Antimicrobial activity of some novel 2-(2-iodophenylimino)-5-arylidenethiazolidin-4-one derivatives
Article Category: Original article
Pubblicato online: 10 ott 2018
Pagine: 405 - 412
DOI: https://doi.org/10.1515/abm-2018-0015
Parole chiave
© 2017 Duy Toan Pham et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.
Infectious diseases are among the most dangerous and deadly diseases worldwide. This is highlighted by the emergence of the
Thiazolidin-4-one is a 5-membered heterocyclic ring structure including sulfur and nitrogen located at positions 1 and 3, respectively, and a carbonyl group on the fourth carbon. This structure has been acknowledged as a powerful pharmacophore because of its therapeutic effects on almost all kinds of diseases [4]. Some notable actions of thiazolidin-4-one are antiproliferative [5], anti-HIV [6], antioxidant [7], anticonvulsant [8], and antimicrobial [910, 11, 12, 13] effects. An aryl substitution at position 5 of thiazolidin-4-one can dramatically increase the potency of pharmacological effects [4]. Related derivatives including 5-arylidene-2-imino-4-thiazolidinones have respectable activities on both bacteria (
Chavan and Pai suggested a simple method for synthesizing a 5-arylidenethiazolidin-4-one ring from initial aromatic amine derivatives [9]. However, the yield of their products was <70%. By adopting their procedure, we aimed to modify the synthetic process to increase the yield.
The objective of this study was to synthesize the 2-(2-iodophenylimino)-5-arylidenethiazolidin-4-one derivatives from 2-iodoaniline, improve the synthetic procedures, and evaluate the antimicrobial activities of the products.
Reagents: 2-iodoaniline, chloroacetic acid, K2CO3, potassium thiocyanate (KSCN), ammonium thiocyanate (NH4SCN), dimethylamine, triethylamine, and aromatic aldehydes (4-methoxybenzaldehyde; 2,4-dichlorobenzaldehyde; 4-chlorobenzaldehyde; 4-fluorobenzaldehyde; 4-methylbenzaldehyde; 4-nitrobenzaldehyde; 2-nitrobenzaldehyde; 2-hydroxybenzaldehyde; 4-hydroxy-3-methoxybenzaldehyde; benzaldehyde; 5-bromo-2-hydroxybenzaldehyde; and 4-dimethylaminobenzaldehyde) were reagent grade or better and imported from Sigma-Aldrich (Singapore).
Solvents: ethanol, dimethylformamide (DMF), glacial acetic acid, toluene, ethyl acetate, methanol, chloroform, dioxane, and dimethylsulfoxide (DMSO) were purchased from Merck (USA) and were laboratory grade or better.
Test medium and positive reference: Mueller–Hinton agar (MHA) was purchased from Sigma-Aldrich, and cephalexin with a purity of >99% was purchased from DHG (Vietnam).
Bacterial strains:
Fungal strains:
The synthetic process was modified from a previous study and is shown in
Scheme 1
Synthesis process for 2-iodophenylimino-5-arylidenethiazolidin-4-one. The initial reactant, 2-iodoaniline, underwent the first acylation with chloroacetic acid, a second cyclization with ammonium thiocyanate, and a final aldol condensation with various aromatic aldehydes.
All compounds synthesized (
The melting points (mps) were measured using an open capillary method with Stuart SMP3 apparatus (Barloworld Scientific, UK). Infrared (IR) spectra were obtained on an FTIR Bruker Alpha T spectrophotometer (Bruker, USA), using a KBr pellet technique. Ultraviolet (UV) spectra were obtained on a UV U2800 spectrophotometer (Hitachi, Japan). Nuclear magnetic resonance (NMR) spectra were obtained using an AV 500 MHz NMR spectrometer (Bruker, USA), with tetramethylsilane as an internal standard and deuterated DMSO (DMSO-
Antimicrobial activity of the synthesized compounds,
| Structure | Name | R | Bacteria | Fungi | |||||
|---|---|---|---|---|---|---|---|---|---|
| E. coli | P. aeruginosa | E. faecalis | S. aureus | MRSA | C. albicans | A. niger | |||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (4-methoxybenzylidene)thiazolidin- | 4”-OCH3 | − | − | − | >1024 | >1024 | − | − | |
| 4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (4-chlorobenzylidene)thiazolidin- | 4”-Cl | − | − | − | 8 | 4 | − | − | |
| 4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (2,4-dichlorobenzylidene)thiazoli- | 2”-Cl | − | − | − | >1024 | >1024 | − | − | |
| din-4-one | 4”-Cl | ||||||||
| 2-(2-Iodophenylimino)-5- | 4”-OH | ||||||||
| (4-hydroxy-3-methoxybenzylidene) | 3”-OCH | − | − | − | 16 | 16 | − | − | |
| thiazolidin-4-one | 3 | ||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (4-fluorobenzylidene)thiazolidin- | 4”-F | − | − | − | 8 | 8 | − | − | |
| 4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | − | − | − | >1024 | >1024 | − | − | ||
| benzylidenethiazolidin-4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (4-methylbenzylidene)thiazolidin- | 4”-CH3 | − | − | − | >1024 | 128 | − | − | |
| 4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (4-nitrobenzylidene)thiazolidin- | 4”-NO2 | − | − | − | 8 | 8 | − | − | |
| 4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (2-nitrobenzylidene)thiazolidin- | 2”-NO2 | − | − | >1024 | 8 | 32 | − | − | |
| 4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (2-hydroxybenzylidene)thiazolidin- | 2”-OH | − | − | − | >1024 | >1024 | − | − | |
| 4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | 2”-OH | ||||||||
| (5-bromo-2-hydroxybenzylidene) | 5”-Br | − | − | − | 64 | 64 | − | − | |
| thiazolidin-4-one | |||||||||
| 2-(2-Iodophenylimino)-5- | |||||||||
| (4-dimethylaminobenzylidene) | 4”-N(CH3)2 | − | − | − | − | – | − | − | |
| thiazolidin-4-one | |||||||||
| Cephalexin | 32 | 4 | 32 | ||||||
The tests were performed in duplicate; (–) indicates negative result (clear zone diameter was less than that for the negative control, DMSO); the number indicates the mean of the MIC (mg/mL) of compounds active against specific microbes.
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Compound
Antibacterial and antifungal activities of the 12 compounds (
The minimum inhibitory concentration (MIC) was determined using an agar dilution method [17]. Tested compounds in DMSO 2% were diluted with MHA medium to obtain accurate concentrations ranging from 2 to 1024 μg/mL. Each concentration was poured into plates contained 1-2 μL of suspension containing experimental strains (104 CFU/mL) and incubated at 35-37°C for 20-24 h. All assays were conducted in duplicate using cephalexin as the positive reference.
The yield of the intermediate
In the original method, the main purpose of adding K2CO3, a weak base, into the acylation reaction was to create a basic condition and consequently reduce the acidic products and shift the reaction in the desired direction [9]. However, adding K2CO3 had no apparent effect on our reaction. This may be a consequence of adding DMF. We used DMF to dissolve 2-iodoaniline; fortunately, DMF can protect the highly reactive chloroacetic acid structure [18] and simultaneously catalyze the aromatic acylation reaction [19]. Therefore, the inclusion of K2CO3 as a catalyst, in our case, was unnecessary.
For the cyclization reaction, the use of NH4SCN resulted in a better yield than with KSCN. This may be explained by the decomposition reaction of the products. NH4Cl can decompose at high temperature to make ammonia, whereas KCl is stable at the same temperature. Therefore, the reaction equilibrium with NH4SCN was shifted to the right, affording more products.Nevertheless, further investigations are needed to substantiate this hypothesis.
All compounds synthesized demonstrated acceptable physicochemical properties as predicted. Notably, the mass spectrum of compound
Compound
As shown in
Compound
Nevertheless, the effect of a nitro group on killing bacteria was clearly demonstrated on compounds
The MICs of 6 compounds illustrated good activity, especially compounds
In the present study, we achieved 3 objectives. The first was synthesis of 12 novel derivatives of 2-(2-iodophenylimino)5-arylidenethiazolidin-4-one, which are not yet to be found in chemical databases such as ChemSpider and PubChem. The second was to improve the synthetic process with simple laboratory equipment. The third was to investigate the antimicrobial activity of the synthesized compounds. Among them, 3 compounds,