Thiobarbituric acid a useful scaffold for medicinal chemistry.

Abstract

Due to the growth number of infectious diseases, a huge demand of new antimicrobial agents are required. In this regard, Thiobarbituric acid (TBA) moieties were explored. As its name indicates, TBA is the sulfur version of the barbituric acid. The work in barbituric moieties dated long ago in 1864 by Baeyer, when it was reported that these barbituric derivatives can be used as anesthetics, sedative or anticonvulsive agents. In the present work and taking advantage that TBA structure shows several points where diversity can be introduced, therefore several functionalities were introduced in the TBA analogues and their antimicrobial properties were studied in Gram-positive and Gram-negative bacteria. (Chapter 1) These are the chemical modifications explored: i) N- substitution, where this site can be substituted with a symmetrical substituents; ii) reaction at C-5 position owing to the high acidity of the protons which includes acylation, acetylation, Schiff bases, Knoevenagel condensation thioamide and enamine formation. The antimicrobial activity screening for the synthesized compounds were against Gram-positive (S. aureus and B. subtilus) and Gram negative (E. coli and P. aeruginosa) bacteria. Among all thiobabituric derivatives synthesized, Boc-Phe-TBA showed a promising activity, which confirms that TBA could be an excellent scaffold when combined with N-protected amino acids for developing antimicrobial compounds. (Chapter 2) The characterization of 20 thiobarbituric derivatives was carried out in different spectroscopy techniques such as: Nuclear Magnetic Resonance (NMR), Ultra violet spectroscopy, Infra-Red spectroscopy and single X-ray crystallography. In NMR characterization the acetylation of TBA was the most interesting due to the fact that this type of compound have the tendency of forming Enol and Keto tautomerism. This was proved by NMR and also by theoretical calculation, and the results confirm that the 1H NMR for this compound (A01)showed resonance at 17.72 ppm (singlet) for OH. This indicate that the enol form is more stable than the keto form. In UV characterization due to the fact TBA derivatives are not known aromatic and yet they are UV active. Therefore the absorption of few TBA derivatives were study in different solvents hence these showed absorption iv at maximum wavelength (max) in the range of 322 – 285 nm respectively. For IR characterization, these derivatives (A01, A02, A03, A04, A06, A10, A12, A13, A14 and A17) were evaluated, and showed absorption stretching frequency of thiocarbonyl (C=S) in three different ranges, 1395– 1570 cm-1 , 1260– 11420 cm-1 and 940 – 1140 cm-1 . For X- ray crystallography, crystals of A01, A02, A06, A13, A17 and A18 were obtained by hot recrystallization from ethanol and the intramolecular H-Bonding formation was observed in all cases, intermolecular H-bonding was observed for A17. (Chapter 3)