Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 9, Issue 4, 2010

An increasing fraction of bacterial isolates show reduced susceptibility to our most trusted antibiotics. In order to prevent this serious medical problem, the elaboration of new types of antibacterial agents or the expansion of bioactivity of the previous drugs is a very important task. Different targets in key areas of the bacterial cell cycle have been studied that would be a new weapon against this threat. In this review we attempt to summarize the recent progress made in the field of some represent bacterial enzyme inhibitors and the structure-based drug design of new broad-spectrum antibacterial agents. Based on the structure design and protein target, more and more novel compounds were discovered for the development of new antibacterial agents. It is expected that this review would serve as a stimulant for new thoughts in the quest for rational designs of more effective antibacterial drugs.The interaction of structure design with enzyme targets is fascinating, and this story is still unfolding for us to discover novel antibacterials.

In recent years, vancomycin has received appreciable attention as an antibiotic drug of last resort. The generally accepted mechanism entails interference with bacterial cell wall synthesis. There is negligible attention to other modes, even though drug action is often multifaceted. This review provides a hypothesis for an additional mechanism of antibacterial action based on the polyphenol residue in the glycopeptide. The functionalities present are monophenol, resorcinol and hydroxybiphenyl, all of which have the potential to produce electron transfer (ET) metabolites capable of generating reactive oxygen species (ROS) and oxidative stress (OS). Considerable literature is presented in support of the thesis. Drug toxicity is rationalized based on the fundamental approach to vancomycin action. This review represents another example in support of the prior ET-ROS-OS unifying mechanism for anti-infective and toxic action. Novel insight may aid in improved drug design.

During the past few decades, the potential of treating infections with nitric oxide (NO) has been firmly demonstrated in various laboratories. Both in vitro and in vivo studies have afforded promising results in terms of reducing microbial loads in chronic wounds in addition to its utility in keeping medical devices free of thrombus formation and bacterial adhesion. The latter antimicrobial effects of NO provide great help in successful integration of orthopedic and vascular implants and prolonging their in vivo life. In all such applications, NO is released from various polymeric materials in which nitrite salts, exogenous NO donors, or even simple NO(g) are incorporated. Recent developments in all such formulations of NO-releasing materials and their specific applications in combating bacteria, fungi and parasites are reviewed in this article.

Neuraminidase (NA), a glycoside hydrolase enzyme, plays pivotal roles in controlling biological functions not only of influenza viruses but also of humans. Zanamivir and oseltamivir designed to target influenza neuraminidase have become extensively used for influenza clinical treatment as its high anti-influenza efficacy. Unfortunately, side effects of these two drugs have been reported in clinical use. An aromatic benzene ring has been pursued as a core structure to derive stereo chemically simplified analogues with desired molecular properties. In our previous study, a series of 2-fluoro benzoic acids were synthesized and evaluated against all four human sialidase enzymes. Herein, we further evaluate the same set of 2-fluoro benzoic acids for inhibitory activity against viral sialidases expressed by influenza A virus. The most active compound 11 (4,5-diacetamido-2-fluoro benzoic acid) has an IC50 of 4.5 μM (N1) and 21 μM (N2) that is ∼60-140 fold more active than its non-fluoro counterpart 10 (3,4-diacetamido benzoic acid) that has an IC50 of 640 μM (N1) and 1400 μM (N2). Molecular docking and calculated binding free energies are in good agreement with the experimental data. Of greater significance was the observation of key interaction of 2-fluoro group with active site for improved activity and could be explored further for higher affinity and selectivity over viral sialidases with suitably substituted 2-fluoro benzoic acids.

The synthesis of 40 new monocyclic β-lactams bearing a morpholine moiety at their N1 positions is described. The structures of these compounds have been confirmed by IR, 1H-NMR, 13C-NMR, Mass spectra and Elemental analysis. The antimicrobial activities of the synthetic compounds have been tested against clinically important fungi including Candida, Aspergillus and Microsporum and Epidermophyton species by broth microdilution method as recommended by CLSI. Inhibition studies showed that some of the tested compounds, in particular those with phenoxy groups, exhibited strong antifungal activities against all tested fungi at concentrations of less than 8 μg/mL, while others only inhibited the growth of dermatophytes or Aspergillus species. These results suggest that the derivatives should be investigated further for possible use in antimicrobial products.