An updated review of synthesis and characterization of some new thiazolidinones containing coumarin moiety and their antimicrobial study.

doi:10.21203/rs.3.rs-3298163/v2

Purpose: The main purposes of this study were to investigate the therapeutic qualities of small ring heterocycles containing nitrogen and sulfur, with a focus on thiazoles, and their potential as pharmaceutically significant compounds. The research aimed to explore the biological actions of substances with thiazole nuclei, including anti-inflammatory, antibacterial, and antifungal characteristics.

Methods: First, coumarin Schiff bases were reacted with iodoacetic acid to create a new class of thiazolidinones. The synthesis of 4-Chloro coumarin 2 and 4-Chloro-3, 4', 3', 4"-tercoumarin 2a was carried out by combining 4-hydroxy coumarin and phosphorus pentachloride (PCl5). Moreover, the combination of toluenediamine sulfate and compound 2 led to the formation of 4-[(4-aminophenyl) amino]-2H-chromen-2-one. To create various Schiff bases of coumarin, 4-[(4-aminophenyl) amino]-2H-chromen-2-one was condensed with different aldehydes. The synthesized compounds' structures were verified using techniques such as IR, 1H NMR, 13C NMR, and elemental analyses (C, H, N).

Results: This investigation suggests the potential of the compound like synthesis of 4-Chloro coumarin 2, 4-Chloro-3, 4', 3', 4"-tercoumarin 2a, and 4-[(4-aminophenyl) amino]-2H-chromen-2-one demonstrated the successful creation of novel compounds through specific reactions. The condensation of 4-[(4-aminophenyl) amino]-2H-chromen-2-one with various aldehydes led to the generation of distinct Schiff bases of coumarin.

Conclusion: In conclusion, the study highlighted the significance of small ring heterocycles containing nitrogen and sulfur, particularly thiazoles, in the development of important pharmaceutical compounds. The successful synthesis of novel compounds through specific reactions underscores the versatility of the methods employed. The structural verification of the newly synthesized compounds further supports the validity of the study's findings.

Medicinal Chemistry

Coumarin

Schiff bases

thiazolidinone

antibacterial

antifungal

4-Thiazolidinones and their derivatives are an important class of compounds in organic and medicinal chemistry. The 4-thiazolidinone ring system is a core structure in various synthetic pharmaceutical agents, which display a broad spectrum of biological activities such as, antitubercular [1], bacterial [2], anti-HIV [3], NSAIDS [4], anti anti-mycobacterial [5], anti-convulsant [6], anti-histaminic [7], anti-cancer [8], anti-protozoal [9], and analgesic [10]

4-Thiazolidinones have recently been reported to be novel inhibitors of the bacterial enzyme Mur B (a precursor during the biosynthesis of peptidoglycan) and also to block some pathogenic mechanisms of bacteria [11]. One of the most eminent heterocyclic motifs, thiazolidine, is a fve- membered heterocycle system having the formula C3H7NS containing one nitrogen and one sulfur atom, and which exhibits notable medicinal and pharmaceutical properties. In the thiazolidine nucleus, a large number of substitutions are possible. Thiazolidine and its composites are key components of many natural products and drugs, and are also present in many synthetic compounds such as anticancer [12–13].

Novobiocin and chlorobiocin are established antimicrobials containing a coumarin skeleton [14]. Due to their significant therapeutic qualities, small ring heterocycles with nitrogen and sulfur have been studied for a very long time. Thiazoles have been crucial in the development of pharmaceutically significant compounds among the several heterocycles investigated in medicinal chemistry. According to a review of the literature, substances with thiazole nuclei exhibit a wide spectrum of biological actions, including anti-inflammatory [15], antibacterial [16], and antifungal [17] characteristics.; We have recently isolated and purified a coumarin derivative named 7-(5-hydroxy-3,7-dimethylocta-2,6-dienyloxy)-chromen-2-one (50-hydroxy- aurapten) for the first time from Lotus lalambensis Schweinf [18]. Coumarin and 7- hydroxycoumarin have anti-tumour actions in vitro and in vivo [19]. Synthesis of 4- thiazolidinone derivative also applicable on the Pearson’s HSAB principle, according to which hard acids prefer to coordinate hard bases and soft acids to soft bases [20].

Many heterocyclic scaffolds has given a new direction to the modern medicinal chemistry-based drug discovery [21].

The incorporation of coumarin nucleus, a biologically accepted pharmacophore, in the 4- thiazolidinone molecule has made it a versatile heterocyclic possessing wide spectrum of biological activity [22], [23], [24], [25].

Coumarin and its derivatives represent one of the most active classes of compound possessing a wide spectrum of biological activity. Many of these compounds have proven to be active as antibacterial, antifungal, anti-inflammatory, anticoagulant, anti-HIV and antitumor agents. Coumarins are widely used as additives in food, perfumes, cosmetics, pharmaceuticals and optical brighteners and would dispersed fluorescent and laser dyes. Coumarins also have the super thermal stability and outstanding optical properties including extended spectral response, high quantum yields and superior photo stability. Optical applications of these compounds, such as laser dyes, nonlinear optical chromophores, fluorescent whiteners, fluorescent probes, polymer science, optical recording and solar energy collectors have been widely investigated. Classical routes to coumarins incorporate Pechmann, Knoevenagel, Perkin, Reformatsky, and Wittig condensation reactions. To make these classical reactions efficacious, several variations in terms of catalyst and reaction conditions have been introduced [26], anthelmintic, hypnotic [27], insecticidal activity and some are serving as anticoagulant agents and fluorescent brighteners. The name coumarin originates from caribbian word ‘‘coumaron’’ for the tonka tree, which was known botanically at one time as Caumarouna odorata. Coumarins are reported to possess important pharmacological activities like antimicrobial [28], anticonvulsant [29], antitumor [30], and anti-inflammatory [31]. 1, 3 , 4- Oxadiazole derivatives are reported to show a broad spectrum of biological activities which include COX inhibitor [32], anticonvulsant [33], antibacterial [34], and antifungal [35].

From the above line of reasoning we directed our work towards synthesis of various coumarin derivatives of biological interest using 4-chloro coumarin as a key starting material.

In order to discover new biologically active compounds, the current effort sought to manufacture new thiazolidinone derivatives containing coumarin moiety. Thus, the synthesis of new derivatives of 4-Thiazolidinones has been accomplished.

All of the compounds employed in the synthesis were experimental grade. On an electrical device made by Veego (Model: VMP-D), the melting points were calculated in an open capillary. Using potassium bromide, the FT-IR spectrophotometer Shimadzu 8400-S was used to record the IR spectra of synthetic chemicals. Thin layer chromatography and high performance thin layer chromatography were carried out on microscopic glass slides (2x7.5 cm) coated with silica gel-G in order to monitor the reactions and determine the identity and purity of the reactants and products. The solvent systems used included toluene-acetone, benzene-ether, and chloroform-methanol, and the spots were visible under UV light. Using DMSO as a solvent and TMS as an internal reference, nuclear magnetic resonance spectra were captured using a Varian 400 MHz model spectrometer (Chemical shifts in ppm).

2.1-Material: 4-Hydroxy coumarin, triethyl amine (TEA), PCl5 (Phosphorus pentachloride), para-toluene diamine sulfate (PTDs), aldehydes, iodoacetic acid.

2.2-Synthesis of 4-chloro coumarin (2):

After being refluxed for an hour and cooling, 4-Hydroxycoumarin 1 (30 g, 0.185 mol) and 70 ml POCl3 were slowly added to 700 g of broken ice while being vigorously stirred. The material was filtered out and subsequently rinsed with freezing water. Azeotropic or heterogeneous distillation with n-hexane, hot filtering of the by-product (15 g, 17%), solvent evaporation, and crystallization produced 21.9 g, 65%, and m.p. 87-89 °C of 4-chloro coumarin [27]. 1H-NMR (400 MHz, DMSO-d6) 7.30-7.91 (m, 3H, Ar-H), 7.93 (d, 1H, H at C-5 of coumarin), 5.75 (s, 1H, H); IR (KBr, cm -1) 1664.62 (C=O of coumarin), 773.48 (Ar-C-Cl); at coumarin's C-3; 13C NMR values of 117.22, 118.14, 124.87, 125.84, 130.18, 146.04, 149.04, 149.22, and 161.23. Anal. Calcd. C, 59.86; H, 2.79 for C9H5ClO2. Found C, 59.86.

4-Chloro-3, 4', 3', and 4"-tercoumarin (by-product) (2a): crystallized from acetic acid to produce yellow crystals with a melting point of 322 to 327 °C. IR (KBr, cm -1); 718 (C=O), 1593-1625 (Aromatic -CH str.), 3039-3080 (C=C), 1187 (C-O str.); 1H-NMR (400 MHz, DMSO- d6) δ 7.46-7.92 (m, 9H, Ar-H), 7.27 (s, 1H, 3'-H); 13C NMR 114.56, 117.60, 118.01, 118.30, 118.83, 118.96, 120.05, 123.40, 124.83, 125.55, 126.00, 126.10, 126.52, 126.69, 132.59, 133.32, 136.13, 149.96, 151.12, 151.95, 156.75, 157.00, 161.80, 163.25. Anal. Calcd. For C27H13ClO6: C, 69.16; H, 2.79.Found C, 69.20; H, 2.75.

2.3-Synthesis of 4-[(4-Aminophenyl)amino]-2H-chromen-2-one (3):

A boiling solution of p-toluenediamine sulfate (6.09 g, 0.05mol) in ethanol (30 mL) was added to a boiling solution of 4-chloro coumarin (10 g, 0.05mol) and a little amount of triethyl amine in ethanol. After being at room temperature for 4-5 hours, the mixture was refluxed for 1 hour.

The precipitate was removed from DMF and then recrystallized. Yield:78 %; m.p. 265-273 C; IR (KBr, cm-1 ) 3341.78 (NH str. for 20 ), 3290.67, (NH for 10 ), 1664.62(C=O of coumarin); 1HNMR (400 MHz, DMSO- d6) δ 6.53-7.26 (m, 7H, Ar-H), 3.31(s, 2H, NH2), 3.76 (s,1H,C- NH), 7.93 (d, 1H, H at C-5 of coumarin), 5.75 (s, 1H, H at C-3 of coumarin); 13C NMR 88.22, 116.51, 118.91, 121.80, 123.59, 124.25, 125.79, 131.84, 132.55, 145.13, 149.08, 155.32, 161.98. Anal. Calcd. For C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found C, 71.40; H, 4.82; N, 11.06.

2.4-General procedure for the synthesis of Schiff bases (4a-i): A catalytic amount of piperidine was added to a solution of compound 3 (1.36g; 0.01mol) in absolute ethanol (50 mL), and the necessary aldehydes (for example, benzaldehyde) were added in equimolecular amounts.

For 8 to 10 hours, the reaction mixture was heated under reflux. To produce 4-[(4-[(E)- phenylmethylidene]amino]-2H-chromen-2-one, it was then cooled to room temperature, poured into crushed ice, filtered, washed, dried, and recrystallized from DMF. Similar methods were used to acquire additional Schiff bases.

2.5-General procedure for the synthesis of thiazolidinone (5a-i): Iodoacetic acid and compound 4a were refluxed together in 80 mL of dry benzene for six hours. By using Dean- Stark equipment, the water that was produced during the reaction was extracted or eliminated azeotropically. TLC was used to monitor the reaction's progress while employing benzene-ether as the eluant. The solid that was produced once the reaction was finished was dissolved in 70 mL of methanol after the benzene had been removed through distillation. To eliminate unreacted acid, this solution was warmed and treated with sodium bicarbonate solution. The resulting solid was filtered, cleaned with ether, and crystallized from methanol to produce 5a. Other compounds (5b-5i) have also been created in a similar manner.

2.6-Characteriaztion of synthesized compounds (5a-i):

3-[4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-2-phenyl-thiazoldin-4-one (5a): Yield: 70%; m.p. 240-2450C; IR (KBr,cm-1): 3296.46 (N-H str.), 1724.42 (C=O of -lactum), and 1664.62 (C=O of coumarin); 1H -NMR (400 MHz, DMSO-d6) 6.40-7.68 (m,13H,Ar-H); 3.76 (s,1H,C- C, 69.52; H; and N, 3.40 were discovered.

2-(4-Nitro-phenyl)-3-[4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-thiazolidin-4-one (5b): Yield: 70%; mp 245-2510C; IR (KBr, cm-1): 3296.46 (N-H str.), 1728.28 (C=O of -lactum), 1664.62 (C=O of coumarin), and 1548.89 cm-1 (N=O str.); 1H -NMR (400 MHz, DMSO-d6) 3.76 (s,1H,C-NH); 8.19 (d, 1H, H at C-5 of coumarin); 5.75 (s, 1H, H at C-3 of coumarin); 4.10 (s,2H,CH2); 13C NMR 38.25, 69.70, 89.10, 117.49, 119.91, 122.48, 123.10, 123.75, 124.10, 124.40, 125.70, 132.60, 136.38, 140.64, 145.70, 148.35, 149.88, 154.70, Anal. Calcd. For = C24H17N3O5S: C, 62.74; H, 3.73; N, 9.15. 160.44, 172.10. C, 62.70, H, 3.74, and N, 9.14 were located.

2-(3-Nitro-phenyl)-3-[4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-thiazolidin-4-one (5c): Yield: 72%; m.p. 259--2650C ; IR (KBr,cm-1): 3296.46 (N-H str.), 1720.70 (C=O of β-lactum), 1664.62 (C=O of coumarin, 1537.32 cm-1 (N=O str.) ; 1H -NMR (400 MHz, DMSO- d6) δ 6.40- 7.70 (m,12H,Ar-H); 3.76 (s,1H,C-NH); 8.19(d, 1H, H at C-5 of coumarin), 5.75 (s, 1H, H at C-3 of coumarin), 4.10 (s,2H,CH2) ;13C NMR 38.25, 69,70, 89.10, 117.49, 117.49, 118.10, 119.05, 119.91,122.48, 123.10, 124.15, 124.40, 128.60, 132.60, 136.38, 140.64, 145.70, 148.35, 149.88, 154.70, 160. Anatomical calculations for the formula C24H17N3O5S are as follows: C = 62.74; H = 3.73; and N = 9.15. C, 62.72, H, 3.74, and N, 9.14 were discovered.

2-(3, 4-Dimethoxy-phenyl)-3-[4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-thiazolidin-4-one (5d): Yield: 68%; m.p. 270-2740C; IR (KBr,cm-1): 3296.46 (N-H str.), 1749.49 (C=O of -lactum), 1664.62 (C=O of coumarin), and 1292.35 cm-1 (Ar-OCH3); 1H -NMR (400 MHz, DMSO-d6) 6.40-7.70 (m,11H An analytical calculation for C26H22N2O5S yielded the following results: C, 65.81; H, 4.67; and N, 5.90.

2-(4-Chloro-phenyl)-3-[4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-thiazolidin-4-one (5e): Yield: 80%, m.p. 262-2680C, IR (KBR, cm-1), 3296.46 (N-H str.), 1732.20 (C=O of -lactum), 1664.62 (C=O of coumarin), and 758.05 cm-1 (Ar- C-Cl); 1H -NMR (400 MHz, DMSO-d6) 6.40–7.66 (m, 12H, Ar–H); 3.76 (s, 1H, C–NH); 8.19 (d, 1H, H at C–5 of coumarin), and 5.75 (s, 1H, H at C–3 coumarin), 4.10 (s,2H,CH2); 13C NMR 38.25, 69.70, 117.49, 118.10, 122.48, 123.10, 124.05, 124.10, 130.45, 132.60, 134.70, 140.64, 140.80, 149.88, 154.70, 160.44, 172.10. C, 64.21; H, 3.82; and N, 6.24 are the analytic values for C24H17ClN2O3S. C, 64.22; H, 3.82; and N, 6.21 were located.

3-[4-(2-Oxo-2H-chromen-4-ylamino)-phenyl]-2-p-tolyl-thiazolidin-4-one (5f): Yield: 76%; m.p. 281-2840C; IR (KBR,cm-1): 3296.46 (N-H str.), 1747.57 (C=O of -lactum), 1664.62 (C=O of coumarin), 1469.81 cm-1 (Ar-CH3); 1H -NMR (400 MHz, DMSO-d6) 6.40- 7.72 (m,12H,Ar- Anal. Calculated values for = C25H20N2O3S are C, 70.07, H, 4.70, and N, 6.54. C, 70.09; H; and N were located.

2-{4-oxo-3-[4-(2-oxo-2H-chromen-4-ylamino-phenyl]-thiazolidin-2-yl}-benzaldehyde (5g): Yield: 75%; m.p. 281-2860C; IR (KBr,cm-1): 3296.46 (N-H str.), 1716.47 (C=O of -lactum), 1664.62 (C=O of coumarin), and 2933.83 (Ar-CHO Str.); 1H -NMR (400 MHz, DMSO-d6) 6.40- 7.70 (m,12H,Ar C, 67.86, H, and N were located.

2-Naphthalen-1-yl-3-[4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-thiazolidin-4-one (5h): Yield: 77%; m.p. 291-2960C; IR (KBr,cm-1): 3296.46 (N-H str.), 1735.63 (C=O of -lactum), 1664.62 (C=O of coumarin), 1H-NMR (400 MHz, DMSO-d6) 6.40-7.90 (m,15H,Ar-H), 3.76 (s,1H,C-NH), C, 72.37, H, 4.36, and N, 6.02 were located.

2-(2-Chloro-quinoline-3-yl)-3{4-(2-oxo-2H-chromen-4-ylamino)-phenyl]-thiazolidin-4-one (5i): Yield: 72%; m.p. 279–2830C; IR (KBr,cm-1): 3296.46 (N-H str.), 1745.20 (C=O of -lactum), 1664.62 (C=O of coumarin), and 823.40 (Cl of quinoline), 1H-NMR (400 MHz, DMSO–d6) 6.40–8.09 (m,13H,Ar–H), 3.76 (s,1H,C–NH), 8.19 (d, 1H, H at C–5 of coumarin), 5.75 (s, 1H, H at C–3 of coumarin), and 4.10 (s,2H, CH2); 13C NMR 36.15, 56.10, 86.10, 116.50, 118.23, 122.62, 124.70.

2.7 Antimicrobial activity :- All the synthesized compounds were tested for their antibacterial and antifungal activity (MIC minimum inhibition concentration) in vitro by broth dilution method with two gram positive bacteria S. aureus and B. subtilis and gram negative bacteria E. coli, P. aeruginosa, and fungi species like C. albicans, A. niger organisms taking ciprofloxacin, ampicillin, chloramphenicol, norfloxacin, flucanazole, griseofulvin, and Nystatin. The drug suspension for the test was grown and diluted in Muller Hinton broth as a nutrient medium. As a diluent, DMSO was utilized, which had no influence on the growth of microorganisms. We carried out a variety of additional microbiological studies to examine the biological profile of the thiazolidinone series. Due to its comparatively strong activity in solid tests with a MIC, we chose the chemical 4-chloro-3, 4', 3', 4'-tercaumarin.

The reactions were all conducted using standard procedures. A necessary intermediary was 4- [(4-Aminophenyl)amino]-2Hchromen-2-one 3 for the preparation of the desired product. From 4-hydroxy coumarin 1, 4-chloro coumarin 2 was created. However, because a sizeable amount of 4-chloro-3, 4', 3', 4"-tercoumarin was produced as a byproduct, the reaction of 1 with POCl5 had limited selectivity. By using n-hexane, the yield of 4-chloro coumarin was increased while the production of the byproduct was greatly reduced. With only a small amount of triethyl amine, the important intermediate 4-[(4-aminophenyl)amino]- 2H-chromen-2-one 3 was readily made from 4-chloro coumarin. Strong bands at 3290.67 cm-1 and 3341.78 cm-1 in the IR spectra of compound 3 confirmed the existence of the 20 -NH group and, respectively, Schiff base was formed when the - CHO group of aldehyde fully interacted with compound 3. There is a stretching vibration for the Schiff base's C=N at a wavelength of 1473–1602 cm-1. Compounds' 1H NMR measurements showed an aromatic proton signal between 6.55-7.52 ppm. Thioglycolic acid interacted with each Schiff base to produce thiazolidinone derivatives. The chemical 5b's IR spectra revealed a distinctive band at 1728.28 cm-1, demonstrating that it is a thiazolidinone with the C=O group. The 1H NMR data of compound 5b exhibited a signal for aromatic protons between 6.40 and 7.70 ppm and a doublet for -CH 2 of thiazolidinones at 4.10 ppm.

The antibacterial activity of each of the recently produced compounds was tested.

According to the results in Table 1, Schiff base 4e demonstrated excellent activity when compared to ampicillin and chloramphenicol, while 5b, 5e, 5f, and 5i showed good activity against E. coli and 5e, 5i significant activity against P. aeruginosa. When compared to the standard drug ampicillin, 4c, 5b, 5e, and 5i showed good activity against S. aureus and 5e and 5i demonstrated significant activity against B. subtilis.

When compared to Griseofulvin, 5h and 5i showed good effectiveness against C. albicans. Each of the remaining substances had fair to moderate effectiveness against the remaining fungi (A. niger).

Table 1 Antimicrobial Study of Synthetic Compound 4a-5i (MIC g/mL):

Minimum inhibitory concentration

Comp. no.	Ar	Gram negative		Gram positive		Fungal species
Comp. no.	Ar	P. aeruginosa	E. coli	B. subtilis	S. Aureus	A. niger	C. albicans
4a	Phenyl	1000	500	1000	500	1000	500
4b	4-Nitro Phenyl	200	200	1000	500	1000	800
4c	3-Nitro Phenyl	200	500	200	100	1000	500
4d	3,4-dimethoxPhenyl	500	200	200	1000	500	100
4e	4-chloro Phenyl	100	50	100	200	> 1000	500
4f	4-methyl Phenyl	200	100	500	1000	500	200
4g	Phenyl 1-2-carboxaldehyde	1000	500	100	800	1000	500
4h	Naphthyl	250	500	100	800	1000	400
4i	2-chloro quinonyl	400	250	100	500	> 1000	400
5a	Phenyl	400	400	400	250	1000	800
5b	4-Nitro Phenyl	250	200	250	200	800	250
5c	3-Nitro Phenyl	500	400	250	500	1000	1000
5d	3,4-dimethox Phenyl	400	250	400	800	500	200
5e	4-chloro Phenyl	100	50	100	200	400	250
5f	4-methyl Phenyl	100	50	250	250	800	200
5g	Phenyl 1-2-carboxaldehyde	500	250	200	500	800	200
5h	Naphthyl	500	400	250	400	400	250
5i	2-chloro quinonyl	100	100	50	100	500	200
Ampicillin		100	100	100	250	-	-
Ciprofloxacin		25	25	50	50	-	-
Chloramphenicol		50	50	50	50	-	-
Norfloxacin		10	10	10	10	-	-
Griseofulvin		-	-	-	-	100	500
Nystatin		-	-	-	-	100	100
Fluconazole		-	-	-	-	10	10

Schiff base 4d was shown to be equipotent to Nystatin based on the findings of the MIC test for fungal activity, while Schiff bases 4a, 4c, 4e, 4f, 4g, and 4h showed substantial activity. 5b, 5d, 5e, 5f, and 5g thiazolidinones.

A number of coumarin-based compounds with thiazolidinone structures were effectively synthesized and evaluated for their in vitro antibacterial activity. The majority of the synthesized compounds, according to the overall finding, were more effective against E. coli, S. aureus, and B. subtilis. Some of the substances were found to be comparable to or stronger than ampicillin and to be less active than other common medications. The majority of the substances showed antifungal activity against C. albicans that was comparable to that of griseofulvin but less potent than that against other fungal species (A. niger).

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Ethical approval statement

Not Applicable.

Informed Consent Statement

Not Applicable

Funding

Not Applicable.

Conflicts of interest

We have no conflicts of interest to disclose. All authors declare that they have no conflicts of interest.

An updated review of synthesis and characterization of some new thiazolidinones containing coumarin moiety and their antimicrobial study.

Status:

Version 2

Abstract

Figures

Introduction

Materials And Methods

Results And Discussion

Conclusion

References

Declarations

Status:

Version 2