Irena Philipova

Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity.

The inhibitors of acetylcholinesterase are the main therapy against Alzheimers disease. Among them, galantamine is the best tolerated and the most prescribed drug. In the present study, 41 galantamine derivatives with known acetylcholinesterase inhibitory activities expressed as IC50 were selected from the literature and docked into a recombinant human acetylcholinesterase by GOLD. A linear relationship between GoldScores and pIC50 values was found and used to design and predict novel galantamine derivatives with indole moiety in the side chain. The four best predicted compounds were synthesized and tested for inhibitory activity. All of them were between 11 and 95 times more active than galantamine. The novel galantamine derivatives with indole moiety have dual site binding to the enzyme--the galantamine moiety binds to the catalytic anionic site and the indole moiety binds to peripheral anionic site. Additionally, the indole moiety of one of the novel inhibitors binds in a region, close to the peripheral anionic site of the enzyme, where the Ω-loop of amyloid beta peptide adheres to acetylcholinesterase. This compound emerges as a promising lead compound for multi-target anti-Alzheimer therapy not only because of the strong inhibitory activity, but also because it is able to block the amyloid beta deposition on acetylcholinesterase.

Synthesis of new enantiopure aminodiols and their use as ligands for the addition of diethylzinc to benzaldehyde

Abstract The synthesis of new enantiopure aminodiols through aminolytic ring opening of chiral epoxy alcohols derived from (+)-camphor and (−)-fenchone is described. The absolute configurations were determined by NMR methods. The aminodiols catalyzed the addition of diethylzinc to benzaldehyde in high yields and with enantioselectivities of up to 80%.

Synthesis and antimycobacterial activity of novel camphane-based agents

A series of six new amidoalcohols was designed and synthesized on the base of the camphor scaffold. Natural amino acids were transformed into their α-hydroxy analogues with retention of configuration, and attached to isobornylamine. The compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. The activity shifts from micromolar to nanomolar inhibitory concentrations depending on the α-hydroxy acid moiety. Two of the most potent compounds exert low level of cytotoxic activity. These camphane-based amido-alcohols present promising potential lead compounds for further elaboration of antimycobacterial agents.

New bis-steroidal axially chiral diols as ligands for the asymmetric addition of diethylzinc to aldehydes

Abstract New axially chiral steroidal binaphthols, prepared from estrone, were applied in the form of their Ti-alkoxides as catalysts for the addition of diethylzinc to aldehydes. The addition reactions proceeded with high yields and enantioselectivities up to 86%.

Novel camphane-based anti-tuberculosis agents with nanomolar activity

A series of new amidoalcohols and amidodiols were designed on the base of the camphor scaffold and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and MDR strain 43. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. Small structural changes in the side chain shift the activity from micromolar to nanomolar inhibitory concentrations. Quantitative structure-activity relationship (QSAR) model is derived to guide the further lead optimization. Two hydrogen bond donors and up to three rings in the molecules are optimal for nanomolar activity. The camphane-based amides present novel promising scaffolds for antimycobacterial agents.

Synthesis and absolute configuration of new chiral epoxyalcohols by stereoselective epoxidation of allylic and homoallylic alcohols with a (1R)-(+)-camphor skeleton

Abstract The chiral nonracemic alcohols 1–5 were stereoselectively epoxidized with the VO(acac) 2 /t-butyl hydroperoxide system. The epoxyalcohols 6–9 resulting from alcohols 1–4 were synthesized in high yields and the obtained diastereoisomers were isolated in pure form by chromatography. The homoallylic alcohol 5 epoxidized 100% diastereoselectively to 10 . The epoxyalcohol 10 underwent a stereoselective intramolecular cyclisation during the epoxydation with rearrangement of the camphor skeleton to the oxatricyclo derivative 11 . The absolute configurations of the new chiral compounds were determined by NMR methods.

(−)-Fenchone derived epoxy alcohols—preparation and configuration

Abstract Several chiral diastereoisomerically pure epoxy alcohols were prepared diastereoselectively in high yields after epoxidation of allyl and homoallyl alcohols containing the 1 R -fenchone skeleton with VO(acac) 2 / t -butyl hydroperoxide. The configurations of some of the new chiral compounds were determined by NMR methods. An interesting rearrangement reaction of an epoxy alcohol to an olefinic diol catalyzed by V 5+ ions was observed.

Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase.

The enzyme acetylcholinesterase is a key target in the treatment of Alzheimers disease because of its ability to hydrolyze acetylcholine via the catalytic binding site and to accelerate the aggregation of amyloid‐β peptide via the peripheral anionic site (PAS). Using docking‐based predictions, in the present study we design 20 novel galantamine derivatives with alkylamide spacers of different length ending with aromatic fragments. The galantamine moiety blocks the catalytic site, while the terminal aromatic fragments bind in PAS. The best predicted compounds are synthesized and tested for acetylcholinesterase inhibitory activity. The experimental results confirm the predictions and show that the heptylamide spacer is of optimal length to bridge the galantamine moiety bound in the catalytic site and the aromatic fragments interacting with PAS. Among the tested terminal aromatic fragments, the phenethyl substituent is the most suitable for binding in PAS.

Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline‐7‐Acetic Acid Derivatives With Amino Acid Moieties

The theophylline‐7‐acetic acid (7‐TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7‐TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7‐TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non‐toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol.

Docking-based design and synthesis of galantamine–camphane hybrids as inhibitors of acetylcholinesterase

Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimers disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aβ) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE‐induced Aβ aggregation. In this study, we describe the design of a series of galantamine–camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191‐ and 369‐fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω‐loop of Aβ binds to AChE. The hybrids cross blood–brain barrier by passive diffusion and are non‐neurotoxic at the inhibitory concentrations.