Current Medicinal Chemistry - Volume 10, Issue 17, 2003

In the present era, acquired immunodeficiency syndrome (AIDS) is the most fatal disorder for which no completely successful chemotherapy could be developed so far. The pandemic spread of this disease has prompted an unprecedented scientific and clinical effort to understand and combat it. The causative agent of AIDS has been identified as a retrovirus of type 1 (HIV-1). Therefore, a great attention has been focused in the recent years on the design and development of anti-HIV drugs and we consequently decided to bring out a hot topic issue on the subject with the title: Advances in the Studies of Anti-HIV Drugs. Owing to a good response from authors, two successive issues had to be devoted as Part I and Part II of the topic. The replicative cycle of HIV-1 presents several viable targets that could be exploited for this purpose. The present issue, as Part I, covers 6 articles, in which the very first article by José A. Esté hits at the virus entry itself into the host cell and reviews the current state of HIV entry inhibitors, their mechanism of action, and their therapeutic value against HIV infection and AIDS. In recent years, tremendous progress has been made in understanding the HIV-1 entry process in which the viral and cellular membranes are fused, resulting in the subsequent delivery of the viral genome into the host cell. The mechanistic insight gained from these studies has led to the formulation of fusion inhibitors. The second article by Baldwin et al. addresses this rapidly developing area of HIV research with a focus on the mechanistic role of fusion inhibitors targeted to the HIV-1 gp41 transmembrane glycoprotein. The process of reverse transcription of genomic RNA into double-stranded DNA is central to the replication of HIV and this process requires the enzyme reverse transcriptase (RT). Therefore, the initial development of anti-HIV drugs was largely based on RT inhibitors, which is still sustaining enough interest of the researchers. Articles 3 and 4, therefore, address some rational bases of designing potential RT inhibitors. While in article 3, Mager discusses an excellent predictive model based on hybrid canonical-correlation neural network (HCCNN) approach for the development of RT inhibitors, in article 4, Pungpo et al. present a Hologram quantitative structure-activity relationships (HQSAR) study that yields another excellent predictive model. The cleavage of large polypeptide precursors into smaller, functional protein fragments, required for packaging and infectivity of budding virions, needs HIV protease. Hence, the studies on HIV-1 protease inhibitors have also been immensely carried out. The fifth article by Kurup et al. discusses the QSARs of several classes of HIV-1 protease inhibitors, pointing out the important physicochemical, electronic, and steric properties of the molecules that govern their activity. The last article by Sriram and Yogeeswari presents the design and development of agents that have broad spectrum of chemotherapeutic properties that may be more effective in the treatment of HIV-1 infection or AIDS. In recent years, isatinimino compounds, which these authors discuss, have been reported to exhibit a broad spectrum of chemotherapeutic properties that include anti-HIV, antituberculous, antifungal and antibacterial activities. I thank all the authors of this part for their excellent stimulating contributions and hope that the readers will greatly enjoy reading them as I did and that these contributions will be of great value to those involved in research in this area.

The replicative cycle of the human immunodeficiency virus (HIV) can be interrupted at several stages. Until recently only the viral reverse transcriptase and protease were the only enzymes targeted by antiretroviral agents. However, the first HIV entry inhibitor (T-20, Enfuvirtide, Fuseon) to be used in humans has been approved by the Food and Drug Administration (FDA). The HIV entry process is considered as an attractive target for chemotherapeutic intervention, as blocking HIV entry into its target cell leads to suppression of viral infectivity, replication and the cytotoxicity induced by virus-cell contacts. HIV-1 entry into target cells is a multistep process: virus attachment is initiated by the binding of trimeric envelope glycoprotein gp120 complexes on the virions to glycosylated T-cell surface receptor (CD4) and HIV GPCR coreceptors (CCR5 or CXCR4) leading to envelope glycoprotein gp41-dependent fusion-pore formation and membrane fusion. A number of compounds are being developed to specifically target each of these steps leading to virus entry and some compounds have reached early clinical development. Conversely, agents such as the CCR5 antagonist Tak-779 and the CXCR4 antagonist AMD3100 are not longer being thought as relevant anti-HIV agents but have given way to new analogues with improved properties. This review summarizes the current state of HIV entry inhibitors, their mechanisms of action and their therapeutic value against HIV infection and AIDS.

In recent years, tremendous progress has been made in understanding the HIV- 1 entry process in which the viral and cellular membranes are fused, resulting in the subsequent delivery of the viral genome into the host cell. The mechanistic insight gained from these studies has led to the formulation of exciting new approaches for therapeutic intervention. One of the first and clinically most advanced drugs to emerge from this effort is the fusion inhibitor T20. T20 acts by freezing a transient structural intermediate of the HIV-1 fusion process, thus blocking an essential step in viral entry. With phase III clinical trials already well underway, the success of T20 indicates that targeting of the viral entry process will soon be an important component of antiretroviral therapy. This review addresses this rapidly developing area of HIV research, with a focus on the mechanistic role of fusion inhibitors targeted to the HIV-1 gp41 transmembrane glycoprotein. We will review the results of recent clinical trials with T20 and discuss possible mechanisms of viral escape through the evolution of drug-resistant HIV-1 variants. We will also discuss ongoing research on fusion inhibitor susceptibility testing and the development of new improved fusion inhibitors.

Beneficial antiviral HIV-1 chemotherapy is associated with adverse reactions. To optimize the desired actions and to lower the side effects of nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors (NNRTIs), quantitative structure-activity relationships (QSARs) were studied by using a series of HEPT derivatives of NNRTIs. Hypothesis testing requires that certain assumptions are approximately satisfied in statistically based QSARs, however. A complementary approach is based on artificial neural network analysis. Model building can be made without the manifold assumptions of statistically based QSAR approaches but the problem is that the number of neural weights increase exponentially (danger of overfitting) under certain circumstances. A way to get more reliable results is to reduce the dimensionality of the two subsets (biological and chemical variables). A suitable method is the canonical correlation analysis. The two subsets of canonical variates are used as outputs (biologically derived variates) and inputs (chemically derived variates) of an optimized backpropagation neural network approach. The contribution summarizes the most recent results of this canonical-correlation backpropagation-neural network QSAR approach. It is shown that noncovalent interactions (lipophilic, steric, hydrogen-bonding, and inductive forces of the substituents) are responsible for the antiviral and cytotoxic actions. The outcome of this analysis produces an internally highly self-consistent result (model robustness). The predictive performance is tested. The butterfly-like conformation of the predicted compound is consistent with the butterfly-like model of other NNRTIs. Molecular simulation shows that the complexed drug interacts with the Tyr181 and Tyr188 residues of the RT. The uracil ring of the drug binds directly with Lys101, and the acyclic side chain (with an intact free hydroxyl function) binds with Lys103. The suggested noncovalent interaction forces are equivalent with that found by the QSAR analysis.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as TIBO, HEPT and dipyridodiazepinone are effective against HIV-1 RT. These NNRTIs are chemically and structurally diverse, but they all bind to a common allosteric site of HIV-1 RT. These inhibitors exhibit high potency, low cytotoxicity and produce few side effects. However, the emergency of drug-resistance viral strain has limited the therapeutic efficiency of the NNRTIs. Several different QSAR studies were reported to identify important structural features responsible for the inhibitory activity of these NNRTIs. In this study, hologram quantitative structure-activity relationships (HQSAR) was applied to three different data sets, 70 TIBO, 101 HEPT and 125 dipyridodiazepinone derivatives. Starting geometries of compounds were taken from available X-ray crystallographic data. Modification and full geometry optimization of all derivatives were performed, based on quantum chemical calculations at the HF / 3-21G level of theory. All derived HQSAR models produce satisfying predictive ability and yield r2 cv values ranging from 0.62-0.84. Moreover, it was also found that the quality of models enhances as the size of fragments increases. The obtained HQSAR results indicate the similarity of the interactions of these three different NNRTIs with the inhibition pocket of the enzyme. Comparisons of different QSAR methods on these NNRTIs data sets were also considered and it could be shown that HQSAR results yield superior predictive models than other 2D-QSAR approaches. In particular, the predictive ability of the models derived from dipyridodiazepinone analogues was significantly improved and apparently revealed differentiating structural requirements between WT and Y181C HIV RT inhibition. Additionally, the quality of QSAR models constructed by CoMFA and HQSAR methods are comparable and the interpretations of the models reinforce each other. It suggests an advantage of HQSAR as a useful tool in designing new potent inhibitors with enhanced HIV-1 RT inhibition activity, especially against mutant enzyme.

An excellent example in the field of rational drug design is the discovery and development of more than a dozen drugs for the treatment of AIDS. The major targets for the development of new chemotherapeutic agents are Reverse Transcriptase and Protease, the enzymes encoded by HIV-1. The introduction of HIV-1 protease (HIV-1 PR) inhibitors, in particular, has drastically decreased the mortality and morbidity associated with AIDS. The inhibition of this enzyme results in production of immature and noninfectious virions. In the present review, a comparative quantitative structure activity relationship (QSAR) study of various peptidomimetic and non-peptidomimetic molecules investigated for their inhibitory activity has been reported. Among the various physicochemical properties studied, hydrophobicity, steric and electronic interactions are found to play important role in binding to the receptor.

HIV is the most significant risk factor for many opportunistic infections like fungal, tuberculosis, etc. The intense media coverage of AIDS puts the public on an emotional roller caster, and inflated promises are engendered by each success. For the moment drugs acting as both HIV-reverse transcriptase inhibitors along with antimicrobial properties are one of the brightest hope. The Non-nucleoside reverse transcriptase inhibitors (NNRTIs) appear ideally suited for further development in the chemoprophylaxis and therapy of HIV infections. In recent years, isatinimino compounds have been reported to exhibit broad-spectrum chemotherapeutic properties that include anti-HIV, antituberculous, antifungal and antibacterial activities. Hence these leads should be regarded as structural hits in the search for more potent antimicrobial compounds with broad-spectrum chemotherapeutic properties for the effective treatment of HIV / AIDS. This review focuses on the design of isatinimino compounds, which resemble the NNRTIs for the development of an ideal anti-HIV drug.

Tubulin protein is a major target for anticancer drug discovery. As a result, antimitotic agents constitute an important class of the current anticancer drugs. Hundreds of tubulin inhibitors, naturally occurring, semisynthetic or synthetic, have been reported. Among these, combretastatin A-4 (CA-4), isolated from a South African tree Combretum caffrum, is one of the most potent antimitotic agents. CA-4 shows strong cytotoxicity against a variety of cancer cells, including multi-drug resistant cancer cell lines. It has also been demonstrated to exert highly selective effects in proliferating endothelial cells. CA-4 disodium phosphate (CA4DP), a water-soluble prodrug of CA- 4, shows potent antivascular and antitumor effects in a wide variety of preclinical tumor models. Consequently, a number of CA-4 analogues has been synthesized and evaluated. In this paper, the structure-activity relationships and pharmacological properties of the CA-4 derivatives as a class of potent antimitotic anticancer agents are reviewed and discussed.

The isoprostanes are a unique series of prostaglandin-like compounds formed in vivo from the free radical-catalyzed peroxidation of arachidonic acid independent of the cyclooxygenase enzyme. The purpose of this article is to summarize our knowledge regarding the isoprostanes and discuss what are avenues for future research. Novel aspects related to the biochemistry of isoprostane formation and methods by which these compounds are analyzed, including potential pitfalls that may occur during the analysis, are discussed first. The isoprostanes possess potent biological activity, and their potential role in mediating certain aspects of the detrimental effects of oxidant stress is then examined. A considerable portion of this review deals with the utility of measuring isoprostanes as markers of oxidant injury both in vitro and in vivo. A number of studies have shown these compounds to be extremely accurate markers of lipid peroxidation in animal models of oxidative stress and have illuminated the role of oxidant injury in association with a number of human diseases.

The majority of nonantibacterial activities discovered for β-lactam derivatives during the last 15 years are based on their ability to form a stable covalent complex with nucleophile in the active site of enzymes regulating fundamental physiological processes in mammalian organism such as serine and cysteine proteases, LDL phospholipase A2, A-independent transacylase and some still indeciphered enzymes. Regulation of their catalytic activity both in vitro and in vivo by compounds designed on the cephalosporin, penicillin and 2-azetidinone base was successfully exploited in the treatment of inflammatory, respiratory, cardiovascular disorders, cancer and other pathologic processes. Availability of X-ray crystallographic data for target enzymes and computational molecular modelling in combination with wide possibilities of structural modifications for commercial natural and synthetic β-lactams and the chiral blocks allow to consider this class of organic compounds as a perspective source of mechanism based nonantibacterial drugs.

A growing body of evidence has shown that oxidative stress may be involved in the development of vascular complications associated with diabetes. However, the molecular mechanism for increased reactive oxygen species (ROS) production in diabetes remains uncertain. Among various possible mechanisms, attention have increasingly been paid to NAD(P)H oxidase as the most important source of ROS production in vascular cells. High glucose level stimulates ROS production through protein kinase C (PKC)-dependent activation of vascular NAD(P)H oxidase. Furthermore, the expression of NAD(P)H oxidase components is increased in micro- and macrovascular tissues of diabetic animals in association with various functional disorders and histochemical abnormalities. These results suggest that vascular NAD(P)H oxidase-driven ROS production may contribute to the onset or development of diabetic micro- or macrovascular complications. In this point of view, the possible new strategy of antioxidative therapy for diabetic vascular complications is discussed in this review.