Synthesis and Bacteriostatic Activities of Bis(thiourea) Derivatives with Variable Chain Length

Abstract

A series of 1,4-bis(decoxyphenyl)carbamothioyl-terephthalamide derivatives was successfully synthesised by reaction of benzene-1,4-dicarbonyl isothiocyanate intermediates with long alkyl chain. The alkylation was performed via Williamson etherification of 4-acetamidophenol with bromoalkanes. The synthesised bis(thiourea) derivatives differed in the chain length, CnH2n+1, where n=10, 12, and 14. The structures of all compounds were characterised by elemental CHN analysis, IR, 1H, and 13C NMR spectroscopies. Bacteriostatic activities of bis(thiourea derivatives which consisted of two folds of N-H, C=O, and C=S and long alkyl chain substituents were carried out against Gram-negative bacteria (Escherichia coli, ATCC 25922) via turbidimetric kinetic method. Bis(thiourea) derivatives with n=10 and n=12 displayed excellent activity against E. coli with MIC of 135 µg/mL and 145 µg/mL, respectively, while bis(thiourea) derivatives with n=14 acted as cutoff point with no antibacterial properties. Similar trend was observed in binding affinity to the active site of enoyl ACP reductase (FabI), which demonstrated binding free energy of -5.3 Kcal/mol and -4.9 and -4.8 Kcal/mol, respectively.

One-Pot Multicomponent Synthesis of Thiourea Derivatives in Cyclotriphosphazenes Moieties

“…The ln value represents the number of colony forming units/mL which followed the expression of ln = 27.1 − 8.56 [21]. coli (PDB entry: 1C14) was obtained from Protein Data Bank (http://www.rcsb.org/pdb/home/home.do) [7,24].…”

“…The studies were carried out via molecular docking to the active site of the enzyme enoyl ACP reductase (FabI) of E. coli (PDB entry: 1C14) using AutoDock Vina 1.1.2 program [7,[22][23][24]. The compounds and binding interactions are shown in Table 1.…”

“…Compounds a-b showed binding free energy of −4.5 kcal/mol and −4.7 kcal/mol, respectively. Based on the importance properties of the aromatic group in earlier studies [6][7][8], the optimisation study via molecular docking was carried out to evaluate the binding free energy of a-b in comparison to the predicted phenyl thiourea a-b. The presence of another aromatic group in a-b demonstrated for a higher binding affinity with the free energy of −5.9 kcal/mol and −6.3 kcal/mol, respectively.…”

“…Multisubstituted thioureas have gained more interest among researchers due to the increase of their pharmaceutical properties. Our recent studies on thiourea reported that compounds that consist of more than one thiourea moiety possess better antimicrobial activities [6][7][8]. It was due to the presence of more active sites of thiourea moieties containing C=S, C=O, and N-H groups, which are easily protonated under acidic condition and interacted with the carboxyl and phosphate groups of the bacterial surfaces, thus enhancing the biological activities [7].…”

“…Our recent studies on thiourea reported that compounds that consist of more than one thiourea moiety possess better antimicrobial activities [6][7][8]. It was due to the presence of more active sites of thiourea moieties containing C=S, C=O, and N-H groups, which are easily protonated under acidic condition and interacted with the carboxyl and phosphate groups of the bacterial surfaces, thus enhancing the biological activities [7]. Various methods have been reported to make this versatile group of thiourea derivatives easily accessible with excellent yields [2,[9][10][11][12].…”