Ivan A. Andreev

Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity

Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.

Discovery of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole as a novel anti-hepatitis C virus targeting scaffold.

Although all-oral direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) treatment is now a reality, todays HCV drugs are expensive, and more affordable drugs are still urgently needed. In this work, we report the identification of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole chemical scaffold that inhibits cellular replication of HCV genotype 1b and 2a subgenomic replicons. The anti-HCV genotype 1b and 2a profiling and effects on cell viability of a selected representative set of derivatives as well as their chemical synthesis are described herein. The most potent compound 39 displayed EC50 values of 7.9 and 2.6 μM in genotype 1b and 2a, respectively. Biochemical assays showed that derivative 39 had no effect on HCV NS5B polymerase, NS3 helicase, IRES mediated translation and selected host factors. Thus, future work will involve both the chemical optimization and target identification of 2-phenyl-4,5,6,7-Tetrahydro-1H-indoles as new anti-HCV agents.

Fragment-Based Discovery of 5-Arylisatin-Based Inhibitors of Matrix Metalloproteinases 2 and 13

Matrix metalloproteinases (MMPs) are well‐established targets for several pathologies. In particular, MMP‐2 and MMP‐13 play a prominent role in cancer progression. In this study, a structure‐based screening campaign was applied to prioritize metalloproteinase‐oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound library. These fragments were prioritized, and the top‐ranking hits were tested in a biological assay to validate the model. Two scaffolds showed consistent activity in the assay, and the isatin‐based compounds were the most interesting. These latter fragments have significant potential as tools for the design and realization of novel MMP inhibitors. In addition to their micromolar activity, the chemical synthesis affords flexible and creative access to their analogues.

Synthesis of Bicyclic Proline Derivatives by the Aza‐Cope–Mannich Reaction: Formal Synthesis of (±)‐Acetylaranotin

Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza-Cope-Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.

Synthesis of 2-phenyl-4,5,6,7-tetrahydro-1H-indoles with a chiral substituent at the nitrogen atom

An efficient method has been developed for the enantioselective synthesis of 2-phenyl-4,5,6,7-tetra-hydro-1H-indoles containing chiral substituents at the nitrogen atom. It is based on opening of the epoxide fragment of 1-phenylethynyl-7-oxabicyclo[4.1.0]heptane with chiral amines and/or amino acid esters followed by intramolecular, metal catalyzed cyclization.

Oxidative Dearomatization of 4,5,6,7-Tetrahydro-1H-indoles Obtained by Metal- and Solvent-Free Thermal 5-endo-dig Cyclization: The Route to Erythrina and Lycorine Alkaloids

A facile one-pot approach based on a thermally induced metal- and solvent-free 5-endo-dig cyclization reaction of the amino propargylic alcohols in combination with Dess-Martin periodinane-promoted oxidative dearomatization of 4,5,6,7-tetrahydroindole intermediates provides an efficient and robust access to 5,6-dihydro-1H-indol-2(4H)ones. Green, relatively mild and operationally simple characteristics of the synthetic sequence are the major advantages, which greatly amplify the developed methodology. The utility of obtained indolones as unified key precursors is demonstrated by the application of these products to the formal total syntheses of a whole pleiad of Erythrina- and Lycorine-type alkaloids, namely (±)-erysotramidine, (±)-erysotrine, (±)-erythravine, (±)-γ-lycorane, and abnormal erythrinanes (±)-coccoline and (±)-coccuvinine.

A Small-Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity

Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self-replicating, misfolded isoform (PrPSc ) of the cellular prion protein (PrPC ). No therapies are available for these pathologies. We capitalized on previously described cell-based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity. Compound 55 may represent the starting point for the development of a completely new class of therapeutics for prion diseases.