Current Medicinal Chemistry - Volume 10, Issue 18, 2003

This Part II of the hot topic issue on Advances in the Studies of Anti-HIV Drugs contains articles mainly related to integrase inhibitors. Presently, the reverse transcriptase (RT) and protease inhibitors, that have been mainly described in Part I, are used in combination to effectively treat the HIV-1 infection. Though this combination therapy has exhibited multiple clinical benefits, the emergence of resistance highlights the need of new anti-HIV agents. Consequently, the researchers focused their attention on new agents able to interfere with additional steps of viral replication and one of them, found to be most crucial, is the integration of the viral DNA into the host cell genome. This step is catalyzed by the enzyme integrase (IN). In the very first article of this issue, Soultrait et al. discuss a combination therapy of RT and IN inhibitors that is based on peptides. Though peptides have long been considered as poor drug candidates, current knowledge on improving the stability and bioavailability of these agents may lead to the effective use of peptides in therapy. Integrase Inhibitors have lately drawn great attention of the chemists and so three most comprehensive articles (2-4), covering all uptodate developments in the area have been fetched. In article 2, Gupta and Nagappa have reviewed all different categories of IN inhibitors, pointing out in each category the important structural features that may be essential for IN inhibition. On the other hand, in article 3, Maurin et al. have presented a detailed study on SARs of these inhibitors and their modes of interaction with the enzyme, and in article 4, Parrill has highlighted even more critically the binding sites, SARs, and future prospectives of these IN inhibitors. In the last article (article 5), Anatasi et al. discuss new antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome several drug deficiencies. Examples of carrierlinked nucleoside prodrugs or nucleoside bioprecursors have been presented and their active mechanism discussed. Thus, this issue covers 5 excellent articles, which I found quite stimulating and informative and hope that the readers will also enjoy reading them. I heartily acknowledge the interest and the zeal that the authors have shown in contributing these articles.

Current treatments of human immunodeficiency virus type 1 (HIV-1) infection consist in the combination of drugs targeting reverse transcriptase (RT) and protease (PR). Despite the multiple clinical benefits of this combination therapy, the emergence of resistance highlights the need for new anti-HIV agents. Agents able to interfere with additional steps of viral replication, such as integration of viral DNA in the host genome, would improve the antiviral potency of the treatment. In this regard, we have focused our interest on peptide-based compounds that have been shown to exhibit potential inhibition of RT and integrase (IN) activities in vitro and in vivo. Recently, the expansion of powerful technologies which allow the selection of peptides exhibiting high affinity for a target protein have provided a new approach to selecting potential anti-HIV drugs. Furthermore, efforts to characterize the protein-protein interactions involved in efficient reverse transcription and integration, as well as the determination of the enzyme structure, have generated a very useful source of data for the development of peptide inhibitors. Finally, while this class of compounds has long been considered as poor drug candidates, current knowledge on improving the stability and bioavailability of these agents would lead to the effective use of peptides in therapy.

A review is presented on different categories of compounds that have been studied for the inhibition of the HIV-1 integrase to develop anti-HIV agents. These compounds are: oligonucleotides (double-stranded, triplex, and G-quartet), curcumin analogues, polyhydroxylated aromatic compounds, diketo acids, caffeoyl- and galloyl - based compounds, hydrazides and amides, tetracyclines, and depsides and depsidones. For all these compounds, the important structural features essential for the inhibition of the integrase are pointed out.

HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. A great number of HIV-1 integrase inhibitors have been described in the last decade and numerous reviews have been published. The biochemical mechanism of HIV-1 DNA integration, the enzyme structure and the possible targets for drug intervention have been thoroughly analyzed. Structure-based drug design including both ligand-based (pharmacophore) and target-based (docking) methods has also been discussed. The recent report of the crystal structure of HIV-1 integrase core domain with an inhibitor has given a new boost leading in the last two years to the emergence of diketoacids (DKAs). To date, with the dicaffeoyltartaric acids they are the only two classes of molecules that meet the criteria necessary to be considered lead molecules in the search for clinically useful inhibitors of HIV-1 integrase. After a survey of the function and the structure of this enzyme and the different available assays for the identification of new IN inhibitors, structure-activity relationships of HIV-1 integrase inhibitors that are expected to interact with the active site (or in its vicinity) will be discussed with emphasis on their different proposed mechanisms of action.

The integrase enzyme encoded by the human immunodeficiency virus plays an integral role in the viral life cycle, but is as yet unexploited as a clinical drug target. Integrase processes the viral DNA in the cytoplasm, translocates to the nucleus, and catalyzes viral DNA insertion into the host genome. A wide variety of chemical structures inhibit integrase in vitro, yet few of these apparently promising compounds have demonstrated similar efficacy in vivo. Multiple binding targets have been identified for different integrase inhibitors. These targets include the integrase enzyme prior to substrate binding, the viral DNA substrate, and the preintegration complex consisting of oligomeric integrase and the viral DNA. Some known inhibitors are effective only in the presence of divalent manganese as the active site metal ion cofactor, whereas others do not discriminate between manganese and magnesium ions. Integrase inhibition in response to ligand binding at one of multiple sites renders derivation of a simple set of structure activity relationships challenging. Progress toward this goal is reviewed in the context of experimental and theoretical structural information about integrase.

In this review, we intend to highlight outstanding concepts of antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome some drug deficiencies. Examples of antiviral carrier-linked nucleoside prodrugs or nucleoside bioprecursors are described, and their active mechanisms discussed. The described nucleoside prodrugs are classified in two structural classes: prodrugs bearing molecular modifications on the sugar moiety and prodrugs bearing molecular modifications on the nucleic base. Despite the important research work accomplished through out the world during the last few years in developing improved antiviral drugs for the treatment of HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HSV (herpes simplex virus), HCMV (human cytomegalovirus), etc-infections, only few nucleoside antiviral prodrugs are marketed, while promising prodrugs deriving from original concepts were developed. The most relevant concepts are discussed: (1) - pronucleotide approach allows the design of prodrugs, which by-pass the first kinase phosphorylation step; (2) - drug design based on Bodor's concept for brain delivery improved drugs and (3) - 5'-O-carbonate nucleosides and deaminase approaches, which allow active drug regeneration. Nonetheless, none of these innovative models have reached the market.

The number and the pharmacological activities of drugs featuring a guanidine group is actually amazing. Many synthetic guanidine derivatives have attracted pharmacologists in search of new antihypertensive drugs for their ability to block adrenergic nerve activity through central and / or peripheral mechanisms. As a result, compounds such as guanethidine, guanabenz, guanfacine, and pinacidil have been introduced in antihypertensive drug therapy. A crude methanol extract of the Venezuelan plant Verbesina caracasana Fries (Compositae), intravenously administered to mice, was found to induce biological effects such as erection of hair, initial stimulation and subsequent blockade of breathing. Biologically controlled purification yielded a series of active guanidine derivatives, namely G1-G7, which were extensively studied with the focus on the following items: The structure determination of the active compounds by spectral data and a set of reactions; -The confirmation of the structures by a biogenetically oriented synthesis; -The study of the pharmacological profiles of the isolated drugs; -The synthesis of analogous and homologous products in the effort to shed some light on the structureactivity relationship. The metabolites of V.caracasana were characterized, in anesthetized rats, as hypotensive drugs of high (G2), mild (G1, G7) and low (G3,G5,G6) potency, devoid of consistent actions in heart rate, and provided with moderate stimulatory effects on cardiac inotropism and breathing (at selected non-toxic intravenous doses). Autonomic neurogenic components and / or peripheral adrenergic and cholinergic receptor-related pathways were involved in the cardiovascular effects. Synthetic analogs and homologs of G1 and G5 were all shown to be hypotensive drugs of low-mild potency, not affecting appreciably cardiac inotropism and / or breathing. The pharmacodynamic differences among the studied compounds were likely to depend on their ability to cross the blood-brain barrier, lipophilicity and pharmacokinetics. Since most of the compounds did not induce reflex tachycardia and depression of myocardial contractility as the majority of the antihypertensive drugs, they might be useful in the treatment of arterial hypertension of various genesis.

The presence of parasitic cysteine proteases and trypanothione reductase in the parasitic protozoa of the genus Trypanosoma and Leishmania has made these enzymes attractive targets for the development of antitrypanosomal and antileishmanial agents. Furthermore, the presence of cysteine proteases in Plasmodium falciparum has presented additional opportunities for the development of chemical scaffolds that could potentially be utilized against all of the aforementioned parasites. While previous reviews on parasitic cysteine proteases and trypanothione reductase covered various aspects, none emphasized the chemistry behind the synthesis of described inhibitors. This review focuses on recent developments in the synthesis of low- molecular weight inhibitors of these enzymes with a bearing on the human diseases of leishmaniasis, malaria and trypanosomiasis. Only those inhibitors whose synthesis has been described in the open literature during the period 1993-mid 2002 have been highlighted. The review thus excludes what may be in the patent literature. Inhibitors synthesized using combinatorial and / or parallel synthesis chemistry as well as polymer-assisted synthesis methodologies have been deliberately omitted from this review because they are a subject of a separate and focused review.

Akuammiline alkaloids are a family of monoterpene indole alkaloids of renewed medicinal interest. These bases act as ligands for a heterogeneous group of molecular targets and, consequently, display a wide variety of pharmacological activities. For example, pseudoakuammigine (2) exhibits opioid activity in vivo, echitamine (4) has been reported to have promising cytotoxic activity, and corymine (121) behaves as an antagonist of the glycine receptor. Oddly enough, these alkaloids have not raised enough interest in the organic synthesis community, remaining inaccessible; even the entry to their pentacyclic framework continues elusive. Recently, several akuammiline bases have been isolated and identified including bisindole alkaloids, such as vingramine (103) or rausutrine (110), which incorporate akuammiline-type subunits. This review covers the advances in the chemistry and pharmacology of akuammiline alkaloids reported within the last ten years.