In Silico Driven Design and Synthesis of Rhodanine Derivatives as Novel Antibacterials Targeting the Enoyl Reductase InhA.

Here, we report on the design, synthesis, and biological evaluation of 4-thiazolidinone (rhodanine) derivatives targeting Mycobacterial tuberculosis (Mtb) trans-2-enoyl-acyl carrier protein reductase (InhA). Compounds having bulky aromatic substituents at position 5 and a tryptophan residue at position N-3 of the rhodanine ring were the most active against InhA, with IC50 values ranging from 2.7 to 30 µM. The experimental data showed consistent correlations with computational studies. Their antimicrobial activity was assessed against Mycobacterium marinum (Mm) (a model for Mtb), Pseudomonas aeruginosa (Pa), Legionella pneumophila (Lp), and Enterococcus faecalis (Ef) by using anti-infective, antivirulence, and antibiotic assays. Nineteen out of 34 compounds reduced Mm virulence at 10 µM. 33 exhibited promising antibiotic activity against Mm with a MIC of 0.21 µM and showed up to 89% reduction of Lp growth in an anti-infective assay at 30 µM. 32 showed high antibiotic activity against Ef, with a MIC of 0.57 µM.

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-SUBSTITUED 4-THIAZOLIDINONES WITH SULFANILAMIDE PHARMACOPHORE.

After incorporation pharmacophores of allylamine and sulfanilamide into 4-thiazolidinone's ring - no antimicrobial activity was determined. This outcome stimulated synthesis of new group - 5-substituted 4-thiazolidinones. In the literature it is noted that the fragment of aldehyde in 5 position of 4-thiazolidinone's ring should give or increase biological activity. So, it was decided to incorporate fragment of aldehyde into 4-thiazolidinone's ring together with sulfanilamide pharmacophore, investigate antimicrobial activity and compare it with initial compounds - sulfanilamides. It was established that new compounds suppressed growth of S. arteus, E. coli, B. subtilis, P. mirabilis, C. albicans. Sulfanilamide, sulfapyridine and/or 2-chlorobenzaldehyde were incorporated into the structure of the most active compounds. It was concluded that synthesis of 4-thiazolidinones substituted by aldehyde in 5 position and sulfanilamide in 2 position are not potential antimicrobial agents.

Synthesis and in vitro antimicrobial study of 4-thiazolidinone containing sulfanilamide.

The title compounds, 3-allyl-2-sulfanylamido-4-thiazolidinones (2a-d), have been synthesized after substitution of amino group of sulfanylamide with allylisothiocyanate and cyclization into 4-thiazolidinones. The synthesized compounds were tested for their antibacterial and antifungal activity (MIC) in vitro) against microorganisms: S. aureus, E. faecalis. E. coli, P. aeruginosa, K. pneumoniae, P. mirabilis, B. subtilis, B. cereus and C. albicans taking sulfadimidine, sulfathiazole, sulfanilamide and sulfamethizole as standard drugs. Synthesized compounds (2a-d) demonstrated selective activity against B. cereus.

Synthesis and antimicrobial properties of naphthylamine derivatives having a thiazolidinone moiety.

OBJECTIVE: The aim of this study was to evaluate the influence of pharmacophores having naphthylamine and nitro groups on the antimicrobial (antibacterial and antifungal) activity of thiazolidinone derivatives. MATERIALS AND METHODS: The initial 5-substituted-2-methylmercaptothiazolidin-4-ones were subjected to S-demethylation to yield 2-amino-substituted thiazolidinones. 4-Nitro-1-naphthylamine, nitrofuran aldehydes, and nitrobenzene aldehydes were used as pharmacophoric compounds having amino or aldehyde groups. Antimicrobial (antibacterial and antifungal) activity of the new compounds was tested in vitro against bacterial cultures - Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Klebsiella pneumoniae - and fungal cultures - Candida albicans, Candida glabrata, Candida krusei, Candida kefyr, Candida tropicalis, and Candida parapsilosis. RESULTS: Microbiological analysis showed that all new thiazolidinone derivatives with nitronaphthylamine substituent possessed antibacterial and antifungal properties. New compounds 2a-b showed similar antibacterial activity in vitro against S. aureus and B. subtilis as aminopenicillins. The lowest antibacterial activity of all newly synthesized compounds was against capsule-forming bacteria K. pneumoniae and against gram-negative bacteria E. coli (minimum inhibitory concentration range, 500-1000 µg/mL). CONCLUSIONS: The minimum inhibitory concentration of naphthylamine derivatives varied in the range of 0.4-1000 µg/mL, and activity of some newly synthesized compounds was similar to the activity of aminopenicillins and fluconazole, an antifungal preparation. Based on the results, it is possible to separate the perspective group of potential antimicrobial compounds.

New ethacridine derivatives as the potential antifungal and antibacterial preparations.

Until the 20th century fungal infections were rather easy cured, and the need of new antifungal drugs was low. However, low choice of antifungal preparations, their toxicity, limited spectrum of action, and ability to produce resistant strains show the need of new effective medicines for systemic fungal diseases in nowadays. Our goal of research was to synthesize new antimicrobial compounds containing three or more pharmacophores in one molecule. The initial 5-substituted-2-methylmercaptothiazolidin-4-ones were subjected to S-demethylation to yield 2-amino-substituted thiazolidinones. Ethacridine, nitrofuran aldehydes and nitrobenzene aldehyde as pharmacophoric amino or aldehyde group having compounds have been used. Antimicrobial (antifungal) activity of the new compounds was screened in vitro in these bacterial cultures: Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Bacillus subtilis ATCC 6633, Klebsiella pneumoniae ATCC 33499 and fungal cultures: Candida albicans ATCC 60193, Candida glabrata, Candida krusei, Candida kefyr ATCC 8614, Candida tropicalis ATCC 8302, Candida parapsilosis. Results showed that the new compounds were significantly more effective as antimicrobial agents than initial preparation ethacridine. Ethacridine derivatives were not only effective against numerous gram-positive and some gram-negative bacteria, but the spectrum of action has been discovered against fungi. Minimal fungistatic concentration varies in the range 10.0-750 microg/mL and antibacterial concentration is in the range 62.5-1000 microg/mL. Compound 2a having nitrofuryl substituent in the fifth position of tiazolidine cycle was the most active of synthesized ethacridine compounds. The obtained results gave the opportunity to separate the perspective group of potential antiinfective compounds.