Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 7, Issue 2, 2008

The human beings face the threat of a highly pathogenic avian influenza virus. The use of anti-influenza drugs is receiving much greater attention to playing an important role as a first-line defense against a new pandemic of influenza virus infection. However, influenza viruses resistant to currently available anti-influenza drugs, such as the M2 proton channel inhibitors and the neuraminidase inhibitors, are emerged frequently during the treatment with drugs. This suggests the need for development of new anti-influenza drugs utilizing alternative antiviral mechanisms and consideration of using anti-influenza drug combinations. Recent studies have clarified that the pathogenesis of influenza virus infection involves not only the virus replication-associated apoptotic cell death in the infected cells, but also the injury of noninfected cells by reactive oxygen species derived from macrophages and neutrophils infiltrated into the virus-infected organs. These findings provide a possibility that an agent with all of the following antiviral, anti-apoptosis and antioxidant activities can be a drug of choice for the treatment of patients with influenza virus infection. Selected antioxidants, such as pyrrolidine dithiocarbamate, N-acetyl-L-cysteine, glutathione, nordihydroguaiaretic acid and thujaplicin, possessed all of these activities. The combination of antioxidants, such as superoxide dismutase and N-acetyl-L-cysteine, with antiviral drug ribavirin synergistically reduced the lethal effect of influenza virus infection. Accumulating number of evidence highlights a potential of selected antioxidants for influenza chemotherapy and a possibility that combination of antioxidants with current anti-influenza drugs can improve usual influenza chemotherapy.

Tetracycline class antibiotics have been a hallmark in terms of safety profile and spectrum of activity for nearly 60 years. Multiple resistance mechanisms have evolved to counter the tetracyclines with both of the chief mechanisms - efflux and ribosomal protection - widely spread in Gram-positive and Gram-negative organisms. The utility of the tetracyclines as growth promoters in domesticated food animals as well as for pest control in aquaculture and horticulture has resulted in the dissemination of tetracycline resistance determinants in the environment, which may act as a reservoir for resistance genes. Focused chemistry efforts to develop tetracycline derivatives not subject to the efflux and ribosomal protection mechanism resulted in the discovery of tigecycline, the first in class glycylcycline antibiotic. Tigecycline has successfully reclaimed the spectrum, safety and efficacy of the tetracyclines.

Celastrol is a quinone methide triterpene present in Celastraceae plants and is known to have multitude arrays of pharmacological activities. A common source of Celastrol is found in Tripterygium wilfordii Hook F which is an ivylike vine. Celastraceae has been used as a traditional medicine in China for hundreds of years. Celastrol has effectively been used in the treatment of autoimmune diseases, chronic inflammation, asthma and neurodegenerative disease. Celastrol was also shown to inhibit cancer cell proliferation and induce leukemic cell death in vitro. The medicinal properties of Celastrol and other terpenes have recently been reported. Recent studies also indicate that Celastrol shows different pharmacological activities associated with anti-infective properties. In the present review, the recent development and the biologic activity of Celastrol and other terpenes as an infective agent is described.

The NNRTIs play an important role in the present therapy against HIV/AIDS. This review discusses the basic principles in the development of NNRTIs for HIV therapy. It also summarizes the NNRTIs in clinical use and the major series of NNRTIs in development phases. The authors intend to provide an overview of the NNRTI research and to elucidate some important factors in directing the future in the field such as genetic barrier, QD dosing, safety profile and combination with other anti-HIV agents. Despite the enormous progress that has been achieved in the NNRTI field in the past two decades, the present clinical pipeline appears to be insufficient to tackle the huge medical need. The efforts of finding new NNRTIs are certainly much motivated and can be highly rewarding.

Treatment of invasive fungal infections with fungicidal antifungal agents is desirable in some clinical situations, particularly in the immunocompromised. However, there are a limited number of fungicidal drugs and most have undesirable side effects. Applicability of amphotericin B and its different lipid formulations is hampered by toxicity and the relatively low attainable serum concentration (not more than 1 μg/ml). Echinocandin antifungals (caspofungin, micafungin and anidulafungin) have a relatively narrow spectrum (Candida and some Aspergillus species), moreover, they are fungistatic against Aspergillus. The newer triazoles (voriconazole and posaconazole) offer broad spectrum of activity against pathogenic yeasts and moulds. Several recent studies described species dependent fungicidal activity of both voriconazole and posaconazole in vitro. These results are supported by results from animal models. This fungicidal activity has been thought to be confined to moulds only, but recent in vitro findings suggest that they exert fungicidal action against certain yeast species as well. Present work focuses on the fungistatic and fungicidal effect of azole antifungals against yeast and moulds, concentrating in particular on voriconale and posaconazole.

The observation that proteinases located at the surface of HIV-1 target cells were involved in viral infection led to the discovery of the anti-HIV-1 properties of serpin A1(α1-proteinase inhibitor, α1-antitrypsin). Antiviral activity could be explained by the capacity of serpin A1 to prevent binding of the HIV envelope glycoprotein to proteinases associated with host cell membranes. Surprisingly, serpin A1 inhibited as well HIV-1 replication and promoter activity. A1- C36, the C-terminal peptide produced after serpin-proteinase complex formation [A1(359-394)] is probably responsible for this intracellular anti-HIV activity because the synthetic, truncated 26-residue peptide A1-C26 [A1(369-394)] , comprising the complete β-hairpin structure of A1-C36, strongly inhibited HIV-1 expression in infected cells. The major receptor involved in internalization of A1-C36 and many serpin-proteinase complexes is CD91, a protein highly expressed in HIV-1-infected true non-progressors. CD91 also internalizes the antiviral defensins, structurally similar to A1-C26. A1- C26 contains a putative internalization signal pentapeptide FVFLM [A1(372-376)]. Synthetic peptides based on this sequence go to the nucleus few minutes after cell membrane interaction. VIRIP (serpin A1(353-372), virus-inhibitory peptide) is a serpin A1 fragment isolated from hemofiltrates of patients with chronic kidney failure. VIRIP does not have the complete internalization sequence and does not affect HIV-1 promoter activity but effectively blocks HIV-1 entry by binding to the fusion peptide of gp41, a crucial component of the HIV envelope glycoprotein complex. C-terminal peptides derived from serpins B9 (anti-granzyme B) and C1 (antithrombin III) were not as active as A1-C26. However, other C-terminal peptides of the more than 500 members of the serpin superfamily could be potential anti-infective agents.

A number of novel quinolone derivatives have been recently reported to posses in vitro and in vivo anti mycobacterial and DNA gyrase inhibition activities. It is known that mycobacteria expressing resistance to both isoniazid and rifampin (multi-drug resistant, MDR) is sensible to fluoroquinolones. Ciprofloxacin, oxfloxacin, moxifloxacin and levofloxacin are increasingly used for the treatment of tuberculosis, because they inhibit the topoisomerases II (DNA gyrases) and IV, essential enzymes to maintain the supercoils in bacterial DNA. It has been demonstrated that complex mutations in DNA gyrase GyrA2GyrB2 associated with quinolone resistance or hypersusceptibility take place in several MDR clinical isolates of M. tuberculosis. In this article we report the anti mycobacterial properties, mode of action and structure activity relationship (SAR) studies of the known quinolone derivatives. Furthermore, we report the synthesis and activity of 3,9-disubstituted-6-oxo-6,9-dihydro-3H-[1,2,3]-triazolo[4,5-h]quinolone-carboxylic acids and their esters as a new class of potent anti mycobacterial agents. The triazoloquinolone derivatives are particularly interesting for their activity against MDR M. tuberculosis.