Synthesis of new 4-thiazolidinone sulfanilamides derivates

Abstract

Antimicrobial resistance is resistance of a microorganism to an antimicrobial medicine to which it was originally sensitive. Resistant organisms are able to withstand attack by antimicrobial medicines, so that standard treatments become ineffective and infections persist increasing risk of spread to others [1]. Resistance is increasing in the EU among certain Gram-negative bacteria such as recently observed for Escherichia coli, also against Gram- positive bacteria such as Staphylococcus aureus [2]. New antimicrobial drug development is essential in order to treat antibiotic-resistant infections. Previously scientists from the Lithuanian university of health sciences department of drug chemistry discovered a synthetic derivate of 4-thiazolidinones has high activity particularly against Staphylococcus aureus (MIC= 0.25 μg/ml) and low toxicity (LD50= 5000 mg/kg). Also many others compounds bearing 4- thiazolidinone scaffold have been reported to have antimicrobial activity [3]. So this research was made in order to expand the new 4-thiazolidinones derivative structure activity relationship patterns. The main research aim – to determine the relationship between structure and antibacterial activity of the newly synthesized 4-thiazolidinones sulfadimidine derivatives to optimize the structure in order to obtain new, more active compounds, summarizing the relationship between pharmacological activity and chemical structure.Figure 1. Reactions scheme. R- sulfanilamides. Conditions: A- room temp., dimethylformamide, 4 hours; B- methyl bromoacetate, room temp., overnight; CHCl, heating, 30 min.To get new derivatives the targeted compounds were prepared in a three steps synthesis, as following (Figure 1). In the first step there were the conversion of amino acid into amino acid dithiocarbamate with carbon disulfide and potassium hydroxide (A). In the second step the amino acid dithiocarbamate was reacted with methyl bromoacetate (B). In next phase there were cyclization to 4- thiazolidinone ring with the sulfanilamide at position N-3 by boiling them in presence of hydrochloric acid for few hours. Then the condensation of 4- thiazolidinone with aldehydes (nitrofurfural and nitrofurfural akrolein) results the formation of 5-nitrofurfuraliden(nitrofurfuralakrolein)-4-thiazolidinone-Nsulfadimidine derivatives. Also there are synthesized compouds in analogy with sulfanilamide fragments at 3 and 4 positions (Figure 2 and 3). Figure 2. Reactions scheme. R- sulfanilamides. Conditions: A- dioxane; BSulfaninamide, ethanol. Figure 3. Synthesized compounds. Structure of compouds was demonstrated in quantitative tests sulfur and nitrogen.