Chemical reactivity and bioactivity properties of pyrazinamide analogs of acetylsalicylic acid and salicylic acid using conceptual density functional theory.

Conventional drugs used to treat Tuberculosis (TB) are becoming ineffective due to the occurrence of multiple drug resistant strains of tuberculosis (TB). This has made the TB disease a a serious global health dilemma. Hence, there is desperate necessity for the advancement of new drugs. In this work, the chemical reactivity and bioactivity of several analogs ofpyrazinamide (PZA) were investigated. PZA is one of the first-line of drugs used to treat tuberculosis and is a key contributor to shortening the treatment time for the disease. Chemical reactivity descriptors of pyrazinamide (PZA) and its analogs of acetylsalicyclic acid and salicyclic acid were investigated using conceptual density functional theory in water as a solvent at the MN12SX/Def2TZVP level of theory. Results have shown that all PZA analogs have improved their global and local reactivity indeces as compared to pyrazinamide based on its electronegativity, electrodonating power, electroaccepting power, eletrophilicity, global hardness and dual descriptor condensed fukui indexes. Moreover, their pKa values are slightly higher than PZA. In terms of its drug-likeness, all PZA analogs passed the Lipinski's Rule of Five criteria. Furthermore, their bioactivity scores are significantly better than pyrazinamide indicating good reaction to G-Protein Coupled Receptor (GPCR) ligands, kinase inhibitors, ion channel modulators, nuclear receptor ligands, protease inhibitors and other enzyme targets. Overall, the PZA analogs are found to be promising anti-tuberculosis drugs. Based on global and local reactivity descriptors, pKa and bioactivity scores, PZA analog of 5-n-Octanoylsalicylic acid is the most reactive among the PZA analogs tested.

Multimeric TAT peptides are effective in vitro inhibitors of Staphylococcus saprophyticus.

TAT (48-60) is a tridecapeptide from the envelope protein of HIV that was previously shown to possess cell-penetrating properties and antibacterial activity, making it a potential drug delivery agent for anticancer drugs and as antibacterial compound. Previous reports indicated that dimerization enhances the desired bioactivity of TAT; hence, we sought to synthesize multimeric TAT peptides. Herein, we describe the effects of multimerization on the antibacterial activity and secondary structure of the peptide. Terminal modifications such as N-acetylation and C-amidation were employed in the design. TATp monomer, dimer, and tetramer were synthesized using solid-phase peptide synthesis, purified by reversed-phase HPLC, and then characterized by mass spectrometry. Multimerization of the peptide did not change the secondary structure conformation. The CD analysis revealed a polyproline-II conformation for all peptide designs. Thus, this study provides a method of increasing the biological activity of the peptide by multimerization while retaining the secondary conformation of its monomeric unit. Furthermore, the bacteria Staphylococcus saprophyticus was found to be susceptible to the dimer and tetramer, with MIC50 of 12.50 µm and <1.56 µm, respectively. This suggests a structure-activity relationship whereby the antibacterial activity increases with increase in valency.

Regenerable Acidity of Graphene Oxide in Promoting Multicomponent Organic Synthesis.

The Brønsted acidity of graphene oxide (GO) materials has shown promising activity in organic synthesis. However, roles and functionality of Lewis acid sites remain elusive. Herein, we reported a carbocatalytic approach utilizing both Brønsted and Lewis acid sites in GOs as heterogeneous promoters in a series of multicomponent synthesis of triazoloquinazolinone compounds. The GOs possessing the highest degree of oxidation, also having the highest amounts of Lewis acid sites, enable optimal yields (up to 95%) under mild and non-toxic reaction conditions (85 °C in EtOH). The results of FT-IR spectroscopy, temperature-programed decomposition mass spectrometry, and X-ray photoelectron spectroscopy identified that the apparent Lewis acidity via basal plane epoxide ring opening, on top of the saturated Brønsted acidic carboxylic groups, is responsible for the enhanced carbocatalytic activities involving Knoevenagel condensation pathway. Recycled GO can be effectively regenerated to reach 97% activity of fresh GO, supporting the recognition of GO as pseudocatalyst in organic synthesis.

A new rearranged dolabellane diterpene from the soft coral Clavularia inflata.

A new dolabellane type diterpene 1 has been isolated through its acetate 1a. The structure of 1a was elucidated by extensive 1D and 2D NMR spectroscopy and confirmed by mass spectrometry. The structure of 1 was deduced by comparison of its NMR spectral data with those of 1a, while its relative stereochemistry was deduced by NOESY. The absolute stereochemistry of C-7 was determined by analyses of 1 separately esterified with R and S O-mandelic acids.