Synthesis and antimicrobial activity of 5-R-benzyl-2-(arylidenehydrazono)thiazolidin-4-ones

© 2020 I. V. Drapak et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Biopolymers and Cell. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited UDC: 547.789.1+547.722


Introduction
The treatment of infectious diseases still remains an important and challenging problem because of a combination of factors including emerging infectious diseases and the increasing number of multi-drug resistant microbial pathogens. The therapeutic problem is of particular importance for hospitalised patients, immune suppressed patients with AIDS or undergoing anticancer therapy and organ transplantation. Though a large number of antibiotics and chemotherapeutics are available for medical use, the emergence of old and new antibiotic resistance caused in the last decades a substantial need for new classes of antibacterial agents. A potential approach to overcome the problem of resistance is to design innovative agents with a different mode of action so that no cross-resistance with the present drugs can occur.
Because heterocycles have a central position in both medicinal and organic chemistry, considerable attention has been focused on their syntheses. The nitrogen heterocycles in particular exhibit diverse biological and pharmacological activities partly due to the similarities with many natural and synthetic molecules with known biological activity. The substituted 4-thiazolidinones are one of the most extensively studied classes of heterocyclic compounds receiving much attention from synthetic organic as well as medicinal chemists because of the diverse range of their biological activities and obvious therapeutic properties [1][2][3]. They are used as antitubercular, antimicrobial, anti-inflammatory, antiviral and anti-HIV agents [1][2][3][4]. In view of biological importance of 4-thiazolidinone derivatives we report the synthesis and primary evaluation of antimicrobial activity [of] new 2-(arylidenehydrazono)-thiazolidin-4-one. Among such compounds, 5-arylidene-2-(aryl-2-ylmethylenehydrazono)thiazolidin-4-ones were studied. Their antimicrobial [5][6][7][8][9], antiviral [10], anti-inflammatory [11], antitumor [12,13] [properties] have been reported. These compounds are also the inhibitors of various enzymes [14][15][16]. At the same time, the less conformational restrictions of 5-benzyl-4-thiazolidinone derivatives are practically unexplored.

Materials and Methods
Chemistry. All starting materials were purchased from Merck and used without purification. NMR spectra were determined with Varian Mercury 400 (400 MHz) spectrometer, in DMSO-d 6 . Melting points were determined in open capillary tubes and are uncorrected. The purity of the compounds was checked by thin-layer chromatography performed with Merck Silica Gel 60 F254 aluminum sheets. (7a, b). A mixture of 0.01 mole of thiosemicarbazone 4a-d or 5, 0.01 mole of ester 3a-j and 0.82 g (0.01 mole) of sodium acetate in 25 ml of ethanol was refluxed for 4 h. After cooling the precipitate was filtered off and recrystallized from ethanol. Yield -4-one (6g)

2-(Furan-2-ylmethylenehydrazono)-5-(3trifluoromethyl-benzyl)-thiazolidin-4-one
Antifungal data collection. Growth inhibition of C. albicans was determined measuring absorbance at 530 nm (OD530), while the growth inhibition of C. neoformans was determined measuring the difference in absorbance between 600 and 570 nm (OD600-570), after the addition of resazurin (0.001 % final concentration) and incubation at 35°C for additional 2 h. The absorbance was measured using a Biotek Synergy HTX plate reader. The percentage of growth inhibition was calculated for each well, using the negative control (media only) and positive control (bacteria without inhibitors) on the same plate as references.

Inhibition. Percentage growth inhibition of an individual sample is calculated based on
Negative controls (media only) and Positive Controls (bacterial/fungal media without inhibitors). Negative inhibition values indicate that the growth rate (or OD600) is higher compared to the Negative Control (Bacteria/fungi only, set to 0 % inhibition). The growth rate for all bacteria and fungi has a variation of -/+ 10 %, which is within the reported normal distribution of bacterial/fungal growth.

Conclusions
A series of new 5-R-benzyl-2-(ary lide ne hydrazono)thiazolidin-4-ones were prepared. The antimicrobial screening of them against Gram positive, Gram negative microorganisms and fungi was performed and the results are described in this paper. It was found that some derivatives are active against Staphylococcus aureus and Cryptococcus neoformans.