Anti-Infective Agents - Volume 12, Issue 1, 2014

In the search of effective, selective and nontoxic antiviral agents, a variety of nucleoside analogues have been synthesized, with different functionalities in the carbohydrate moiety and/or the heterocyclic base. Nucleoside analogues bearing double or triple bonds are recognized as an important class of biologically active compounds and appear to be prominent drugs in the management of several viral infections, including HSV, HIV, HBV, HCV and HCMV. Currently, unsaturated nucleoside mimetics, such as stavudine, abacavir and entecavir have been approved for the treatment of viral infections, while elvucitabine and β-L-2´-F-d4C are in clinical trials. The purpose of this review is to give an update of the recent developments on nucleosides and nucleoside analogues with unsaturation, in both cyclic and acyclic forms, which possess promising therapeutic potential, mainly antiviral. It covers analogues with ring sizes from three to six and provides useful data, aiming at enhancing chemical reactivity as a result of the sugar and base conformations.

Albinterferon alfa-2b (albIFN) has been studied for the treatment of chronic hepatitis C virus infection in combination with ribavirin at different dose regimens ranging 900-1500 µg once every 2 (q2w) or 4 (q4w) weeks. Analyses on efficacy and safety exposure-response relationships in Genotype2/3 (G2/3) interferon-naïve patients were conducted to explore an improved risk-benefit of therapy. Data from 972 G2/3 patients were included in the exposure-response analysis. Major antiviral response endpoints of Sustained Virologic Response (SVR) and Rapid Virologic Response (RVR) exposure- response were modeled using logistic regression. The reported adverse event AE frequencies were tabulated vs quartiles of albIFN exposure. Body weight based exposure were estimated based on the population pharmacokinetic (PK) model and simulations were performed according to the weight based exposure and the exposure-response relationship. Within the G2/3 interferon-naive patients, albIFN Cavg but not Cmax or Cmin was associated with efficacy, along with certain baseline characteristics. For a given Cavg, dosing q2w was more active than q4w for RVR; Cavg was modestly associated with SVR, while no effect of dose interval was observed. Cavg was associated with a number of adverse events and laboratory abnormalities, especially at the higher exposure quartiles. The weight-based dose regimen (20 µg/kg) was predicted to decrease the subjects in the higher two quartiles of exposure by about half, compared with the fixed 1500 µg dose. This potential improvement was predicted to have a better overall safety profile with similar efficacy, but the overall reduction in AE’s would be small. As albIFN Cavg was significantly associated with both efficacy and safety outcomes, a weight-based regimen would be unlikely to significantly improve the risk benefit in comparison to the standard of care.

Listeria monocytogenes, the responsible agent for listeriosis, is one of several microorganisms which can be transmitted from mother to fetus/neonate by vertical transmission. The aim of this study was to characterize a bacteriocin produced by Pediococcus pentosaceus SB83 for vaginal application, to prevent colonization of pregnant women with L. monocytogenes. Bacteriocin SB83 showed inhibitory activity against L. monocytogenes (serotypes 1/2a 1/2b and 4b) but did not inhibit vaginal lactic acid bacteria. Additionally, bacteriocin SB83 inhibited the growth of Enterococcus faecalis, Enterococcus faecium and Bacillus subtilis. Bacteriocin SB83 was produced at maximum levels between 24 h and 36 h of growth (6400 AU/mL against serotype 1/2b and 4b, 3200 AU/mL against serotype 1/2a). Significant reduction in antimicrobial activity was observed after treatment of cell-free supernatants with proteinase K, pepsin, papain and trypsin. Bacteriocin SB83 was resistant to treatments with Tween 80, Tween 20, Triton X-100, SDS and EDTA. This bacteriocin was stable at pH values between 4 and 6.5; a decrease in activity was observed at pH 2 and above 8. A decrease in antibacterial activity was recorded at 100 °C and 121 °C. In the range 4 °C to 80 °C, antimicrobial activity was not affected. The activity of bacteriocin did not change in simulated vaginal fluid (pH 4.2, 5.5 and 6.5). The molecular size of bacteriocin SB83 was between 3.5 and 6.5 kDa.In conclusion, the bacteriocin produced by P. pentosaceus SB83 has been proved to be resistant to several conditions, including conditions in the vaginal tract (pH and components of vaginal fluid).

Squalamine, a natural aminosterol compound isolated from the dogfish shark Squalus acanthias, is reported to possess high antimicrobial activities. Herein, we assessed its in vitro genotoxic properties by using the Ames test and the micronucleus assay. All the experimental results demonstrate that squalamine is a non genotoxic molecule and call for further work to evaluate its potent human therapeutic use as a new class of antinfectious agents.

The effect of varying concentrations of Tween 80 on the antimicrobial potency of platensimycin and triclosan was investigated using both Streptococcus agalactiae (S. agalactiae) and methicillin-resistant Staphylococcus aureus (MRSA). In the presence of very low concentrations of Tween 80 (0.02%) both platensimycin and triclosan were rendered ineffective against S. agalactiae. A linear concentration-dependence was found with the antimicrobial activity of triclosan against MRSA showing a loss in effectiveness with increasing concentrations of Tween 80. Platensimycin, on the other hand, demonstrated improved antibiotic activity at higher concentrations of Tween 80. The differential effects of these two agents have implications for the regulation of lipids in Gram positive organisms and the viability of bacterial fatty acid synthesis inhibitors as antibiotics.

In search of new antimicrobial agents with improved potency, we have synthesized a series of N-substituted thiazolidinedione-pyrazole based 3-(3-(1H-pyrrol-1-yl)propyl)-5-((3-(substituted phenyl)-1-phenyl-1H-pyrazol-4-yl) methylene)thiazolidine-2,4-diones (6a-j) in two successive steps. Initial step involves Knoevenagel type condensation of 3-(substituted phenyl)-1-phenyl-1H-pyrazole-4-carbaldehydes (2a-j) with thiazolidine-2,4-dione (3) to furnish intermediate compounds (4a-j). Finally, target compounds (6a-j) were achieved via one-pot reaction of compounds (4a-j), 1,3-dibromopropane and 1H-pyrrole (5). The chemical structures of all the newly synthesized compounds were established based on IR, 1H NMR, 13C NMR and mass spectra. All the synthesized compounds (4a-j, 6a-j) were evaluated for their in vitro antimicrobial activity.

In recent years, extensive researches have emphasized the fact that polyamines conjugates acting as possessing antitumor, antimicrobial candidates are becoming important in the biogical and medicinal field. In this review, a general design strategy of polyamine conjugates as well as recent progress in both fundamental mechanism studies and potent therapeutic use as anti infectious agents are provided for the readers.

Preparation of new series of 1-[4-(5-Phenyl-4,5 dihydro-1H-pyrazole-3-yl)-phenyl]-pyrrole-2,5-dione and 1-[4- (5-Phenyl-4,5 dihydroisooxazole-3-yl)-phenyl]-pyrrole-2,5-dione derivatives, derived from α,β-unsaturated ketones with objective of obtaining lead compounds for future development as antiviral agents. The inhibition of virus-induced cytopathicity or plaque formation in HEL [herpes simplex virus type 1 (HSV-1) (KOS), HSV-2 (G), vaccinia virus, vesicular stomatitis virus, cytomegalovirus (HCMV), and varicella-zoster virus (VZV)], Vero (parainfluenza-3, reovirus-1, Sindbis virus and Coxsackie B4), HeLa (vesicular stomatitis virus, Coxsackie virus B4, and respiratory syncytial virus) or MDCK [influenza A (H1N1; H3N2) and influenza B] cell cultures by synthesized derivatives. All the compounds were characterized by physical, spectroscopic and elemental analysis. Among the fourteen synthesized targets only compounds 3g and 4e showed activity against RSV (EC50 = 37 µ M and 46 µ M with affecting cell morphology at concentrations of, respectively, 254 µ M and 286 µ M) Compound 3g also showed weak activity against feline corona virus (EC50 value of 29 µM and a MCC of 107 µ M) for CRFK cells. Feline corona virus was also weakly inhibited by compound 3f (EC50=39 µM) that altered cell morphology at a concentration of 231 µ M. Except for feline corona virus, none of the other viruses was inhibited by compound 3f. Low selectivity indices (SIs), defined as ratio MCC/EC50, were observed SI=4 and SI=6 for compounds 3g and 3f against feline corona virus respectively, while SI=6 for compound 4e against RSV, and SI=7 for compound 3g against RSV. Biological evaluation was performed using acyclovir, brivudin, gancilcovir, cidofovir against herpes and poxviruses while ribavirin against RNA viruses, reference standard drugs.

A series of 30 novel thiazolidine-2,4-diones (3a-o, 4a-o) have been synthesized and evaluated for their antibacterial and antifungal activities against pathogenic microorganisms Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Klebsiella pneumonia, and fungal strains Candida albicans, Aspergillus niger using two fold serial dilution method.. In the present study thiazolidine- 2,4-dione derivatives has been substituted with electronegative groups at the 3rd and the 5th position. Some of the compounds have shown promising antimicrobial activity.

Bacterial biofilms are defined as a surface attached community of bacteria embedded in a matrix of extracellular polymeric substances that they have produced. When in the biofilm state, bacteria are more resistant to antibiotics and the host immune response than are their planktonic counterparts. Biofilms are increasingly recognized as being significant in human diseases such as; lung infections of cystic fibrosis (CF), colitis, urethritis, conjunctivitis, otitis, endocarditis, and periodontitis. Given the prominence of biofilms in infectious diseases, there has been an increased effort toward the development of small molecules that will modulate bacterial biofilm development and maintenance. In this review, we highlight the development of small molecules that inhibit and/or disperse bacterial biofilms through non-microbicidal mechanisms. The review provides a general overview of how bacteria develop into biofilm communities, why they are important, and the regulation of this process by quorum sensing. This is followed by a discussion of the numerous small molecules that have been identified as possessing the ability to control biofilm development.