Next Article in Journal
3-Ethoxycarbonyl-1,4-benzodioxin-2-carboxylic Acid
Previous Article in Journal / Special Issue
1-(Dicyanomethylene)-3-hydroxy-1H-indene-2-carboxylic Acid
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molbank
Volume 2024
Issue 3
10.3390/M1872
molbank-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Communication

Synthesis and Antimicrobial Evaluation of 2-[2-(9H-Fluoren-9-ylidene)hydrazin-1-yl]-1,3-thiazole Derivatives

by
Kazimieras Anusevičius
1,*,
Ignė Stebrytė
1 and
Povilas Kavaliauskas
2
1
Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų, Rd. 19, LT-50254 Kaunas, Lithuania
2
Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, 527 East 68th Street, New York, NY 10065, USA
*
Author to whom correspondence should be addressed.
Molbank 2024, 2024(3), M1872; https://doi.org/10.3390/M1872
Submission received: 28 July 2024 / Revised: 13 August 2024 / Accepted: 17 August 2024 / Published: 19 August 2024
(This article belongs to the Collection Heterocycle Reactions)
Browse Figures
Versions Notes

Abstract

:
Fluorenyl-hydrazonothiazole derivatives 2–7 were synthesized by the Hantzsch reaction from 2-(9H-fluoren-9-ylidene)hydrazine-1-carbothioamide (1) and the corresponding α-halocarbonyl compounds in THF or 1,4-dioxane solvent. A base catalyst is not necessary for synthesising thiazoles, but it can shorten the reaction time. The antimicrobial properties of all synthesized compounds were screened for multidrug-resistant microorganism strains. The minimum inhibitory concentration of the tested compounds against Gram-positive bacteria and fungi was higher than 256 μg/mL, but several compounds had activity against Gram-positive strains.

Graphical Abstract

1. Introduction

Infectious diseases are nowadays a significant cause of morbidity and mortality throughout the world, and the ability of microorganisms to adapt to currently known antibiotics is a relevant problem. These factors lead to research on and the development of scaffolds for new antimicrobial compounds [1,2]. Heterocyclic compounds containing nitrogen and sulphur atoms have a significant role in medical chemistry, and they are widely used in the development of bioactive compounds, drugs, and industrial products [2,3,4,5]. Compounds containing a thiazole ring occupy an important place in the search for new derivatives with antimicrobial properties [6,7,8,9,10,11,12,13,14]. The Hantzsch thiazole synthesis is one of the most common methods for obtaining thiazole moieties in molecules [15]. For the synthesis of 1,3-thiazoles by reacting thiosemicarbazide derivatives with various haloketones, very different reaction conditions are chosen, e.g., aprotic solvents are used [16,17] and protic [18,19] solvents are used. Also, the reactions are carried out with a base catalyst [20,21,22] or without a base catalyst [23,24,25].
Molecules containing a fluorene scaffold are found in a variety of biologically significant compounds, such as those that are anticancer [26,27], antimicrobial [28], used for the treatment of Alzheimer’s disease [29], and related to antioxidant activity [30]. According to Ray, S. et al., the introduction of a fluorene moiety into the molecule of some derivatives improves their pharmacological and pharmacokinetic properties [31].
In our previous works [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32], 2-aminothiazoles and their derivatives were synthesized by the Hantzsch reaction, and some compounds showed promising antimicrobial activity. In the course of continuing research on the synthesis of 2-aminothiazole derivatives, several new fluorenyl-hydrazinthiazoles derivatives were synthesized and evaluated for their antimicrobial activity.

2. Results and Discussion

Synthesis and Characterization

In this work, the starting compound 2-(9H-fluoren-9-ylidene)hydrazine-1-carbothioamide (1) from fluorenone was synthesized by the method described in the literature [33,34]. The synthesis of compound 1 was carried out by the reaction of fluorenone and thiosemicarbazide in 1,4-dioxane in the presence of a catalytic amount of glacial acetic acid. In this project, 2-[2-(9H-fluoren-9-ylidene)hydrazinyl]-1,3-thiazol-4(5H)-one (2) was resynthesized by the method described in the literature [35,36]. However, tetrahydrofuran was observed to dissolve reagents better than alcoholic solvents and was therefore chosen for this work (Scheme 1). Analytical data for thiazolone derivative 2 are consistent with the literature [36]. The structure of all synthesized compounds 2–7 was confirmed by the data of the 1H and 13C NMR spectra (Supplementary Materials, Figures S1–S26).
2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-1,3-thiazole (4a) was synthesized by reacting carbothioamide 1 with chloroacetaldehyde in THF without a base catalyst. In the reaction, product 4a was obtained as a hydrochloride salt due to the low solubility of the organic salts in THF solvents; during the synthesis, precipitates were formed. Product 4a was obtained in a relatively pure form because unreacted reactants and by-products remained in the filtrate or were washed by filtering. The basic analogue of compound 4a was obtained by dissolving the crystals in glacial acetic acid and diluting the solution with 10% aqueous sodium acetate. Other compounds 4b–i were synthesized under analogous reaction conditions and shown in Scheme 1. A.P. Kaur et al. [36] performed the ultrasonic synthesis of compounds 4e and 4g in DMF solvent, and the reaction time was achieved very quickly, with excellent yields of 80–82%. In this work, the synthesis of compound 4e was carried out in DMF solvent by heating the reaction mixture to 70–80 °C. Crystals from the reaction mixture were not formed, and resins appeared when the solution was diluted by water, which made it more complicated to separate and purify the products. However, crystals of the product were formed during the reaction or after the mixture had cooled, when tetrahydrofuran was used as a solvent for the synthesis with 72–92% yield.
In the 1H NMR spectrum for thiazole 4a, proton signals of the thiazole ring are visible at 6.64 and 7.21 ppm, and fluorene ring signals are identified as two multiplets at 7.26–7.54 and 7.69–7.91 ppm and one doublet at 8.67 ppm. The NH proton signal is not observed in this spectrum, which could be due to the rapid movement of the proton between the nucleophilic centers. Alternatively, it may be observed as a broad peak. For example, the NH proton signal is observed as a broad singlet at 10.18 ppm in the 1H NMR spectrum of compound 4b. Analogous NMR spectral data are assigned for other compounds 4b–d (Supplementary Materials, Figures S3–S20)
4,5-Disubstituted thiazole derivatives 5, 6 were synthesized by reacting carbothioamide 1 with 3-chloro-2,4-pentanedione or ethyl 2-chloroacetoacetate, as shown in Scheme 1. In this case, sodium acetate was used in the reactions as a catalyst; reactions can be performed without a base, but the progress of the reactions was slower. Also, the synthesis of compound 5 was slower in tetrahydrofuran than in 1,4-dioxane, so it was decided to change the solvent. Compounds 5 and 6 are the data of the 1H and 13C NMR spectra (Supplementary Materials, Figures S21–S24).
Quinoxaline-fused thiazole 7 was prepared by the reactions of carbothioamide 1 with 2,3-dichloroquinaxoline. This reaction was carried out in 1,4-dioxane in the presence of sodium acetate at reflux for 12 h. An initial attempt to synthesize thiazole 7 was carried out in acetic acid in the presence of sodium acetate [13], but product 7 was obtained with a 20% yield. 2,3-Dichloroquinoxaline is poorly soluble in tetrahydrofuran; therefore, compound 7 was synthesized in 1,4-dioxane with an 81% yield.
Fluorenyl-hydrazonothiazole derivatives 2–7 were tested against multidrug-resistant Gram-positive and Gram-negative bacteria or fungi strains. However, compounds 2–7 do not show antimicrobial activity against multidrug-resistant Gram-negative pathogens, e.g., K. pneumoniae, P. aeruginosa, and E. coli; also, they were not found to have any significant activity against drug-resistant virulent fungi, e.g., C. auris, and C. albicans. All synthesized compounds showed minimal inhibition concentration lower than 256 mg/mL.
Preliminary tests of synthesized compounds 2–7 against multidrug-resistant pathogens showed that thiazolone 2, like thiazole 4d and 4f, has better than 256 mg/mL antibacterial activity against Gram-positive bacteria S. aureus and E. faecalis. In this work, the compounds 2, 4e, and 4g are known, as is their antimicrobial activity [36]. Comparing the results of the antimicrobial properties of known compounds, our test with multidrug-resistant virulent organisms has a minimum inhibitory concentration higher than that reported in the publication.

3. Materials and Methods

Chemistry

Reaction progress and compound purity-monitored TLC aluminum plates precoated with Silica gel with F 254 nm (Merck KGaA, Darmstadt, Germany) were used. Melting points in an open capillary with a B-540 melting point apparatus (Büchi Corporation, New Castle, DE, USA) were determined and uncorrected. A Perkin–Elmer Spectrum BX FT–IR spectrometer (Perkin–Elmer Inc., Waltham, MA, USA) was used to record the IR spectra (ν, cm−1) from KBr tablets. The NMR spectra were recorded on Bruker Ascend 400 (1H 400 MHz, 13C 101 MHz). The chemical shifts (δ) were reported in parts per million (ppm) and calibrated from the standard of solvent the signal of DMSO-d6 (2.50 ppm) for 1H NMR and (39.43 ppm) for 13C NMR. The Elemental Analyzer CE-440 was used for elemental analyses (C, H, N) in good agreement (±0.3%) with the calculated values. All reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and were used without purification.
2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-1,3-thiazol-4(5H)-one (2) (See Figures S1 and S2 for NMR spectra)
A mixture of carbothioamide 1 (0.25 g, 1 mmol), monochloroacetic acid (0.12 g, 1.3 mmol), sodium acetate (0.25 g, 3 mmol), and 15 mL tetrahydrofuran was refluxed for 2.5 h. The reaction mixture was cooled down and diluted with 50 mL water; precipitate was filtered off and washed with water and propan-2-ol. 1,3-Thiazol-4(5H)-one 4 was purified by recrystallization method from methanol, yield 0.24 g (83%), m.p. 210–212 °C, data found in ref. 211–215 °C [35,36]. 1H NMR (400 MHz, DMSO-d6) δ: 3.98 (s, 2H, CH2), 7.35 (t, 2H, J = 7.5 Hz, HAr); 7.40–7.58 (m, 4H, HAr), 7.75 (d, 1H, J = 7.4 Hz, HAr), 7.78–7.91 (m, 2H, HAr), 12.26 (br. s, 1H, NH); 13C NMR (101 MHz, DMSO-d6) δ: 33.15 (CH2), 120.46, 120.49, 121.90, 128.23, 129.82, 130.85, 131.09, 131.38, 136.12, 140.26, 141.30 (CAr), 156.02 (C=N), 168.30 (C=O), 174.04 (N=C–S). Anal. Calcd for C16H11N3OS: C 65.51%, H 3.78%, N 14.32%. Found: C 65.31%, H 3.64%, N 14.16%.
A general method for the synthesis of 1,3-thiazole derivatives 4a–i
A mixture of carbothioamide 1 (0.25 g, 1 mmol), corresponding α-haloketone (1.1 mmol), and 20 mL tetrahydrofuran was refluxed from 1 to 24 h. The reaction was monitored by TLC method (eluent–acetone/hexane 1:2). When the reaction finished, the reaction mixture was cooled down, and precipitate was filtered off and washed with diethyl ether. Products 4a–i were purified by dissolving crystals in 10 mL glacial acetic acid, and appropriate solutions were diluted by 50 mL 10% sodium acetate aqueous solution. The precipitate was filtered off and washed with water and dried, then products were recrystallized from 1,4-dioxane.
2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-1,3-thiazole (4a) (See Figures S3 and S4 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with chloroacetaldehyde solution ~50 wt. % in H2O (0.17 g, 2.2 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 12 h. The product 4a yield was 0.21 g (76%), m.p. 198–199 °C. FTIR (KBr) vmax: 3416 (NH), 1602, 1554 (2C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 6.64 (d, 1H, J = 4.4 Hz, HThiazol), 7.21 (d, 1H, J = 4.4 Hz, HThiazol); 7.26–7.54 (m, 4H, HAr) 7.69–7.91 (m, 3H, HAr), 8.67 (d, 1H, J = 7.5 Hz, HAr); 13C NMR (101 MHz, DMSO-d6) δ: 104.43, 105.10 (C–S), 120.08, 120.12, 120.23, 120.69, 127.59, 127.64, 127.79, 128.21, 128.71, 129.25, 129.51, 131.04, 137.02, 138.74, 139.99, 147.89 (CAr + CThiazol), 152.64 (C=N), 173.70 (N=C–S). Anal. Calcd for C16H11N3S: C 69.29%, H 4.00%, N 15.15%. Found: C 69.24%, H 3.89%, N 15.09%.
2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-4-methyl-1,3-thiazole (4b) (See Figures S5 and S6 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with chloroacetone (0.10 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 6 h. The product 4b yield was 0.22 g (75%), m.p. 180–181 °C. FTIR (KBr) vmax: 3417 (NH); 1609, 1585 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 2.16 (s, 3H, CH3), 6.27 (s, 1H, HThiazol), 7.23–7.51 (m, 4H, HAr), 7.66–7.91 (m, 3H, HAr), 8.70 (d, 1H, J = 7.6 Hz HAr), 10.18 (br. s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 13.95 (CH3), 99.78 (C–S), 120.15, 120.87, 127.64, 127.68, 128.24, 128.87, 129.69, 130.90, 135.56, 136.96, 138.80, 140.12 (CAr + CThiazol), 148.19 (C=N), 173.63 (N=C–S). Anal. Calcd for C17H13N3S: C 70.08%, H 4.50%, N 14.42%. Found: C 70.03%, H 4.43%, N 14.32%.
4-(Chloromethyl)-2-[2-(9H-fluoren-9-ylidene)hydrazinyl]-1,3-thiazole (4c) (See Figures S7 and S8 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with 1,3-dichloroacetone (0.14 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 16 h. The product 4c yield was 0.25 g (78%), m.p. 192–193 °C. FTIR (KBr) vmax: 3419 (NH); 1608, 1501 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 4.66 (s, 2H, CH2), 6.86 (s, 1H, HThiazol), 7.23–7.54 (m, 4H, HAr), 7.74 (d, 1H, J = 7.4 Hz, HAr), 7.82 (d, 1H, J = 7.4 Hz, HAr), 7.87 (d, 1H, J = 7.4 Hz HAr), 8.61 (d, 1H, J = 7.6 Hz, HAr), 11.40 (br. s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 39.13 (CH2), 106.62 (CH–S), 120.21, 120.24, 120.85, 127.79, 128.05, 129.13, 129.99, 130.57, 136.84, 138.84, 140.34 (CAr + CThiazol), 147.63 (C=N), 172.78 (N=C–S). Anal. Calcd for C17H12ClN3S: C 62.67%, H 3.71%, N 12.90%. Found: C 62.51%, H 3.54%, N 12.73%.
Ethyl {2-[2-(9H-fluoren-9-ylidene)hydrazinyl]-1,3-thiazol-4-yl}acetate (4d) (See Figures S9 and S10 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with ethyl 4-chloroacetoacetate (0.18 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 24 h. The product 4d yield was 0.26 g (72%), m.p. 145–146 °C. FTIR (KBr) vmax: 3411 (NH); 1732 (O=C–O); 1604, 1586 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 1.22 (t, 3H, J = 7.1 Hz, CH3), 3.67 (s, 2H, CH2), 4.14 (q, 2H, J = 7.1 Hz, CH2CH3), 6.49 (s, 1H, HThiazol), 7.08–7.60 (m, 4H, HAr), 7.75 (d, 1H, J = 7.5 Hz, HAr), 7.81 (d, 1H, J = 7.4 Hz, HAr), 7.86 (d, 1H, J = 7.4 Hz, HAr), 8.66 (d, 1H, J = 7.6 Hz, HAr), 10.36 11.40 (br. s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 14.12 (CH3), 33.88 (CH2), 60.73 (CH2CH3), 103.12 (CH–S), 120.15, 120.78, 127.66, 127.69, 128.15, 128.25, 128.85, 129.69, 130.86, 133.72, 136.96, 138.77, 140.12 (CAr + CThiazol), 147.79 (C=N), 169.01 (N=C–S) 173.26 (C=O). Anal. Calcd for C20H17N3O2S: C 66.10%, H 4.71%, N 11.56%. Found: C 65.95%, H 4.63%, N 11.47%.
2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-4-phenyl-1,3-thiazole (4e) (See Figures S11 and S12 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with ethyl 2-bromoacetophenone (0.22 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 0.5 h. The product 4e yield was 0.31 g (89%), m.p. 156–157 °C, data found in ref. [36] 156–157 °C. FTIR (KBr) vmax: 3412 (NH); 1599, 1491 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 7.20 (s, 1H, HThiazol), 7.28–7.58 (m, 7H, HAr), 7.65–8.05 (m, 5H, HAr), 8.68 (d, 1H, J = 7.5 Hz, HAr). 13C NMR (101 MHz, DMSO-d6) δ: 102.47 (CH–S) 120.19, 120.22, 120.81, 125.44, 127.75, 127.78, 128.03, 128.34, 128.80, 129.06, 129.94, 130.50, 136.89, 138.77, 140.32 (CAr + CThiazol), 147.23 (C=N), 172.83 (N=C–S). Anal. Calcd for C22H15N3S: C 74.76%, H 4.28%, N 11.89%. Found: C 74.59%, H 4.04%, N 11.84%.
4-(3,4-Dichlorophenyl)-2-[2-(9H-fluoren-9-ylidene)hydrazinyl]-1,3-thiazole (4f) (See Figures S13 and S14 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with ethyl 2-bromo-3′-chloroacetophenone (0.26 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 5 h. The product 4f yield was 0.30 g (85%), m.p. 205–206 °C. FTIR (KBr) vmax: 3335 (NH); 1607,1596 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 7.14–7.59 (m, 6H, HAr), 7.68–7.93 (m, 4H, HAr), 7.97 (s, 1H, HThiazol), 8.61 (br. s, 1H, HAr), 12.12 (br. s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 105.09 (CH–S) 120.22, 120.31, 120.85, 124.01, 125.16, 127.84, 129.24, 130.17, 130.64, 133.67, 136.77, 138.76, 140.49 (CAr + CThiazol), 148.77 (C=N), 171.54 (N=C–S). Anal. Calcd for C22H13Cl2N3S: C 62.57%, H 3.10%, N 9.95%. Found: C 62.35%, H 3.04%, N 9.67%.
4-(4-Chlorophenyl)-2-[2-(9H-fluoren-9-ylidene)hydrazinyl]-1,3-thiazole (4g) (See Figures S15 and S16 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with ethyl 2-bromo-4′-chloroacetophenone (0.26 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 5 h. The product 4g yield was 0.34 g (87%), m.p. 184–185 °C; found in ref. [36] 182–184 °C. FTIR (KBr) vmax: 3401 (NH); 1591, 1559 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 7.21–8.03 (m, 2H, HAr + HThiazol), 8.56 (br. s, 1H, HAr), 12.15 (br. s, 1H, HAr). 13C NMR (101 MHz, DMSO-d6) δ: 105.10 (CH–S) 120.25, 120.35, 120.86, 127.22, 127.85, 127.88, 128.82, 129.24, 130.12, 130.29, 132.71, 136.81, 138.78, 140.45 (CAr + CThiazol), 158.50 (C=N), 165.55 (N=C–S). Anal. Calcd for C22H14ClN3S: C 68.12%, H 3.64%, N 10.83%. Found: C 68.25%, H 3.50%, N 10.68%.
2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-4-(4-fluorophenyl)-1,3-thiazole (4h) (See Figures S17 and S18 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with ethyl 2-bromo-3′-fluoroacetophenone (0.22 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 3 h. The product 4h yield was 0.30 g (82%), m.p. 196–197 °C. FTIR (KBr) vmax: 3433 (NH); 1616, 1552 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 7.20 (s, 1H, HThiazol), 7.26–7.51 (m, 6H, HAr), 7.77 (d, 1H, J = 7.3 Hz, HAr), 7.84 (d, 1H, J = 7.4 Hz, HAr), 7.86–8.03 (m, 3H, HAr), 8.64 (d, 1H, J = 7.6 Hz, HAr), 12.11 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 102.44 (CH–S) 115.54, 115.76, 120.16, 120.66, 127.55, 127.63, 127.69, 128.80, 129.71, 136.95, 138.53, 140.13, 160.68, 163.11 (CAr + CThiazol), 148.04 (C=N), 172.15 (N=C–S). Anal. Calcd for C22H14FN3S: C 71.14%, H 3.80%, N 11.31%. Found: C 71.29%, H 3.94%, N 11.14%.
4-{2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-1,3-thiazol-4-yl}benzonitrile (4i) (See Figures S19 and S20 for NMR spectra)
The reaction of carbothioamide 1 (0.25 g, 1 mmol) with ethyl 2-bromo-4′-cyanoacetophenone (0.22 g, 1.1 mmol) was carried out in 20 mL tetrahydrofuran by heating under reflux for 4 h. The product 4i yield was 0.35 g (92%), m.p. 209–210 °C. FTIR (KBr) vmax: 3415 (NH); 1608, 1556 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 7.23–7.55 (m, 4H, HAr) 7.63 (s, 1H, HThiazol), 7.77 (d, 1H, J = 7.4 Hz, HAr), 7.84 (d, 1H, J = 7.4 Hz, HAr), 7.91 (t, 3H, J = 7.6 Hz, HAr), 8.08 (d, 2H, J = 8.1 Hz, HAr), 8.56 (d, 1H, J = 7.6 Hz, HAr), 12.16 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 107.57 (CH–S) 110.02, 115.06, 118.86, 120.21, 120.32, 120.76, 126.06, 127.54, 127.80, 129.10, 130.06, 132.77, 136.81, 138.58, 140.38, 142.77 (CAr + CThiazol), 146.26 (C=N), 172.61 (N=C–S). Anal. Calcd for C23H14N4S: C 73.00%, H 3.73%, N 14.80%. Found: C 72.85%, H 3.61%, N 14.78%.
1-{2-[2-(9H-Fluoren-9-ylidene)hydrazinyl]-4-methyl-1,3-thiazol-5-yl}ethan-1-one (5) (See Figures S21 and S22 for NMR spectra)
A mixture of carbothioamide 1 (0.25 g, 1 mmol), 3-chloro-2,4-pentanedione (0.15 g, 1.1 mmol), sodium acetate (0.25 g, 3 mmol), and 20 mL tetrahydrofuran was refluxed for 12 h. Then, the reaction mixture was cooled down and diluted with 20 mL water; precipitate was filtered off and washed with diethyl ether. Product 5 was purified by recrystallization method from 1,4-dioxane, m.p. 253–254 °C, yield 0.26 g (79%). FTIR (KBr) vmax: 3405 (NH); 1652, 1604 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 2.40 (s, 3H, CH3), 2.61 (s, 3H, CH3), 7.12–7.62 (m, 4H, HAr) 7.65–8.06 (m, 3H, HAr), 8.68 (d, 1H, J = 7.6 Hz, HAr). 13C NMR (101 MHz, DMSO-d6) δ: 14.77 (CH3), 29.07 (CH3), 116.57, 120.23, 120.25, 121.23, 127.83, 127.85, 128.92, 129.54, 130.21, 131.22, 136.66, 139.34, 140.53, 145.54 (CAr + CThiazol), 151.15 (C=N); 169.81 (N=C–S), 188.72 (C=O). Anal. Calcd for C19H15N3OS: C 68.45%, H 4.53%, N 12.60%. Found: C 68.32%, H 4.37%, N 12.36%.
Ethyl 2-[2-(9H-fluoren-9-ylidene)hydrazinyl]-4-methyl-1,3-thiazole-5-carboxylate (6) (See Figures S23 and S24 for NMR spectra)
A mixture of carbothioamide 1 (0.25 g, 1 mmol), ethyl 2-chloroacetoacetate (0.18 g, 1.1 mmol), sodium acetate (0.25 g, 3 mmol), and 20 mL tetrahydrofuran was refluxed for 24 h. Then, the reaction mixture was cooled down and diluted with 20 mL water; precipitate was filtered off and washed with diethyl ether. The product 6 was purified by recrystallization method from 1,4-dioxane, m.p. 185–186 °C, yield 0.30 g (77%). FTIR (KBr) vmax: 3411 (NH); 1715 (C=O); 1605, 1582 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (t, 3H, J = 7.1 Hz, CH2CH3), 2.47 (s, 2H, CH3), 4.21 (q, 2H, J = 7.1 Hz, CH2CH3), 7.16–7.54 (m, 5H, HAr), 7.71–7.92 (m, 3H, HAr), 8.66 (d, 1H, J = 7.5 Hz, HAr), 10.95 (br. s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 13.82 (CH2CH3), 14.82 (CH3), 60.52 (CH2CH3), 103.62, 120.23, 121.21, 127.83, 128.84, 129.50, 130.18, 131.19, 136.66, 139.30, 140.51, 147.21 (CAr + CThiazol), 150.89 (C=N); 161.39 (C=O), 170.23 (N=C–S). Anal. Calcd for C20H17N3O2S: C 66.10%, H 4.72%, N 11.56%. Found: C 66.93%, H 4.57%, N 11.38%.
2-[2-(9H-Fluoren-9-ylidene)hydrazinyl][1,3]thiazolo [4,5-b]quinoxaline (7) (See Figures S25 and S26 for NMR spectra)
A mixture of carbothioamide 1 (0.25 g, 1 mmol), 2,3-dichloroquinoxaline (0.24 g, 1.2 mmol), sodium acetate (0.25 g, 3 mmol), and 20 mL 1,4-dioxane was refluxed for 12 h. Then, the reaction mixture was cooled down and diluted with 20 mL water; precipitate was filtered off and washed with diethyl ether. Product 7 was purified by recrystallization method from 1,4-dioxane, m.p. 251–252 °C, yield 0.31 g (81%). FTIR (KBr) vmax: 3428 (NH); 1627, 1608, 1573 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6) δ: 7.10–8.10 (m, 12H, HAr), 9.93 (s, 1H, NH). 13C NMR (101 MHz, DMSO-d6) δ: 120.97, 123.83, 127.36, 127.56, 127.94, 127.97, 129.04, 129.40, 130.08, 133.51, 133.82, 134.86, 139.10, 139.44, 141.44, 141.90, 142.49, 142.94, 143.17, 145.11, (CAr + CThiazol), 148.68, 148.78, 156.80 (C=N); 163.87 (N=C–S). Anal. Calcd for C22H13N5S: C 69.64%, H 3.45%, N 18.46%. Found: C 69.45%, H 3.50%, N 18.21%.

4. Conclusions

A series of 2-aminothiazole derivatives containing fluorenyl hydrazone moiety in the molecules were synthesized by the Hantzsch reaction mechanism and evaluated for their in vitro antimicrobial activity using strains of multidrug-resistant bacterial and fungal pathogens preliminarily. Thiazolone 2 possesses the most potent activity against the tested strains of multidrug-resistant S. aureus and E. faecalis ATCC.

Supplementary Materials

The following are available online, Figure S1: 1H-NMR of compound 2, Figure S2: 13C-NMR of compound 2, Figure S3: 1H-NMR of compound 4a, Figure S4: 13C-NMR of compound 4a, Figure S5: 1H-NMR of compound 4b, Figure S6: 13C-NMR of compound 4b, Figure S7: 1H-NMR of compound 4c, Figure S8: 13C-NMR of compound 4c, Figure S9: 1H-NMR of compound 4d, Figure S10: 13C-NMR of compound 4d, Figure S11: 1H-NMR of compound 4e, Figure S12: 13C-NMR of compound 4d, Figure S13: 1H-NMR of compound 4f, Figure S14: 13C-NMR of compound 4f, Figure S15: 1H-NMR of compound 4g, Figure S16: 13C-NMR of compound 4g, Figure S17: 1H-NMR of compound 4h, Figure S18: 13C-NMR of compound 4h, Figure S19: 1H-NMR of compound 4i, Figure S20: 13C-NMR of compound 4i, Figure S21: 1H-NMR of compound 5, Figure S22: 13C-NMR of compound 5, Figure S23: 1H-NMR of compound 6, Figure S24: 13C-NMR of compound 6, Figure S25: 1H-NMR of compound 7, Figure S26: 13C-NMR of compound 7.

Author Contributions

Conceptualization, K.A. and P.K.; methodology, K.A.; software, K.A.; validation, K.A., I.S. and P.K.; formal analysis, K.A.; investigation, K.A., I.S. and P.K.; resources, K.A.; data curation, K.A.; writing—original draft preparation, K.A.; writing—review and editing, K.A.; visualization, K.A.; supervision, K.A.; project administration, K.A.; funding acquisition, K.A. All authors have read and agreed to the published version of the manuscript.

Funding

This study received no external funding.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding author.

Acknowledgments

I want to thank Vytautas Mickevičius for administrative and technical support and materials used for experiments.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Mishra, R.; Sachan, N.; Kumar, N.; Mishra, I.; Chand, P. Thiophene Scaffold as Prospective Antimicrobial Agent: A Review. J. Heterocycl. Chem. 2018, 55, 2019–2034. [Google Scholar] [CrossRef]
  2. Mishra, I.; Mishra, R.; Mujwar, S.; Chandra, P.; Sachan, N. A Retrospect on Antimicrobial Potential of Thiazole Scaffold. J. Heterocycl. Chem. 2020, 57, 2304–2329. [Google Scholar] [CrossRef]
  3. Gürsoy, E.; Güzeldemirci, N.U. Synthesis and Primary Cytotoxicity Evaluation of New Imidazo[2,1-b]Thiazole Derivatives. Eur. J. Med. Chem. 2007, 42, 320–326. [Google Scholar] [CrossRef]
  4. Aridoss, G.; Amirthaganesan, S.; Kim, M.S.; Kim, J.T.; Jeong, Y.T. Synthesis, Spectral and Biological Evaluation of Some New Thiazolidinones and Thiazoles Based on t-3-Alkyl-r-2,c-6-Diarylpiperidin-4-Ones. Eur. J. Med. Chem. 2009, 44, 4199–4210. [Google Scholar] [CrossRef] [PubMed]
  5. Kashyap, S.J.; Garg, V.K.; Sharma, P.K.; Kumar, N.; Dudhe, R.; Gupta, J.K. Thiazoles: Having Diverse Biological Activities. Med. Chem. Res. 2012, 21, 2123–2132. [Google Scholar] [CrossRef]
  6. Abdel-Wahab, B.F.; Khidre, R.E.; Awad, G.E.A. Design and Synthesis of Novel 6-(5-Methyl-1H-1,2,3-Triazol-4-Yl)-5-[(2-(Thiazol-2-Yl)Hydrazono)Methyl]Imidazo[2,1-b]Thiazoles as Antimicrobial Agents. J. Heterocycl. Chem. 2017, 54, 489–494. [Google Scholar] [CrossRef]
  7. Abu-Melha, S.; Edrees, M.M.; Salem, H.H.; Kheder, N.A.; Gomha, S.M.; Abdelaziz, M.R. Synthesis and Biological Evaluation of Some Novel Thiazole-Based Heterocycles as Potential Anticancer and Antimicrobial Agents. Molecules 2019, 24, 539. [Google Scholar] [CrossRef]
  8. Althagafi, I.; El-Metwaly, N.; Farghaly, T.A. New Series of Thiazole Derivatives: Synthesis, Structural Elucidation, Antimicrobial Activity, Molecular Modeling and MOE Docking. Molecules 2019, 24, 1741. [Google Scholar] [CrossRef] [PubMed]
  9. Deshineni, R.; Velpula, R.; Koppu, S.; Pilli, J.; Chellamella, G. One-pot Multi-component Synthesis of Novel Ethyl-2-(3-((2-(4-(4-aryl)Thiazol-2-yl)Hydrazono)Methyl)-4-hydroxy/Isobutoxyphenyl)-4-methylthiazole-5-carboxylate Derivatives and Evaluation of Their in Vitro Antimicrobial Activity. J. Heterocycl. Chem. 2020, 57, 1361–1367. [Google Scholar] [CrossRef]
  10. Jagadale, S.; Chavan, A.; Shinde, A.; Sisode, V.; Bobade, V.D.; Mhaske, P.C. Synthesis and Antimicrobial Evaluation of New Thiazolyl-1,2,3-Triazolyl-Alcohol Derivatives. Med. Chem. Res. 2020, 29, 989–999. [Google Scholar] [CrossRef]
  11. Minickaitė, R.; Grybaitė, B.; Vaickelionienė, R.; Kavaliauskas, P.; Petraitis, V.; Petraitienė, R.; Tumosienė, I.; Jonuškienė, I.; Mickevičius, V. Synthesis of Novel Aminothiazole Derivatives as Promising Antiviral, Antioxidant and Antibacterial Candidates. Int. J. Mol. Sci. 2022, 23, 7688. [Google Scholar] [CrossRef] [PubMed]
  12. Cascioferro, S.; Parrino, B.; Carbone, D.; Schillaci, D.; Giovannetti, E.; Cirrincione, G.; Diana, P. Thiazoles, Their Benzofused Systems, and Thiazolidinone Derivatives: Versatile and Promising Tools to Combat Antibiotic Resistance. J. Med. Chem. 2020, 63, 7923–7956. [Google Scholar] [CrossRef] [PubMed]
  13. Kavaliauskas, P.; Grybaitė, B.; Vaickelionienė, R.; Sapijanskaitė-Banevič, B.; Anusevičius, K.; Kriaučiūnaitė, A.; Smailienė, G.; Petraitis, V.; Petraitienė, R.; Naing, E.; et al. Synthesis and Development of N-2,5-Dimethylphenylthioureido Acid Derivatives as Scaffolds for New Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens. Antibiotics 2023, 12, 220. [Google Scholar] [CrossRef] [PubMed]
  14. Sadek, B.; Al-Tabakha, M.M.; Fahelelbom, K.M.S. Antimicrobial Prospect of Newly Synthesized 1,3-Thiazole Derivatives. Molecules 2011, 16, 9386–9396. [Google Scholar] [CrossRef] [PubMed]
  15. Arshad, M.F.; Alam, A.; Alshammari, A.A.; Alhazza, M.B.; Alzimam, I.M.; Alam, M.A.; Mustafa, G.; Ansari, M.S.; Alotaibi, A.M.; Alotaibi, A.A.; et al. Thiazole: A Versatile Standalone Moiety Contributing to the Development of Various Drugs and Biologically Active Agents. Molecules 2022, 27, 3994. [Google Scholar] [CrossRef] [PubMed]
  16. Al-Omair, M.A.; Sayed, A.R.; Youssef, M.M. Synthesis and Biological Evaluation of Bisthiazoles and Polythiazoles. Molecules 2018, 23, 1133. [Google Scholar] [CrossRef]
  17. Abdallah, A.M.; Gomha, S.M.; Zaki, M.E.A.; Abolibda, T.Z.; Kheder, N.A. A Green Synthesis, DFT Calculations, and Molecular Docking Study of Some New Indeno[2,1-b]Quinoxalines Containing Thiazole Moiety. J. Mol. Struct. 2023, 1292, 136044. [Google Scholar] [CrossRef]
  18. Ivasechko, I.; Yushyn, I.; Roszczenko, P.; Senkiv, J.; Finiuk, N.; Lesyk, D.; Holota, S.; Czarnomysy, R.; Klyuchivska, O.; Khyluk, D.; et al. Development of Novel Pyridine-Thiazole Hybrid Molecules as Potential Anticancer Agents. Molecules 2022, 27, 6219. [Google Scholar] [CrossRef]
  19. Wang, H.; Zhou, Y.; Lu, L.; Cen, J.; Wu, Z.; Yang, B.; Zhu, C.; Cao, J.; Yu, Y.; Chen, W. Identification of 5-Thiocyanatothiazol-2-Amines Disrupting WDR5-MYC Protein-Protein Interactions. ACS Med. Chem. Lett. 2024, 15, 1143–1150. [Google Scholar] [CrossRef]
  20. Shahin, I.G.; Abutaleb, N.S.; Alhashimi, M.; Kassab, A.E.; Mohamed, K.O.; Taher, A.T.; Seleem, M.N.; Mayhoub, A.S. Evaluation of N-Phenyl-2-Aminothiazoles for Treatment of Multi-Drug Resistant and Intracellular Staphylococcus Aureus Infections. Eur. J. Med. Chem. 2020, 202, 112497. [Google Scholar] [CrossRef]
  21. Khayyat, A.N.; Mohamed, K.O.; Malebari, A.M.; El-Malah, A. Design, Synthesis, and Antipoliferative Activities of Novel Substituted Imidazole-Thione Linked Benzotriazole Derivatives. Molecules 2021, 26, 5983. [Google Scholar] [CrossRef] [PubMed]
  22. Fouad, M.A.; Zaki, M.Y.; Lotfy, R.A.; Mahmoud, W.R. Insight on a New Indolinone Derivative as an Orally Bioavailable Lead Compound against Renal Cell Carcinoma. Bioorg. Chem. 2021, 112, 104985. [Google Scholar] [CrossRef]
  23. Liu, W.; Tao, C.; Tang, L.; Li, J.; Jin, Y.; Zhao, Y.; Hu, H. A Convenient and Efficient Synthesis of Heteroaromatic Hydrazone Derivatives via Cyclization of Thiosemicarbazone with Ω-bromoacetophenone. J. Heterocycl. Chem. 2011, 48, 361–364. [Google Scholar] [CrossRef]
  24. Sim, K.-M.; Chung, L.-P.; Tan, K.-L.; Tan, Y.-T.; Kee, X.-L.; Teo, K.-C. One-Pot Multicomponent Synthesis of Hydrazinyl Thiazoles Bearing an Isatin Moiety in Aqueous Medium. Lett. Org. Chem. 2024, 21, 192–200. [Google Scholar] [CrossRef]
  25. Wang, Y.T.; Huang, X.; Cai, X.C.; Kang, X.X.; Zhu, H.L. Synthesis, Biological Evaluation and Molecular Docking of Thiazole Hydrazone Derivatives Grafted with Indole as Novel Tubulin Polymerization Inhibitors. J. Mol. Struct. 2024, 1301, 137343. [Google Scholar] [CrossRef]
  26. Urade, R.; Chang, W.-T.; Ko, C.-C.; Li, R.-N.; Yang, H.-M.; Chen, H.-Y.; Huang, L.-Y.; Chang, M.-Y.; Wu, C.-Y.; Chiu, C.-C. A Fluorene Derivative Inhibits Human Hepatocellular Carcinoma Cells by ROS-Mediated Apoptosis, Anoikis and Autophagy. Life Sci. 2023, 329, 121835. [Google Scholar] [CrossRef]
  27. Wang, X.; Wang, Y.; Yu, J.; Qiu, Q.; Liao, R.; Zhang, S.; Luo, C. Reduction-Hypersensitive Podophyllotoxin Prodrug Self-Assembled Nanoparticles for Cancer Treatment. Pharmaceutics 2023, 15, 784. [Google Scholar] [CrossRef]
  28. Vlad, I.M.; Nuță, D.C.; Ancuceanu, R.V.; Costea, T.; Coanda, M.; Popa, M.; Marutescu, L.G.; Zarafu, I.; Ionita, P.; Pirvu, C.E.D.; et al. Insights into the Microbicidal, Antibiofilm, Antioxidant and Toxicity Profile of New O-Aryl-Carbamoyl-Oxymino-Fluorene Derivatives. Int. J. Mol. Sci. 2023, 24, 7020. [Google Scholar] [CrossRef] [PubMed]
  29. Pasieka, A.; Panek, D.; Zaręba, P.; Sługocka, E.; Gucwa, N.; Espargaró, A.; Latacz, G.; Khan, N.; Bucki, A.; Sabaté, R.; et al. Novel Drug-like Fluorenyl Derivatives as Selective Butyrylcholinesterase and β-Amyloid Inhibitors for the Treatment of Alzheimer’s Disease. Bioorg. Med. Chem. 2023, 88–89, 117333. [Google Scholar] [CrossRef]
  30. Zhang, X.; Xu, J.-K.; Wang, J.; Wang, N.-L.; Kurihara, H.; Kitanaka, S.; Yao, X.-S. Bioactive Bibenzyl Derivatives and Fluorenones from Dendrobium Nobile. J. Nat. Prod. 2007, 70, 24–28. [Google Scholar] [CrossRef]
  31. Ray, S.; Pathak, S.R.; Chaturvedi, D. Organic Carbamates in Drug Development. Part II: Antimicrobial Agents—Recent Reports. Drugs Future 2005, 30, 0161. [Google Scholar] [CrossRef]
  32. Parašotas, I.; Anusevičius, K.; Vaickelionienė, R.; Jonuškienė, I.; Stasevych, M.; Zvarych, V.; Komarovska-Porokhnyavets, O.; Novikov, V.; Belyakov, S.; Mickevicius, V. Synthesis and Evaluation of the Antibacterial, Antioxidant Activities of Novel Functionalized Thiazole and Bis(Thiazol-5-Yl)Methane Derivatives. Arkivoc 2018, 2018, 240–256. [Google Scholar] [CrossRef]
  33. Youssef, N.S.; El Zahany, E.A.; Anwar, M.M.; Hassan, S.A. Synthesis, Characterization, and Antitumor Activity of Some Metal Complexes with Schiff Bases Derived from 9-Fluorenone as a Polycyclic Aromatic Compound. Phosphorus Sulfur Silicon Relat. Elem. 2008, 184, 103–125. [Google Scholar] [CrossRef]
  34. Pavlenko, A.F.; Moshchitskii, S.D. Synthesis of Physiologically Active Compounds of the Thiosemicarbazone Series and Derivatives. Chem. Heterocycl. Compd. 1967, 3, 195–196. [Google Scholar] [CrossRef]
  35. Doddagaddavalli, M.A.; Kalalbandi, V.K.A.; Naik, T.R.R.; Joshi, S.D.; Seetharamappa, J. Fluorenone–Thiazolidine-4-One Scaffolds as Antidiabetic and Antioxidant Agents: Design, Synthesis, X-ray Crystal Structures, and Binding and Computational Studies. New J. Chem. 2023, 47, 13581–13599. [Google Scholar] [CrossRef]
  36. Kaur, A.P.; Gautam, D. Ultrasound Aided Expedient Synthesis, Characterization and Antimicrobial Studies of Fluorenyl-Hydrazono-Thiazole Derivatives. Asian J. Chem. 2019, 31, 2245–2248. [Google Scholar] [CrossRef]
Molbank 2024 m1872 sch001
Scheme 1. Synthesis of thiazole derivatives 2–7.
Scheme 1. Synthesis of thiazole derivatives 2–7.
Molbank 2024 m1872 sch001
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Anusevičius, K.; Stebrytė, I.; Kavaliauskas, P. Synthesis and Antimicrobial Evaluation of 2-[2-(9H-Fluoren-9-ylidene)hydrazin-1-yl]-1,3-thiazole Derivatives. Molbank 2024, 2024, M1872. https://doi.org/10.3390/M1872

AMA Style

Anusevičius K, Stebrytė I, Kavaliauskas P. Synthesis and Antimicrobial Evaluation of 2-[2-(9H-Fluoren-9-ylidene)hydrazin-1-yl]-1,3-thiazole Derivatives. Molbank. 2024; 2024(3):M1872. https://doi.org/10.3390/M1872

Chicago/Turabian Style

Anusevičius, Kazimieras, Ignė Stebrytė, and Povilas Kavaliauskas. 2024. "Synthesis and Antimicrobial Evaluation of 2-[2-(9H-Fluoren-9-ylidene)hydrazin-1-yl]-1,3-thiazole Derivatives" Molbank 2024, no. 3: M1872. https://doi.org/10.3390/M1872

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop