# Synthesis and Evaluation of Some New Thiazolidin-4-One Derivatives as Potential Antimicrobial Agents

Authors: B. A. Baviskar; S. S. Khadabadi; S. L. Deore
Journal: Journal of Chemistry
 (2013)

---

## Abstract

A new series ofN-{4-methyl-5-[4-(4-oxo-2-phenyl(1,3-thiazolidin-3-yl)]-5-sulfanyl(1,2,4-triazol-3-yl)-1,3-thiazol-2-yl }acetamide (7a-l) was synthesized in order to determine their antimicrobial activity and feasible structure–activity relationships. The compounds were synthesized in good yield and the structures of all newly synthesized compounds were established on the basis of their IR, 1HNMR, and elemental analysis. The synthesized compounds were tested in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi and antifungal activity against Aspergillus niger, Candida albicans by measuring the zone of inhibition in mm.


---

## Body

## 1. Introduction

Heterocycles bearing nitrogen, sulphur, and thiazole moieties constitute the core structure of a number of biologically interesting compounds. Literature survey shows that thiazole derivatives play a very important role in biological fields such as antimicrobial [1–4], antidiabetic [5], antiviral [6], anti-inflammatory [7], antituberculosis [8], and anticancer [9] activities. 1,2,4-Triazole is among the various heterocycles that have received the most attention during the last two decades as potential antimicrobial agents [10–13]. Schiff base has good antimicrobial [14], and antifungal [15] activity, and it can be prepared by the acid-catalysed reaction of aldehyde or ketone and amines [16]. Thiazolidin-4-one [17] derivatives are known to exhibit diverse bioactivities such as antidiarrheal [18], anticonvulsant [19], antimicrobial [20–22], antidiabetic [23], antihistaminic [24], anticancer [25, 26], anti-HIV [27], cyclooxygenase inhibitory [28], antiplatelet activating factor [29–31]. Hence, it is thought of interest to accommodate thiazolidin-4-one and 2-amino benzothiazole moieties in single molecular framework and screen them for their antimicrobial activity. Today, the trend in antimicrobial drug design [32] is to clubbing two or three heterocyclic molecules having different sites or mechanisms of action, and this initiated our construction of compounds containing thiazole, triazole, and thiazolidin-4-one ring systems in the same matrix to serve as a new scaffold towards the development of novel antimicrobial agents. In view of these data, we aimed the synthesis of thiazolyltriazole-substituted thiazolidin-4-one as antimicrobial agents.


## 2. Result and Discussion

In this present work, a series of new compounds was synthesized. Thus, starting from the ethyl 2-amino-4-methylthiazole-5-carboxylate1 was synthesized as per reported procedure [33]. Ethyl 2-acetamido-4-methylthiazole-5-carboxylate (2), N-(5-(hydrazinecarbonyl)-4-methylthiazol-2-yl)acetamide (3), potassium dithiocarbazinate (4), N-(5-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)-4-methylthiazol-2-yl)acetamide (5), and N-(5-(4-(benzylideneamino)-5-mercapto-4H-1,2,4-triazol-3-yl)-4-methyl thiazol-2-yl)acetamide (6a–l) were prepared as per reported procedure [34]. The Schiff bases on cyclization with mercapto acetic acid in the presence of anhydrous 1,4-dioxane and triturated with an excess of 10% NaHCO3 solution furnished N-{4-methyl-5-[4-(4-oxo-2-phenyl(1,3-thiazolidin-3-yl)]-5-sulfanyl(1,2,4-triazol-3-yl)-1,3-thiazol-2-yl}acetamide (7a–l) as shown in Scheme 1. The structures of the various synthesized compounds were assigned on the basis of elemental analysis, IR, and 1HNMR spectral data. Spectral and analytical data of the title compounds (7a–l) are shown in Tables 1 and 2. The compounds are evaluated for their antimicrobial activity, and results are summaries in Table 3. From the antimicrobial screening, it was observed that all the compounds exhibited activity against all the organisms employed. Looking at the structure activity relationship, marked inhibition in bacteria was observed in the compounds bearing R = H–, 4-Cl–, 2-OH–, 4-OH–, 4-(CH3)2N–, 4-CH3– (7a, 7b, 7c, 7f, 7g, 7k) substitutions whereas compound (7d, 7e, 7h, 7i, 7j, 7l) showed moderate to good activity. Fungicidal screening data also revealed that compounds bearing R = H–, 4-Cl–, 4-(CH3)2N–, 3,4,5-(OCH3)3–, 4-Br–, 4-CH3– (7a, 7c, 7g, 7j, 7k) imparted maximum activity to the compounds, where as compounds (7b, 7d, 7e, 7f, 7h, 7i) showed moderate to good activity.Table 1
Spectral and analytical data of the title compounds(7a-l).
Compound
R
Molecular formula
Mol. wt.
Yield (%)
MP (°C)
Elemental analysis Calcd./(found)
IR (KBr, cm−1)
C
H
N
7a
–H
C17H15N6O2S3
432
72
96–98
47.21 (47.14)
3.73 (3.80)
19.43 (19.38)
3334 (NH), 2465 (S–H), 1742, 1728 (both C=O), 1620 (C=N str.), 1591 (C=C str.), 1349 (C–N), 688 (C–S–C str.)
7b
2-OH–
C17H16N6O3S3
448
65
195-194
45.52 (45.44)
3.60 (3.65)
18.74 (18.82)
3292 (Ph–OH Str.), 3234 (NH), 2460 (S–H), 1720, 1700 (both C=O), 1628 (C=N str.), 1598 (C=C str.), 1351 (C–N), 689 (C–S–C str.)
7c
4-Cl–
C17H15N6O2S2Cl
467
65
120–122
43.72 (43.67)
3.24 (3.28)
18.00 (18.07)
3290 (NH), 2458 (S–H), 1720, 1695 (both C=O), 1622 (C=N), 1600 (C=C str.), 1350 (C–N), 760 (C–Cl), 690 (C–S–C str.)
7d
3-NO2–
C17H15N7O4S2
477
68
208–210
42.76 (42.71)
3.17 (3.22)
20.53 (20.57)
3360 (NH), 2444 (S–H), 1700, 1689 (both C=O), 1610 (C=N str.), 1523 (–NO2 str), 1352 (C–N), 709 (C–S–C str.).
7e
2-NO2–
C17H15N7O4S2
477
70
210–212
42.76 (42.68)
3.17 (3.15)
20.53 (20.60)
3172 (NH), 2527 (S–H), 1740, 1700 (both C=O str.), 1610 (C=N str.), 1588 (C=C str.), 1520 (–NO2 str.), 1349 (C–N), 704 (C–S–C str.)
7f
4-OH–
C17H16N6O3S3
448
70
117–120
45.52 (45.42)
3.60 (3.66)
18.74 (18.78)
3295 (Ph–OH Str.), 3199 (NH), 2435 (S–H), 1738, 1709 (both C=O), 1636 (C=N str.), 1585 (C=C str.), 1350 (C–N), 672 (C–S–C str.)
7g
4-(CH3)2N–
C19H21N7O2S3
475
60
200–202
47.98 (47.94)
4.45 (4.54)
20.61 (20.65)
3380–3290 (bs, NH), 2460 (S–H), 1720, 1680 (both C=O), 1610 (C=N), 1588 (C=C str.), 1335 (C–N), 692 (C–S–C str.).
7h
3,4,5-(OCH3)3–
C20H22N6O5S3
522
57
174–176
45.96 (45.92)
4.24 (4.29)
16.08 (16.13)
3272 (NH), 2394 (S–H), 1718–1673 (both C=O), 1646 (C=N str.), 1588 (C=C str.), 1351 (C–N), 1150 (C–O–C), 689 (C–S–C str.)
7i
4-OCH3–
C18H18N6O3S3
462
40
130–132
46.74 (46.70)
3.92 (3.96)
18.17 (18.21)
3370–3250 (bs, NH), 2403 (S–H), 1715, 1690 (both C=O), 1620 (C=N), 1585 (C=C str.), 1340 (C–N), 1145 (C–O–C), 680 (C–S–C str.)
7j
4-Br–
C17H15N6O2S3Br
511
70
188–190
39.93 (39.89)
2.96 (3.00)
16.43 (16.48)
3175 (NH), 2366 (S–H), 1738, 1690 (both C=O str.), 1605 (C=N str.), 1578 (C=C str.), 1518 (–NO2 str.), 1349 (C–N), 701 (C–S–C str.). 512 (C–Br),
7k
4-CH3–
C18H18N6O2S3
446
50
204–206
48.41 (48.36)
4.06 (4.10)
18.82 (18.86)
3395–3260 (bs, NH), 2400 (S–H), 1715–1695 (both C=O), 1610 (C=N), 1581 (C=C str.), 1348 (C–N), 695 (C–S–C str.)
7l
4-F–
C17H15N6O2S3F
450
55
180–182
45.32 (45.27)
3.36 (3.41)
18.65 (18.69)
3385–3280 (bs, NH), 2430 (S–H), 1725–1695 (both C=O), 1618 (C=N), 1588 (C=C str.), 1348 (C–N), 1235 (C–F), 688 (C–S–C str.)Table 2
1HNMR spectral data of compounds.
Compound
1HNMR (DMSO-d6, ppm)
7a
δ 2.0 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.8 (s, 2H, CH2, thizolidin-4-one), 6.02 (s, 1H, CH, thizolidin-4-one), 7.0–7.28 (m, 5H, ArH), 9.2 (s, 1H, NH), 13.87 (br s, 1H, SH)
7b
δ 2.1 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.95 (s, 2H, CH2, thizolidin-4-one), 5.35 (s, 1H, OH), 5.96 (s, 1H, CH, thizolidin-4-one), 6.8–7.2 (m, 4H, ArH), 9.1 (s, 1H, NH), 13.79 (br s, 1H, SH)
7c
δ 2.04 (s, 3H, CH3), 2.3 (s, 3H, CH3), 3.92 (s, 2H, CH2, thizolidin-4-one), 5.89 (s, 1H, CH, Thizolidin-4-one), 7.08–7.42 (m, 4H, ArH), 9.15 (s, 1H, NH), 13.89 (br s, 1H, SH)
7d
δ 2.01 (s, 3H, CH3), 2.48 (s, 3H, CH3), 3.8 (s, 2H, CH2, thizolidin-4-one), 5.98 (s, 1H, CH, thizolidin-4-one), 7.59–8.15 (m, 4H, ArH), 9.05 (s, 1H, NH), 12.98 (br s, 1H, SH)
7g
δ 2.07 (s, 3H, CH3), 2.54 (s, 3H, CH3), 3.06 (s, 6H, CH3), 3.91 (s, 2H, CH2, thizolidin-4-one), 5.85 (s, 1H, CH, thizolidin-4-one), 6.64 (s, 2H, ArH, J=7.5 Hz), 7.05 (s, 2H, ArH, J = 7.5 Hz), 9.25 (s, 1H, NH), 13.88 (br s, 1H, SH)
7h
δ 2.03 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.83 (s, 9H, OCH3), 3.97 (s, 2H, CH2, thizolidin-4-one), 5.95 (s, 1H, CH, thizolidin-4-one), 7.07 (s, 2H, ArH, J = 1.5 Hz), 9.25 (s, 1H, NH), 13.78 (br s, 1H, SH)
7j
δ 2.08 (s, 3H, CH3), 2.5 (s, 3H, CH3), 3.82 (s, 2H, CH2, thizolidin-4-one), 6.01 (s, 1H, CH, thizolidin-4-one), 7.08–7.85 (m, 4H, ArH), 9.35 (s, 1H, NH), 13.82 (br s, 1H, SH)
7k
δ 2.11 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.98 (s, 3H, CH3), 3.76 (s, 2H, CH2, thizolidin-4-one), 6.11 (s, 1H, CH, thizolidin-4-one), 7.05–7.18 (m, 4H, ArH), 9.45 (s, 1H, NH), 13.58 (br s, 1H, SH)Table 3
Antimicrobial and antifungal activity of compounds(7a-l).
Compound
R
Antibacteriala
Antifungala
S.a.
P.a.
E.c.
S.t.
A.n.
C.a.
7a
H–
18
26
20
22
19
26
7b
2-OH–
16
11
15
14
14
10
7c
4-Cl–
12
22
10
20
24
24
7d
3-NO2–
10
08
11
09
13
12
7e
2-NO2–
09
07
10
09
09
07
7f
4-OH–
14
25
17
22
18
23
7g
4-(CH3)2N–
18
23
21
18
19
16
7h
3,4,5-(OCH3)3–
10
12
12
14
17
15
7i
4-OCH3–
08
12
10
11
09
13
7j
4-Br–
11
24
12
19
22
28
7k
4-CH3–
20
27
21
25
20
25
7l
4-F–
13
15
13
19
12
16
Penicillin
—
22
30
28
26
—
—
Griseofulvin
—
—
—
—
—
28
34
aZone of inhibition is measured in mm.
S.a.: Staphylococcus aureus, E.c.: Escherichia coli, P.a.: Pseudomonas aeruginosa, S.t.: Salmonella typhi, A.n.: Aspergillus niger, C.a.: Candida albicans.Scheme 1


## 3. Experimental Section

The melting points were recorded on electrothermal apparatus and are uncorrected. IR spectra were recorded in KBr on a Perkin-Elmer model-983.1HNMR spectrum was recorded on Varian Mercury 300 MHz instrument using DMSO-d6 as solvent (chemical shift in δ ppm), using TMS as internal standard. Elemental analysis was performed on a Heracus CHN analyzer. Analyses indicated by the symbols of the elements of functions were within ±/0.4% of the theoretical values.Synthesis of N-{4-methyl-5-[4-(4-oxo-2-phenyl(1,3-thiazolidin-3-yl)]-5-sulfanyl(1,2,4-triazol-3-yl)-1,3-thiazol-2-yl}acetamide(7a). The compound 6a (0.01 mole) was refluxed with mercapto acetic acid (0.015 mole, 1.38 gm) in the presence of anhydrous 1,4-dioxane (25 mL) at 120°C for 10–12 hrs. The reaction mixture was then cooled and triturated with an excess of 10% NaHCO3 solution. The precipitate was formed; filtered, washed several times with water, and recrystallised in DMSO. Other thiazolidin-4-ones (7b–l) were obtained in similar manner.


## 4. Antimicrobial Activity

The synthesized compounds(7a–l) were screened for their in vitro antibacterial activity against Staphylococcus aureus,Escherichia coli,Pseudomonas aeruginosa, and Salmonella typhi and antifungal activity against Aspergillus niger, and Candida albicans by measuring the zone of inhibition in mm. The antimicrobial activity was performed by cup plate method [35–38] at concentration 100 μg/mL in DMSO and reported in Table 3 for antibacterial and antifungal activities. Nutrient agar was employed as culture medium, and DMSO was used as solvent control for antimicrobial activity. Penicillin and griseofulvin were used as standard for antibacterial and antifungal activities, respectively.


## 5. Conclusion

In continuation of our previous studies to find new agents against microbial infection, a series ofN-{4-methyl-5-[4-(4-oxo-2-phenyl(1,3-thiazolidin-3-yl)]-5-sulfanyl(1,2,4-triazol-3-yl)-1,3-thiazol-2-yl}acetamide (7a–l)was synthesized and its antimicrobial activity was determined. The adopted method is simple, inexpensive, gave good yields. As we consider all results obtained from antibacterial and antifungal tests together we can say that entire compounds tested are active towards bacteria and fungi.



---

*Source: 656271-2012-10-18.xml*