount), appropriate acid chloride (0.01 mol)

was added dropwise with constant vigorous stirring.

After 25 min. of stirring, acidic alumina (10 g) was

added. Dichloromethane then was evaporated in vacuo,

and mixture was kept inside the alumina bath and irra-

diated for 5–6 min at the power level of 300 W. The mix-

ture was cooled and the product was extracted with

ether. Ether was distilled oﬀ and product thus obtained

was crystallized from n-hexane-carbon tetrachloride

mixture.

4.8.5.

N-[3-{[2-(2-Benzoylhydrazino)-2-oxoethyl]sulfa-

nyl}-5-({2-[(chloroacetyl)amino]-1,3-thiazol-4-yl}methyl)-

4H-1,2,4-triazol-4-yl]-3-nitro benzamide (7q). Yield 82%;

yellow microcrystals; mp 241–244 ꢁC; ¹H NMR

(300 MHz, CDCl₃), d (ppm): 3.34 (s, 2H, CH₂), 3.67

(s, 2H, SCH₂), 4.15–4.23 (dd, 2H, J_NH–NH= 4.23 Hz,

J_NH–NH= 4.46 Hz), 4.36 (s, 2H, CH₂Cl), 6.52 (s, 1H,

thiazole CH), 7.17–7.72 (m, 9H, ArH), 8.45 (s, 2H,

NH); MS (%) 630 (84, M⁺), 548 (17), 389 (26), 374

(46), 331 (58), 247 (14), 242 (13), 223 (100), 194 (29),

136 (21); Anal. calcd for C₂₄H₂₀ClN₉O₆S₂: C, 45.75;

H, 3.20; N, 20.01. Found: C, 45.88; H, 3.43; N, 20.18.

4.8.1. N-[3-{[2-(2-Acetylhydrazino)-2-oxoethyl]sulfanyl}-

5-({2-[(chloroacetyl)amino]-1,3-thiazol-4-yl}methyl)-4H-

1,2,4-triazol-4-yl]-3-nitrobenzamide (7m). Yield 86%; yel-

low microcrystals; mp 241–244 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 2.12 (s, 3 H, CH₃), 3.43 (s, 2H, CH₂),

3.74 (s, 2H, SCH₂), 4.11–4.20 (dd, 2H, J_NH–NH

=

4.8.6.

N-[3-{[2-(2-Benzoylhydrazino)-2-oxoethyl]sulfa-

4.21 Hz, J_NH–NH= 4.48 Hz), 4.54 (s, 2H, CH₂Cl), 6.63

(s, 1H, thiazole CH), 7.23–7.53 (m, 4H, ArH), 8.32 (s,

2H, NH); MS (%) 568 (56, M⁺), 489 (29), 462 (45),

408 (27), 389 (71), 318 (41), 274 (16), 223 (100), 188

(29), 179 (22); Anal. calcd for C₁₉H₁₈ClN₉O₆S₂: C,

40.18; H, 3.19; N, 22.19. Found: C, 40.34; H, 3.42; N,

22.27.

nyl}-5-({2-[(acetyl)amino]-1,3-thiazol-4-yl}methyl)-4H-

1,2,4-triazol-4-yl]-3-nitrobenzamide (7r). Yield 74%; yel-

low powder; mp 286–288 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 2.38 (s, 3H, CH₃), 3.68 (s, 2H, CH₂),

3.71 (s, 2H, SCH₂), 4.13–4.21 (dd, 2H, J_NH–NH

=

4.23 Hz, J_NH–NH= 4.54 Hz), 6.12 (s, 1H, thiazole CH),

6.94–7.21 (m, 9H, ArH), 8.09 (s, 2H, NH); MS (%)

595 (86, M⁺), 496 (71), 431 (14), 357 (78), 329 (38),

305 (41), 287 (17), 241 (35), 167 (100), 109 (37), 98

(19); Anal. calcd for C₂₄H₂₁N₉O₆S₂: C, 48.40; H, 3.55;

N, 21.16. Found: C, 48.58; H, 3.72; N, 21.34.

4.8.2. N-[3-{[2-(2-Acetylhydrazino)-2-oxoethyl]sulfanyl}-

5-({2-[(acetyl)amino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-

triazol-4-yl]-3-nitrobenzamide (7n). Yield 71%; yellow

microcrystals; mp 227–229 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 2.42 (s, 6H, CH₃), 3.74 (s, 2H, CH₂),

4.8.7.

N-[3-{[2-(2-Benzoylhydrazino)-2-oxoethyl]sulfa-

3.87 (s, 2H, SCH₂), 4.20–4.28 (dd, 2H, J_NH–NH

4.35 Hz, J_NH–NH= 4.76 Hz), 6.27 (s, 1H, thiazole CH),

7.11–7.32 (m, 4H, ArH), 8.18 (s, 2H, NH); MS (%)

=

nyl}-5-({2-[(benzoyl)amino]-1,3-thiazol-4-yl}methyl)-4H-

1,2,4-triazol-4-yl]-3-nitrobenzamide (7s). Yield 79%; yel-

low microcrystals; mp 229–233 ꢁC; ¹H NMR

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

4005

(300 MHz, CDCl₃), d (ppm): 3.16 (s, 2H, CH₂), 3.31 (s,

2H, SCH₂), 4.32–4.39 (dd, 2H, J_NH–NH= 4.37 Hz,

J_NH–NH= 4.74 Hz), 6.47 (s, 1H, thiazole CH), 7.11–

7.82 (m, 14H, ArH), 8.26 (s, 2H, NH); MS (%) 658

(91, M⁺), 587 (66), 526 (19), 471 (16), 436 (68), 376

(34), 316 (61), 223 (100), 111 (37), 119 (54); Anal. calcd

for C₂₉H₂₃N₉O₆S₂: C, 52.96; H, 3.52; N, 19.17. Found:

C, 52.79; H, 3.67; N, 19.33.

4.8.12. 3-[N-(4-[4-(3-Nitrobenzoylamino)-5-(2-[2-(2-chloro-

acetyl)hydrazino]-2-oxo-ethylsulfanyl)-4H-1,2,4-triazol-

3-yl]methyl-1,3-thiazol-2-yl)amino]propanoic acid (7x).

Yield 80%; yellow microcrystals; mp 237–239 ꢁC; ¹H

NMR (300 MHz, CDCl₃), d (ppm): 2.11–2.18 (q, 2H,

CH₂, J = 4.68 Hz), 3.23–3.29 (t, 2H, CH₂, J = 7.3 Hz),

3.53 (s, 2H, CH₂), 3.71 (s, 2H, SCH₂), 4.07–4.16 (dd,

2H, J_NH–NH= 4.4 Hz, J_NH–NH= 4.7 Hz), 4.23 (s, 2H,

CH₂Cl), 6.49 (s, 1H, thiazole CH), 7.12–7.19 (m, 4H,

ArH), 8.54 (s, 2H, NH) 11.17 (br, 1H, OH) ; MS (%)

598 (91, M⁺), 512 (69), 482 (12), 438 (89), 376 (73),

264 (58), 234 (76), 223 (100), 166 (28), 123 (21); Anal.

calcd for C₂₀H₂₀ClN₉O₇S₂: C, 40.17; H, 3.37; N,

21.08. Found: C, 40.34; H, 3.56; N, 21.24.

4.8.8. 3-{N-(4-[(4-(3-Nitrobenzoylamino)-5-[2-(2-benzoylhyd-

razino)-2-oxoethyl]sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-1,3-

thiazol-2-yl)amino}propionic acid (7t). Yield 83%; yellow

microcrystals; mp 230–235 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 2.21–2.29 (q, 2H, CH₂, J = 4.5 Hz),

3.14–3.21 (t, 2H, CH₂, J = 7.7 Hz), 3.62 (s, 2H, CH₂),

3.85 (s, 2H, SCH₂), 4.25–4.37 (dd, 2H, J_NH–NH

=

4.9. General procedure for N-[3-({2-[(2E)-2-benzylidenehyd-

razino]-2-oxoethyl}sulfanyl)-5-({2-[(substituted)amino]-1,3-

thiazol-4-yl}methyl)-4H-1,2,4-triazol-4-yl]-3-nitrobenzamide

(8e–h)

4.7 Hz, J_NH–NH= 4.9 Hz), 6.61 (s, 1H, thiazole CH),

7.26–7.35 (m, 9H, ArH), 8.32 (s, 2H, NH) 10.87 (br,

1H, OH) ; MS (%) 625 (97, M⁺), 542 (17), 505 (47),

486 (53), 451 (68), 364 (24), 307 (37), 223 (100), 197

(41), 164 (46); Anal. calcd for C₂₅H₂₃N₉O₇S₂: C,

47.99; H, 3.11; N, 20.15. Found: C, 48.17; H, 3.27;

N, 20.41.

A solution of (6e–h) (0.01 mol) with benzaldehyde

(0.01 mol) was prepared in 10 mL ethanol. To this,

acidic alumina (10 g) was added. Ethanol then was

evaporated in vacuo, and mixture was kept inside

the alumina bath and irradiated for 1 min at the

power level of 300 W. The mixture was cooled and

poured on ice. The solid thus separated was ﬁltered

and extracted with ether. Ether was distilled oﬀ and

product thus obtained was crystallized from hot

ethanol.

4.8.9. N-[3-{[2-(2-chloroacetylhydrazino)-2-oxoethyl]sulfa-

nyl}-5-({2-[(chloroacetyl)amino]-1,3-thiazol-4-yl}methyl)-4H-

1,2,4-triazol-4-yl]-3-nitro benzamide (7u). Yield 77%; yellow

microcrystals; mp 233–237 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 3.12 (s, 2H, CH₂), 3.38 (s, 2H, SCH₂),

4.21–4.33 (dd, 2H, J_NH–NH= 4.10 Hz, J_NH–NH= 4.52 Hz),

4.47 (s, 4H, CH₂Cl), 6.67 (s, 1H, thiazole CH), 7.25–7.56

(m, 4H, ArH), 8.24 (s, 2H, NH); MS (%) 602 (84, M⁺),

513 (46), 474 (13), 431 (68), 417 (49), 328 (42), 274 (12),

223 (100), 184 (18), 161 (34); Anal. calcd for

C₁₉H₁₇Cl₂N₉O₆S₂: C, 37.88; H, 2.84; N, 20.93. Found: C,

37.97; H, 2.98; N, 21.16.

4.9.1. N-[3-({2-[(2E)-2-Benzylidenehydrazino]-2-oxoethyl}sul-

fanyl)-5-({2-[(chloro-acetyl)amino]-1,3-thiazol-4-yl}methyl)-

4H-1,2,4-triazol-4-yl]-3-nitro benzamide (8e). Yield 81%;

1

brown powder; mp 222–224 ꢁC; H NMR (300 MHz,

CDCl₃), d (ppm): 3.77 (s, 2H, CH₂), 4.16 (s, 2H,

SCH₂), 4.13 (s, 2H, CH₂Cl), 6.22 (s, 1H, thiazole

CH), 7.30–7.62 (m, 9H, ArH), 8.16 (S, 3H, NH),

8.27 (S, 1H, N@CH); MS (%) 614 (69, M⁺), 502

(19), 457 (37), 379 (21), 315 (58), 246 (24), 195

(35), 134 (100), 107 (11.4), 88 (12.3); Anal. calcd

for C₂₄H₂₀ClN₉O₅S₂: C, 46.94; H, 3.28; N, 20.53.

Found: C, 46.73; H, 3.42; N, 20.65.

4.8.10. N-[3-{[2-(2-Chloroacetylhydrazino)-2-oxoethyl]sulfa-

nyl}-5-({2-[(acetyl)amino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-

triazol-4-yl]-3-nitrobenzamide (7v). Yield 57%; dark brown

microcrystals; mp 166–168 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 2.53 (s, 3H, CH₃), 3.81 (s, 2H,

CH₂), 3.92 (s, 2H, SCH₂), 4.17 (s, 2H, CH₂Cl), 4.28–

4.34 (dd, 2H, J_NH–NH= 4.52 Hz, J_NH–NH= 4.92 Hz),

6.41 (s, 1H, thiazole CH), 7.26–7.46 (m, 4H, ArH),

8.32 (s, 2H, NH); MS (%) 568 (54, M⁺), 487 (36), 437

(84), 369 (54.2), 284 (9.3), 238 (100), 158 (12), 128

(37), 77 (32); Anal. calcd for C₁₉H₁₈ClN₉O₆S₂: C,

40.18; H, 3.19; N, 22.19. Found: C, 40.32; H, 3.35; N,

22.36.

4.9.2. N-[3-({2-[(2E)-2-Benzylidenehydrazino]-2-oxoethyl}sul-

fanyl)-5-({2-[(acetyl)amino]-1,3-thiazol-4-yl}methyl)-

4H-1,2, 4-triazol-4-yl]-3-nitrobenzamide (8f). Yield 83%;

pale brown powder; mp 178–180 ꢁC; ¹H NMR

(300 MHz, CDCl₃), d (ppm): 2.32 (s, 3H, CH₃), 3.97

(s, 2H, CH₂), 4.21 (s, 2H, SCH₂), 6.25 (s, 1H, thiazole

CH), 7.31–7.65 (m, 9H, ArH), 8.26 (s, 3H, NH), 8.36

(s, 1H, N@CH); MS (%) 580 (94, M⁺), 519 (41), 487

(9.6), 431 (26), 413 (8.4), 389 (100), 365 (20); Anal.

calcd for C₂₄H₂₁N₉O₅S₂: C, 49.73; H, 3.65; N, 21.75.

Found: C, 49.54; H, 3.77; N, 21.86.

4.8.11. N-[3-{[2-(2-Chloroacetylhydrazino)-2-oxoethyl]sulfa-

nyl}-5-({2-[(benzoyl)amino]-1,3-thiazol-4-yl}methyl)-4H-

1,2,4-triazol-4-yl]-3-nitrobenzamide (7w). Yield 78%;

yellow microcrystals; mp 232–235 ꢁC; ¹H NMR

(300 MHz, CDCl₃), d (ppm): 3.27 (s, 2H, CH₂), 3.46(s,

2H, SCH₂), 4.13–4.22 (dd, 2H, J_NH–NH= 4.11 Hz,

J_NH–NH= 4.57 Hz), 4.41 (s, 2H, CH₂Cl), 6.39 (s, 1H,

thiazole CH), 7.29–7.63 (m, 9H, ArH), 8.41 (s, 2H,

NH); MS (%) 585 (79, M⁺), 621 (16), 513 (27), 415

(42), 384 (67), 306 (41), 264 (34), 223 (100), 167 (26),

144 (18); Anal. calcd for C₂₄H₂₀ClN₉O₆S₂: C, 45.75;

H, 3.20; N, 20.01. Found: C, 45.87; H, 3.39; N, 20.17.

4.9.3. N-[3-({2-[(2E)-2-Benzylidenehydrazino]-2-oxoethyl}sul-

fanyl)-5-({2-[(benzoyl)amino]-1,3-thiazol-4-yl}methyl)-4H-

1,2,4-triazol-4-yl]-3-nitro benzamide (8g). Yield 81%; yel-

low microcrystals; mp 217–219 ꢁC; ¹H NMR (300 MHz,

CDCl₃), d (ppm): 3.63 (s, 2H, CH₂), 4.17 (s, 2H, SCH₂),

6.23 (s, 1H, thiazole CH), 7.21–7.64 (m, 14H, ArH), 8.16

(s, 3H, NH), 8.41 (s, 1H, N@CH); MS (%) 642 (79, M⁺),

4006

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

521 (25), 455 (52), 413 (63), 368 (9.2), 308 (41), 284 (31),

242 (37), 178 (100), 128 (15.2), 97 (28), 87 (7.4); Anal.

calcd for C₂₉H₂₃N₉O₅S₂: C, 54.28; H, 3.61; N, 19.65.

Found: C, 54.43; H, 3.75; N, 19.80.

ArH), 8.08 (s, 2H, NH), 12.43 (s, 1H, SH); MS (%)

548 (76, M⁺), 454 (32), 350 (30), 335 (100), 323 (2.93),

222 (12.26), 220 (3.73), 207 (5.86), 192 (7.07); Anal.

calcd for C₁₈H₁₇N₁₁O₄S₃: C, 39.48; H, 3.13; N, 28.14.

Found: C, 39.64; H, 3.32; N, 28.31.

4.9.4. 3-{N-[4-(4-(3-Nitrobenzoylamino)-5-[(2-oxo-2-2-[(Z)-

1-benzylidene]hydrazino-ethyl)sulfanyl]-4H-1,2,4-triazol-3-

ylmethyl)-1,3-thiazol-2-yl]amino} propanoic acid (8h). Yield

78%; yellow microcrystals; mp 120–122 ꢁC; ¹H NMR

(300 MHz, CDCl₃), d (ppm): 2.65–2.71 (t, 2H, CH₂,

J = 4.7 Hz), 3.23-3.31 (q, 2H, CH₂, J = 7.5 Hz), 3.92 (s,

2H, CH₂), 4.17 (s, 2H, SCH₂), 4.32 (t, 1H, NH,

J = 8.3 Hz), 6.23 (s, 1H, Thiazole CH), 7.17–7.63 (m,

9H, ArH), 8.15 (s, 2H, NH), 8.32 (s, 1H, N=CH), 10.87

(br s, 1H, OH); MS (%) 609 (74, M⁺), 497 (45), 426

(13), 364 (63), 326 (32), 248 (65), 185 (12), 146 (100), 109

(37), 87 (42); Anal. calcd for C₂₅H₂₃N₉O₆S₂: C, 49.25;

H, 3.80; N, 20.68. Found: C, 49.11; H, 3.74; N, 20.57.

4.10.3. N-[3-{[(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-

triazol-3-yl)methyl]sulfanyl}-5-({2-[(benzoyl)amino]-1,3-

thiazol-4-yl}methyl)-4H-1,2,4-triazol-4-yl]-3-nitrobenza-

mide (9g). Yield 80%; cream microcrystals; mp 264–

266 ꢁC; ¹H NMR (300 MHz, CDCl₃), d (ppm): 2.41

(s, 2H, NH₂), 3.75 (s, 2H, CH₂), 4.34 (s, 2H, CH₂),

6.23 (s, 1H, thiazole CH), 7.14–7.74 (m, 9H, ArH),

8.17 (s, 2H, NH), 12.63 (s, 1H, SH); MS (%) 510

(93.3, M⁺), 513 (24), 476 (21), 432 (16), 421 (12), 323

(65), 308 (41), 289 (27), 230 (38), 207 (100), 142

(35.7), 109 (23); Anal. calcd for C₂₃H₁₉N₁₁O₄S₃: C,

45.31; H, 3.14; N, 25.27. Found: C, 45.50; H, 3.30;

N, 25.20.

4.10. General preparation of N-[3-{[(4-Amino-5-thioxo-4,5-

dihydro-1H-1,2,4-triazol-3-yl)methyl]sulfanyl}-5-({2-[(substi-

tuted)amino]-1,3-thiazol-4-yl}methyl)-4H-1,2,4-triazol-4-yl]-

3-nitrobenzamide (9e–h)

4.10.4. 3-[(4-[5-[(4-Amino-5-sulfanyl-4H-1,2,4-triazol-3-

yl)methyl]sulfanyl-4-(3-nitro

benzoylamino)-4H-1,2,4-

triazol-3-yl]methyl-1,3-thiazol-2-yl)amino] propanoic acid

(9h). Yield 77%; cream microcrystals; mp 237–239 ꢁC;

¹H NMR (300 MHz, CDCl₃), d (ppm): 2.13 (s, 2H,

NH₂), 2.46–2.49 (t, 2H, CH₂, J = 4.3 Hz), 3.14–3.20

(q, 2H, CH₂, J = 6.7 Hz), 3.98 (s, 2H, CH₂), 4.23–4.29

(t, 1H, NH, J = 7.3 Hz), 4.36 (s, 2H, CH₂), 6.26 (s,

1H, thiazole CH), 7.27–7.56 (m, 4H, ArH), 8.17 (s,

1H, NH), 10.64 (br s, 1H, OH), 12.35 (s, 1H, SH); MS

(%) 578 (84, M⁺), 497 (23), 450 (47), 438 (38), 371

(25), 370 (75), 354 (10), 235 (100), 220 (22), 207 (68),

192 (70); Anal. calcd for C₁₉H₁₉N₁₁O₅S₃: C, 39.51; H,

3.32; N, 26.67. Found: C, 39.36; H, 3.22; N, 26.51.

The compounds (6e–h) (0.01 mol) was dissolved in alco-

holic potassium hydroxide (0.01 mol) and kept for stir-

ring. Carbon disulﬁde (0.015 mol) was added dropwise

to the solution with stirring. Thick solid mass was ob-

tained, to which 50 mL of absolute alcohol was added.

Stirring was continued for 16 h. At the end of 16th-h

dry ether was added to the mixture. The precipitate (thi-

ocarbazate) obtained was taken immediately for the

next step.

A solution of thiocarbazate (0.01 mol) with hydrazine

hydrate (0.01 mol) was prepared in 10 mL ethanol. To

this, acidic alumina (10 g) was added. Ethanol then

was evaporated in vacuo, and mixture was kept inside

the alumina bath and irradiated for 5–6 min at the

power level of 300 W. The mixture was cooled and

poured on ice. The solid thus separated was ﬁltered

and extracted with ether. Ether was distilled oﬀ and

product thus obtained was crystallized from hot ethanol.

4.11. Pharmacological activity

4.11.1. Antitubercular activity. Primary screening was

conducted at 6.25 lg mL^ꢀ1against M. tuberculosis

H37Rv (ATCC 27294) in BACTEC 12B medium using

a broth microdilution assay, the Microplate Alamar

Blue Assay (MABA).²⁹Compounds exhibiting ﬂuores-

cence were tested in the BACTEC 460 radiometric sys-

tem.³⁰Compounds showing more than/95% inhibition

in the primary screening were considered active and

then re-tested at lower concentrations against M. tuber-

culosis H37Rv in order to determine the actual MIC,

using MABA. The MIC is deﬁned as the lowest con-

centration eﬀecting a reduction in ﬂuorescence of 95%

with respect to the controls. Rifampin (RMP) was used

as the reference compound (RMP MIC = 0.015–

0.125 mg mL^ꢀ1). We also have done cytotoxicity anal-

ysis of the above-synthesized compounds, using neutral

red uptake by using Vero-C-1008 cell line at various

concentrations (6.25 lg/mL to 50 lg/mL), none of them

were found toxic. Hence the activities of the above-syn-

thesized compounds were not due to cytotoxicity of

compounds.

4.10.1. N-[3-{[(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-tria-

zol-3-yl)methyl]sulfanyl}-5-({2-[(chloroacetyl)amino]-1,3-thia-

zol-4-yl}methyl)-4H-1,2,4-triazol-4-yl]-3-nitro-benzamide

1

(9e). Yield 72%; cream microcrystals; mp 228–230 ꢁC; H

NMR (300 MHz, CDCl₃), d (ppm): 2.16 (s, 2H, NH₂),

3.76 (s, 2H, CH₂), 4.07 (s, 2H, CH₂), 4.25 (s, 2H, CH₂Cl),

6.20 (s, 1H, Thiazole CH), 7.23–7.67 (m, 4H, ArH), 8.11 (s,

2H, NH), 12.49 (s, 1H, SH); MS (%) 582 (82, M⁺), 467

(31), 431 (26), 384 (31), 326 (13.2), 247 (15), 226 (17), 125

(100); Anal. calcd for C₁₈H₁₆ClN₁₁O₄S₃: C, 37.14; H,

2.77; N, 26.47. Found: C, 37.36; H, 2.86; N, 26.55.

4.10.2. N-[3-{[(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-tria-

zol-3-yl)methyl]sulfanyl}-5-({2-[(acetyl)amino]-1,3-thiazol-4-

yl}methyl)-4H-1,2,4-triazol-4-yl]-3-nitrobenzamide (9f).

Yield 71%; cream microcrystals; mp 252–254 ꢁC; ¹H

NMR (300 MHz, CDCl₃), d (ppm): 2.13 (s, 2H, NH₂),

2.35 (s, 3H, CH₃), 3.79 (s, 2H, CH₂), 4.14 (s, 2H,

CH₂), 6.19 (s, 1H, thiazole CH), 7.11–7.35 (m, 4H,

4.11.2. Antimicrobial activity. The compounds listed in

Tables 1 and 2 were screened for the antimicrobial activ-

ity against diﬀerent microorganisms under the following

conditions.

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

4007

Table 4. Antibacterial activity of the compounds 1a–d, 2a–h, 3a–h, 4a–

h, 5a–h, 6a–h, 7a–x, 8a–h and 9a–h

Table 4 (continued)

Compound

Organisms

Compound

Organisms

Sa

Pa

Ec

St

Sa

Pa

Ec

St

7u

7v

14

12

14

24

25

21

22

31

30

32

30

27

28

26

21

20

18

24

26

34

16

18

11

26

19

20

24

27

30

31

30

32

20

21

19

24

26

13

27

28

35

12

18

24

19

20

23

18

26

24

25

26

22

23

20

19

18

21

20

17

31

18

14

12

24

17

20

21

22

25

26

24

27

20

18

19

23

21

18

19

18

30

1a

1b

1c

1d

2a

2b

2c

2d

2e

2f

18

28

22

25

20

16

11

22

16

11

28

23

24

29

21

18

27

26

25

24

28

31

30

24

22

28

25

18

20

22

26

24

22

16

32

23

29

19

28

24

25

27

26

20

21

28

19

18

24

25

26

27

33

20

24

21

32

18

12

17

27

20

22

20

16

10

17

22

16

24

25

28

21

27

29

30

32

24

26

28

20

27

29

24

26

24

23

16

22

24

22

11

22

18

16

32

26

20

23

24

28

21

19

24

21

26

22

24

25

21

20

23

24

34

18

10

18

30

12

10

14

22

18

20

18

20

10

15

20

12

16

18

29

24

20

22

27

26

24

21

26

23

27

21

19

20

22

24

10

20

22

20

24

20

12

26

18

19

22

17

16

24

20

21

26

21

20

18

19

18

19

18

30

14

10

30

14

10

12

24

14

16

14

16

18

22

16

12

19

18

17

12

20

24

26

19

18

16

24

19

25

24

21

17

24

12

10

16

18

20

18

24

20

12

14

24

22

18

17

20

21

22

23

19

18

20

17

18

23

21

20

22

24

29

12

14

18

27

12

14

7w

7x

8a

8b

8c

8d

8e

8f

8g

8h

9a

9b

9c

2g

2h

3a

3b

3c

3d

3e

3f

9d

9e

9f

9g

9h

Gent

3g

3h

4a

4b

4c

4d

4e

4f

Sa: S. taphylococcus aureus, Ec: Escherichia coli, Pa: Pseudomonas

aeruginosa, St: Salmonella typhosa, Gent: Gentamycin.

Method: Well diﬀusion

method,³¹

Solvent: chloroform

Medium: the nutrient

agar medium,

Concentrations: 50 lM

and 100 lM

Standard: the antibiotic

4g

4h

5a

5b

5c

5d

5e

5f

Condition: 24 h at

24–28 ꢁC,

gentamycin

5g

5h

6a

6b

6c

6d

6e

6f

The nutrient agar medium, 20 mL, was poured into the

sterile petri dishes. To the solidiﬁed plates, wells were

made using a sterile cork borer 10 mm in diameter.

The 24-hour subcultured bacteria were inoculated in

the Petri-plates, with a sterile cotton swab dipped in

the nutrient broth medium. After inoculating, the com-

pounds were dissolved separately with the chloroform

solvent and poured into the wells with varying concen-

trations ranging from 50 to 100 lM using a micropi-

pette. The plates were left over for 24 h at 24–28 ꢁC.

The antibiotic Gentamycin was used as a standard for

comparative study Table 4.

6g

6h

7a

7b

7c

7d

7e

7f

The percentage of inhibition was calculated by the

formula

7g

7h

7i

% Inhibition ¼ Diameter of the inhibition zone ꢂ 100

7j

7k

7m

7n

7o

7p

7q

7r

7s

7t

Acknowledgments

Authors are thankful to Dr. K.G. Bothara, Principal,

AISSMS College of Pharmacy, Pune, India, for provid-

ing the facilities and Tuberculosis Antimicrobial Acqui-

sition and Coordinating Facility (TAACF) for the

antitubercular activity.

4008

M. R. Shiradkar et al. / Bioorg. Med. Chem. 15 (2007) 3997–4008

17. Aldo, A.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi,

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Synthesis of new S-derivatives of clubbed triazolyl thiazole as anti-Mycobacterium tuberculosis agents

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