New anti‐HIV agents and targets

Abstract

Virtually all the compounds that are currently used or are subject of advanced clinical trials for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e., tenofovir disoproxil fumarate); (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 (i.e., bicyclam (AMD3100) derivatives) and CCR5 (i.e., TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs, and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e., phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs ( i.e., TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii), as in the case of PIs, a different, modified peptidic (i.e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs.

Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-Diarylthiourea as Urea Mimetics

“…For example, the Raf-1 inhibitor BAY 43-9006 is developed for cancer and inflammatory disorders 1 and the cyclic urea Mozenavir is studied for HIV. 2 1,3-Diarylurea is frequently encountered as a privileged structure for many biological targets. 3 They constitute an essential part of pharmacophores for biological targets such as p38 and raf kinases, 6,4 vascular endothelial growth receptor 2 (VRGFR-2), 5 inosine monophosphate dehydrogenase (IMPDH), 6 highly potent and selective human A 2B adenosine receptor antagonists 7 and cyclin-dependent kinase 2 (CDK2) inhibitors.…”

“…For example, while some of these urea-based inhibitors bind to an allosteric site causing a significant rearrangement of the target protein structure 9,10 others bind to the active site such as the ATP pocket with the urea function participating in a bi-dentate hydrogen bond. 11 Bioisosteric replacements of the amide and thioamide functions included heterocyclic systems such as the [1,2,4]-and [1,3,4]oxadiazoles and [1,2,4]triazoles. 12 Such replacements led to [1,2,4]triazoles which were active antimycobacterials 13 and potent, selective 5-HT 1D receptor agonists.…”

“…11 Bioisosteric replacements of the amide and thioamide functions included heterocyclic systems such as the [1,2,4]-and [1,3,4]oxadiazoles and [1,2,4]triazoles. 12 Such replacements led to [1,2,4]triazoles which were active antimycobacterials 13 and potent, selective 5-HT 1D receptor agonists. 14 Another interesting application of triazole was to employ it as a cis-amide bond surrogate.…”

Marine Snails and Slugs: a Great Place To Look for Antiviral Drugs

“…Numerous successful antivirals are either marine derived or analogs of marine compounds. Indeed, vidarabine (adenine arabinoside, or "ara-A"), acyclovir, and zidovudine (azidothymidine) have been commercially synthesized with semisynthetic modifications from or are structural analogs of the arabinosyl nucleosides isolated from the sponge Cryptotethia crypta (66,67). Under selective pressure, some human viruses have become resistant to a number of commercial drugs.…”

Novel Role of 3-Phosphoglycerate Kinase, a Glycolytic Enzyme, in the Activation of L-Nucleoside Analogs, a New Class of Anticancer and Antiviral Agents

“…Despite the unnatural L-configuration, these analogs are able to utilize the salvage pathway of deoxynucleoside metabolism to be phosphorylated to the active triphosphate form (3,4). Similar to the D-nucleoside analog counterparts, L-nucleoside analog triphosphates exert their pharmacological activity through incorporation into cellular or viral DNA, leading to chain termination or inhibition of viral reverse transcriptase or DNA polymerase (5)(6)(7)(8)(9)(10). In the past decade, the realization that L-nucleosides are capable of being activated in cells has led to the discovery of several antiviral pyrimidine L-deoxynucleoside analogs.…”