Thiobarbituric acid a useful scaffold for medicinal chemistry.

Masters Degree. University of KwaZulu-Natal, Durban.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

Investigation of the N-terminus amino functional of Arg10-Teixobactin

Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In this regard, a large number of analogs with substitutions in both the cycle and the tail has been described. Here, we report the contribution of the N-terminus residue, N-Me-d-Phe, to the activity of Arg10-teixobactin. On the basis of our findings, we conclude that the N-terminus accepts minimum changes but not the presence of long alkyl chains. The presence of a positive charge is a requirement for the activity of the peptide. Furthermore, acylation of the N-terminus leads to total loss of activity

Solid-Phase Peptide Synthesis Using a Four-Dimensional (Safety-Catch) Protecting Group Scheme

Peptides of importance to both academia and industry are mostly synthesized in the solid-phase mode using a two-dimensional scheme. The so-called Fmoc/tBu strategy, where the groups are removed by piperidine and TFA, respectively, is currently the method of choice for peptide synthesis. However, as the molecular diversity of cyclic and branched peptides becomes a challenging interest, a high level of orthogonal dimensionality is required, such as through triorthogonal protection schemes. Here we present a fourth category of orthogonal protecting groups that are stable under cleavage conditions, including the TFA treatment that removes the tBu-based groups. At the end of the synthetic process and upon some chemical manipulation, the groups in this fourth category were removed with TFA. This new concept of protecting groups could facilitate the synthesis and manipulation of difficult peptides.This work was partially funded by the National Research Foundation (NRF) (Blue Sky’s Research Program no. 120386). We thank Geraldo. A. Acosta, University of Barcelona, for the HRMS and NMR characterization.Peer reviewe

Investigation of the N-Terminus Amino Function of Arg10-Teixobactin

Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In this regard, a large number of analogs with substitutions in both the cycle and the tail has been described. Here, we report the contribution of the N-terminus residue, N-Me-d-Phe, to the activity of Arg10-teixobactin. On the basis of our findings, we conclude that the N-terminus accepts minimum changes but not the presence of long alkyl chains. The presence of a positive charge is a requirement for the activity of the peptide. Furthermore, acylation of the N-terminus leads to total loss of activity

The synthesis of solid supports carrying base labile linkers to generate 3'-phosphate oligonucleotides

Oligonucleotides carrying 3'-terminal phosphates and conjugates are important tools in molecular biology and diagnostic purposes. We described the preparation of solid supports carrying the base labile linker 4-((2-hydroxyethyl)sulfonyl)benzamide for the solid-phase synthesis of 3'-phosphorylated oligonucleotides. These supports are fully compatible with the phosphoramidite chemistry yielding the desired 3'-phosphate oligonucleotides in excellent yields. The use of mild deprotection conditions allows the generation of partially protected DNA fragments.This work was financially supported by the Spanish Ministerio de Ciencia e Innovación (MICINN) (Projects PID2020-118145RB-I00, CPP2021-008792 and PID2022-137893OB-I00), and NRF-South Africa. This research was also supported by CIBER - Consorcio Centro de Investigación Biomédica en Red (CB06/01/0019), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and the European Regional Development Fund (ERDF). The oligonucleotide synthesis was performed by the ICTS ‘‘NANBIOSIS” and specifically by the oligonucleotide synthesis platform (OSP) U29 at IQAC-CSIC (https://www.nanbiosis.es/portfolio/u29-oligonucleotide-synthesis-platform-osp/). We thank Dr. Ramon Güimil-Garcia (BioNTech RNA Pharmaceuticals) for his encouragement and discussions.Peer reviewe