Human immunodeficiency virus compounds

Balzarini J, Hao Z, Herdewijn P, Johns DG, De Clercq E. Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylme-thoxyethyl)adenine, a potent anti-human immunodeficiency virus compound. Proc Natl Acad Sci USA 1991 88 1499-1503. 

This methodology has been applied to the synthesis of the dihydropyran portion 32 of tipranavir (33), an anti-human immunodeficiency virus compound (Scheme 28.23).56-70 The dihydropyran 32 can be accessed from the cyclopentene 34 by what is formally a tandem AROM/RCM reaction. 

Schroder, H. C., Wenger, R., Gemer, H., Reuter, P., Kuchino, Y., Sladic, D., and Muller, W. E., Suppression of the modulatory effects of the antileukemic and anti-human immunodeficiency virus compound avarol on gene expression by tryptophan, Cancer Res., 49[8], 2069, 1989. 

A functional library based on betulinic acid (17, Figure 5.8), a scaffold isolated from plants, is an example of using a synthetic strategy that involves semisynthetic modifications and DOS by scaffold decoration. Kashiwada et al. described the library design and evaluation of betulinic acid derivatives as anti-HIV (human immunodeficiency virus) compounds. ... 

The first lead compounds for non-nucleoside reverse transcriptase (RT) inhibitors (NNRTl) were discovered about 15 years ago (Pauwels et al. 1990 Merluzzi et al. 1990 Goldman et al. 1991 De Clercq 1993 Riibsamen-Waigmann et al. 1997). Since then they have become an important ingredient of the dmg combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HlV-1) infections. Starting from the HEPT and TIBO derivatives, numerous classes of compounds have been described as NNRTIs. Four compounds (nevirapine, delavirdine, efavirenz and etravirine) have so far been approved for clinical use and several others are the subject of clinical trials (Balzarini 2004 Stellbrink 2007). 

In this chapter, we have described the spectrum of antiviral activities that have been discovered beyond the world of nucleoside analogues, protease and fusion inhibitors. The compounds and mechanisms described here may one day add significantly to the armamentarium of antiviral agents, not only against Herpes Simplex, Hepatitis B and Human Immunodeficiency Virus, but also against Hepatitis C and Human Cytomegalovirus. 

SAR studies were carried out by de Bruyne et al. [92] on a series of dimeric procyanidins, considered as model compounds for antiviral therapies. On the whole, proanthocyanidins containing EC dimers exhibited more pronounced activity against herpes simplex virus (HSV) and human immunodeficiency virus (HIV), while the presence of ortho-trihydroxyl groups in the B-ring appeared to be essential in all proanthocyanidins exhibiting anti-HSV effects. Galloylation and polymerization reinforced the antiviral activities markedly. 

Thiourea compounds have been observed to inhibit human immunodeficiency virus (HIV) reverse transcriptase, a viral enzyme that is responsible for the reverse transcription of the retroviral RNA to proviral DNA. Phenethylthiazoylthiourea (PETT) compounds were discovered as potent inhibitors of HIV type 1 and display certain structure-activity relationships among various substituents in their structure.199 207 Furthermore, thiourea derivatives have been found to be potent and selective viral inhibitors, antifungal and antibacterial compounds.208 215... 

A few nitrogen-substituted allenes themselves are known as biologically active compounds [154], For example, the 9-(4 -hydroxy-1, 2 -butadienyl)adenine (268a) was found to inhibit in vitro replication and cytopathic effects of human immunodeficiency viruses HIV-1 and HIV-2 [155], More recently, an increase in the anti-HIV activity in cell cultures using the adenallene phosphotriester derivative 268b was reported (Scheme 8.72) [156]. 

In order to identify novel lead compounds with antiviral effects, methanol and aqueous extracts of some medicinal plants in the Zingiberaceae family were screened for inhibition of proteases from human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and human cytomegalovirus (HCMV). By bioassay-guided fractionation, eight fiavones were isolated from the black rhizomes of Kaempferia parviflora Wall, ex Baker. The most effective inhibitors, 5-hydroxy-7-methoxyfiavone and 5,7-dimethoxyflavone, inhibited HIV-1 protease, with an inhibitory concentration 50 (IC50) values of 19 0,M. Moreover, 5-hydroxy-3,7-dimethoxyflavone inhibited HCV protease and HCMV protease, with IC50 values of 190 and 250 pM, respectively. 

Pharmacological research has also benefited from the development of sophisticated tools because they have made it possible for researchers to determine the exact molecular structure of compounds involved in the disease process. With this information, they can devise molecules that bond with and inactivate those compounds (just as enzymes bond with substrates). Consider just one example of this process the development of a drug to treat human immunodeficiency virus (HIV) infection. 

The rapid spread of acquired immune deficiency syndrome (AIDS) has prompted numerous efforts to develop therapeutic agents against the human immunodeficiency virus type 1 (HIV-1) [2351. Efforts have focused on inhibition of the virally encoded reverse transcriptase (RT) enzyme, which is responsible for the conversion of retroviral RNA to proviral DNA. The nucleoside RT inhibitors 3 -azidothymidine (AZT) and dideoxyinosine (ddl) have proven to be clinically useful anti HIV-1 agents [236], but due to their lack of selectivity versus other DNA polymerases, these compounds are flawed by their inherent toxi-... 

Cycloaddition of a variety of alkynes to the azido function of 3 -azido-2, 3 -dideoxythymidine and 3 -azido-2,3-dideoxyuridine yields products (e.g., 716) with a 1,2,3-triazol-l-yl substituent in the 3 -position (Equation (60)). By contrast to the parent compounds, these triazolyl derivatives have no appreciable activity against human immunodeficiency virus <89JHC1635>. Cycloadditions of 4-azido-6-methyl-2//-pyran-2-one with alkynes leads to triazoles (717) <93JHC317>. 

Nearly 40 million people are infected with the human immunodeficiency virus (HIV). Over half of those infected reside in sub-Saharan Africa. Worldwide during 2004, it is estimated that nearly 14,000 people a day were infected. Human immunodeficiency virus type 1 is the primary etiological source for the acquired immunodeficiency syndrome (AIDS). Fortunately, people infected with HIV are leading longer and more productive lives due to the availability of more effective therapies. Better medicines have evolved due to the efforts of scientists worldwide who find targets and compounds that inhibit the virus life-cycle. The current treatment for HIV infection is via a drug cocktail that usually includes a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

Pyrrolopyridines substituted at the 2-position of dipyridodiazepinones have been prepared for study as nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase <1997JME2430>. Compound 141, synthesized from pyrrolo[2,3-, ]pyridine as a starting material, has emerged as a novel inhibitor of HIV-1. Compound 141 acts by interfering with the initial viral entry process <2003JME4236>. 

Furoannelated analogs of uracil acyclic nucleosides were prepared as compounds with potential as anti-HIV agents (HIV = human immunodeficiency virus). Hence, 6-benzyluracil 320 is converted to the precursor 321 first by hydroxymethylation, silylation in situ with bis(trimethylsilyl)acetamide (BSA), then by alkylation (Scheme 28) <2001S559>. Ring closure to 322 was effected by treatment with lead tetraacetate and calcium carbonate <2004AP148>. 

The Pd-catalyzed carbonylation of o-vinylaryl bromides using Mo(CO)6 as CO source with microwave irradiation gave indanone 338 and 3-acylaminoindanone 340, which are key intermediates for the synthesis of inhibitors of human immunodeficiency virus type 1 (HIV-1) protease and Plasmepsin I and II (Scheme 46). These polycyclic compounds were obtained in less than 30 min in high yields. The results clearly indicate the power and advantage of this protocol, especially for the combinatorial parallel synthesis of a library of compounds. 

Brennan TM, Taylor DL, Bridges CG, Leyda JP, Tyms AS. The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442 alone and in combination with other anti-HIV compounds. Antiviral Res 1995 26 173-187. 

Lamellarin T-V and Y sulfates (67-70) were isolated from an unidentified ascidian from the Arabian Sea coast of India [97]. Four additional lamellarin sulfates, the 20-sulfates of lamellarins B, C and L and lamellarin G 8-sulfate (71-74) were isolated from Didemnum chartaceum from the Great Barrier Reef [98]. Unusually long relaxation times were observed for certain signals in the H NMR spectra of these compounds. Lamellarin a 20-sulfate (75) was isolated from an unidentified ascidian from India and was an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase [99]. 

Because of the importance of l,3-diazepin-2-ones as human immunodeficiency virus 1 (HIV-1) protease inhibitors, considerable computational effort has been devoted to the analysis of the structure <1998JA4570> and binding properties <2004JME6673, 2004BMC5819, 1999JME249> of these compounds. 

In a more recent continuation of these studies, Campiani and co-workers carried out semi-empirical calculations on a series of active compounds related to 2. This led to the identification of several structural and conformational features responsible for this activity <2005JME4367>. Docking into the human immunodeficiency virus 1 (HIV-1) reverse transcriptase non-nucleotide binding site (RT NNBS) of a compound of type 3 (X = O) highlighted that one of the phenyl rings of this compound protrudes toward the catalytic site <2005JME7153>. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Reports that colchicine showed promising activity as an inhibitor of human immunodeficiency virus (HIV) replication (133,134) initiated the synthesis of derivatives of colchicine and thiocolchicine as potential inhibitors of HIV replication in H9 lymphocytic cells (135). Colchicine was found to be slightly active at nontoxic doses. All the other compounds, which were found inactive in this assay, were derivatives of colchiceine and/or A/-deacetylcolchicine. It is well established that both of these structural changes reduce dramatically binding to tubulin, and the reported results are, therefore, not completely surprising. 

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