Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids.

HIV integrase, encoded at the 3'-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of "no-return" in HIV infection. Integrase is a significant target in anti-HIV drug discovery.

A novel molecule with notable activity against multi-drug resistant tuberculosis.

Multi-drug resistant tuberculosis (MDR-TB) is emerging as a serious global health problem, which has been elevated through co-infection involving HIV and MDR-Mtb. The discovery of new compounds with anti-MDR TB efficacy and favorable metabolism profiles is an important scientific challenge. Using computational biology and ligand docking data, we have conceived a multifunctional molecule, 2, as a potential anti-MDR TB agent.

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.

Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the "point of no return" in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor 1, that exhibits potent antiviral activity and a favorable metabolism profile.

Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor.

The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile with respect to isozymes of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT). However, the total synthesis of this significant HIV integrase inhibitor has not been reported.

Synthesis of a novel carbocyclic analog of bredinin.

The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described.

Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations.

While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome.

A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5'-diphospho-glucuronosyltransferase metabolism profile.

Research efforts on the human immunodeficiency virus (HIV) integrase have resulted in two approved drugs. However, co-infection of HIV with Mycobacterium tuberculosis and other microbial and viral agents has introduced added complications to this pandemic, requiring favorable drug-drug interaction profiles for antiviral therapeutics targeting HIV. Cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) are pivotal determining factors in the occurrence of adverse drug-drug interactions.

Solid-state tautomeric structure and invariom refinement of a novel and potent HIV integrase inhibitor.

The conformation and tautomeric structure of (Z)-4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide, C27H22F3N3O5, in the solid state has been resolved by single-crystal X-ray crystallography. The electron distribution in the molecule was evaluated by refinements with invarioms, aspherical scattering factors by the method of Dittrich et al. [Acta Cryst.

Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity.

Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC(50) 70 nM), strategically assembled on a pyridinone scaffold.

Base-functionalized carbocyclic nucleosides: design, synthesis, and mechanism of antiviral activity.

New carbocyclic ribonucleosides with unsaturated groups at the C-2 position of the nucleobase were designed as potential RNA antiviral compounds. The design was based on the expectation that the monophosphates of these compounds would be inhibitors of the enzyme, IMPDH. Appropriate methodologies were developed to achieve the target molecules.

A heterocyclic molecule with significant activity against dengue virus.

There are no specific approved drugs or vaccines for the treatment or prevention of infectious dengue virus and there are very few compounds known that inhibit the replication of this virus. This letter describes the concise synthesis of two uracil-based multifunctional compounds. One of these compounds (1) has strong activity against dengue virus.

Isonucleosides: design and synthesis of new isomeric nucleosides with antiviral potential.

Isonucleosides discovered in our laboratory have been found to have interesting antiviral activity. The design, development of methodology, and stereochemical synthesis of new isonucleosides of anti-HCV interest are described. Antiviral results are cited.

Biologically-validated HIV integrase inhibitors with nucleobase scaffolds: structure, synthesis, chemical biology, molecular modeling, and antiviral activity.

Integrase, an enzyme of the pol gene of HIV, is a significant viral target for the discovery of anti-HIV agents. In this presentation, we report on the continuation of our work on the discovery of diketo acids, constructed on nucleobase scaffolds, that are inhibitors of HIV integrase. An example of our synthetic approach to inhibitors with purine nucleobase scaffolds is given.

IMPDH as a biological probe for RNA antiviral drug discovery: synthesis, enzymology, molecular docking, and antiviral activity of new ribonucleosides with surrogate bases.

Our interest in the discovery of molecules with antiviral activity against RNA viruses led us to the design of ribonucleosides with surrogate bases with the intent of using inhibition of inosine monophosphate dehydrogenase (IMPDH) as a probe for antiviral drug discovery. A general methodology for the preparation of these compounds is discussed. Kinetic parameters of the inhibition studies with IMPDH, which were carried out spectrophotometrically by monitoring the formation of NADH, are given.

Inosine monophosphate dehydrogenase as a probe in antiviral drug discovery.

Inosine monophosphate (IMP) dehydrogenase (IMPDH) is a significant enzyme in the purine nucleotide biosynthetic pathway. IMPDH is viewed as an important biological target in the quest for drugs in the antiviral therapeutic area. This review article is focused on the chemistry and biology of IMPDH inhibitors and the use of IMPDH inhibition data as a probe in antiviral drug discovery.

A novel strategy to assemble the beta-diketo acid pharmacophore of HIV integrase inhibitors on purine nucleobase scaffolds.

Claisen condensation, the key step in constructing the pharmacophore of aryl beta-diketo acids (DKA) as integrase inhibitors, fails in certain cases of highly electron-deficient heterocycles such as purines. A general synthetic strategy to assemble the DKA motif on the purine scaffold has been accomplished. The synthetic sequence entails a palladium-catalyzed cross-coupling, a C-acylation involving a tandem addition/elimination reaction, and a novel ferric ion-catalyzed selective hydrolysis of an enolic ether in the presence of a carboxylic acid ester.

HIV integrase inhibitors as therapeutic agents in AIDS.

HIV-1 integrase is a protein of Mr 32 000 encoded at the 3'-end of the pol gene. Integration of HIV DNA into the host cell chromosomal DNA apparently occurs by a carefully defined sequence of DNA tailoring (3'-processing (3'P)) and coupling (integration) reactions. Integration of HIV DNA into human DNA represents the biochemical completion of the invasion of the human cell (e.

Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery.

Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme of de novo purine nucleotide biosynthesis and is viewed as an important target in the quest for discovery of drugs in the antiviral, antibacterial and anticancer therapeutic areas. This review focuses on the medicinal chemistry, drug discovery and chemical biology of IMPDH. Examples of IMP and cofactor site-directed inhibitors, allosteric inhibitors and isoform-selective inhibitors are presented.

Novel HIV integrase inhibitors with anti-HIV activity: insights into integrase inhibition from docking studies.

The mechanism of integrase is generally accepted to be dependant on the presence of two divalent metal ions in the active site. However, the only available crystal structures of HIV-1 integrase contain either one or no metal ions, hampering structure-based design studies of integrase inhibitors. For this reason, a two-metal ion model of integrase was constructed.

A novel diketo phosphonic acid that exhibits specific, strand-transfer inhibition of HIV integrase and anti-HIV activity.

We have synthesized novel phosphonic acid analogues of beta-diketo acids. Interestingly, the phosphonic acid isostere, 2, of our anti-HIV compound, 1, was an inhibitor of only the strand transfer step, in stark contrast to 1. Compound 2 had lower anti-HIV activity than 1, but was more active and less toxic than the phosphonic acid analogue of L-708906.

Azadideoxyadenosine: synthesis, enzymology, and anti-HIV activity.

Synthesis of an azanucleoside, a new analogue of dideoxyadenosine, is described. This compound is only slowly deaminated by mammalian adenosine deaminase and it is a substrate for adenosine kinase. It exhibits in vitro anti-HIV activity.

Beta-diketo acids with purine nucleobase scaffolds: novel, selective inhibitors of the strand transfer step of HIV integrase.

The HIV pol gene encodes three viral enzymes that are required for its replication. While drug discovery involving the viral targets, reverse transcriptase and protease, has resulted in useful therapeutic agents, such efforts on HIV integrase have not produced a single FDA-approved drug. In the work focused on the discovery of inhibitors of HIV integrase, we have synthesized new beta-diketo acids with purine nucleobase scaffolds that are potent inhibitors of the strand transfer steps of wild-type HIV-1 integrase.

Synthetic approaches to nuclease-resistant, nonnatural dinucleotides of anti-HIV integrase interest.

New, nonnatural dinucleotide 5'-monophosphates with a surrogate isonucleoside component of L-related stereochemistry, have been synthesized. Structures of the target compounds were confirmed by multinuclear NMR spectra (1H, 13C, 31P, COSY), UV hypochromicity, FAB HRMS data and X-ray crystallography. These compounds are totally resistant to cleavage by 3'- and 5'-exonucleases.

HIV integrase inhibitors with nucleobase scaffolds: discovery of a highly potent anti-HIV agent.

HIV integrase is essential for HIV replication. However, there are currently no integrase inhibitors in clinical use for AIDS. We have discovered a conceptually new beta-diketo acid that is a powerful inhibitor of both the 3'-processing and strand transfer steps of HIV-1 integrase.