Synthesis and disinfection effect of the pyridine-4-aldoxime based salts

PubMed ID: 25719739A set of new quaternary ammonium compounds based on pyridine-4-aldoxime was synthesized, characterized with analytical data (NMR, EA, HPLC, MS) and tested for in vitro antimicrobial activity (antibacterial, antifungal) and cytotoxicity. Quaternary pyridinium-4-aldoxime salts with length of alkyl side chain from C8 to C20 and belonging to the group of cationic surfactants were investigated in this work. An HPLC experimental protocol for characterization of mixtures of all homologues has been found. Antimicrobial evaluation found that yeast-type fungi were most sensitive towards C14 and C16 analogues, whereas the C16 analogue was completely ineffective against filamentous fungi. Antibacterial assessment showed versatility of C14 and relatively high efficacy of C16 against G+ strains and C14 against G− strains. Notably, none of the studied compounds exceeded the efficacy and versatility of the benzalkonium C12 analogue, and benzalkonium analogues also exhibited lower cytotoxicity in the cell viability assay.Web of Science2033696368

Ligand-based 3D QSAR analysis of reactivation potency of mono- and bis-pyridinium aldoximes toward VX-inhibited rat acetylcholinesterase

PubMed ID: 25588616To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure–activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R2 = 0.9989, QLOO2 = 0.9090, QLTO2 = 0.8921, QLMO(20%)2 = 0.8853, Rext2 = 0.9259, SDEPext = 6.8938; 2. R2 = 0.9962, QLOO2 = 0.9368, QLTO2 = 0.9298, QLMO(20%)2 = 0.9248, Rext2 = 0.8905, SDEPext = 6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds.Web of Science5612911

Structural Properties of Potential Synthetic Vaccine Adjuvants - TLR Agonists

PubMed ID: 26295466Toll like receptors (TLRs) are a family of transmembrane proteins which play a key role in innate immunity. When TLRs come into contact with a potential threat, they initiate a signaling cascade leading to release of cytokines and chemokines, maturation of antigen presenting cells and immune activation. Molecules which can activate TLRs may be utilized for vaccine development and act as vaccine adjuvants. Adjuvants can facilitate production of more effective vaccines based on antigens produced by recombinant techniques or by DNA vaccines, which are often poorly immunogenic since they lack the endogenous innate immunostimulatory components of the pathogen. In this paper the structural properties of such prospective compounds are thoroughly discussed. - See more at: http://www.eurekaselect.com/134203/article#sthash.A755yJzh.dpufWeb of Science22293325330

6-Hydroxyquinolinium salts differing in the length of alkyl side-chain: Synthesis and antimicrobial activity

Quaternary ammonium salts substituted with a long alkyl chain exemplify a trustworthy group of medicinal compounds frequently employed as antifungal and antibacterial agents. A great asset of these surfactants underlying their widespread use is low local and system toxicity in humans. In this Letter, a series of novel quaternary 6-hydroxyquinolinium salts with varying length of N-alkyl chain (from C10 to C18) was synthesized and tested for in vitro activity against pathogenic bacterial and fungal strains. 6-Hydroxyquinolinium salt with C12 alkyl chain seems to be very interesting candidate due to a high antimicrobial efficacy and cytotoxic safety.Web of Science24225241523

Synthesis, antimicrobial evaluation and molecular modeling of 5-hydroxyisoquinolinium salt series; the effect of the hydroxyl moiety

In the present paper, we describe the synthesis of a new group of 5-hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C10–C18), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non-hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C18) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C14, C16) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G− bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C14) against G+ strains and 15 (C16) against fungi. The electronic properties and desolvation energies of 5-hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy.Web of Science24484884

Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: biological activities, molecular modeling and QSAR studies

In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.Web of Science12171169