Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer's and Other Neurodegenerative Diseases

Alzheimer’s disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure−activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases

Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells

The Kruppel-like Factors 2 and 4 (KLF2/4) are transcription factors and master regulators of endothelial cells (ECs) phenotype and homeostasis. KLF2/4 are important blood-flow-responsive genes within ECs that differentially regulate the expression of factors that confer anti-inflammatory, antithrombotic, and antiproliferative effects in ECs. We found that genetic inactivation of endothelial Krit1 (Krev interaction trapped protein 1) or Heg1 (Heart of glass) led to upregulation of KLF2/4 expression levels. We also observed that vasoprotective proteins, endothelial nitric oxide synthase (eNOS) and thrombomodulin (TM), are upregulated by the increase of KLF2/4 as a result of loss of endothelial KRIT1. Here, we developed a high-throughput screening assay to identify inhibitors of the HEG1-KRIT1 interaction and identified sirtinol (HKi001) as a promising hit inhibitor. The crystal structure of sirtinol bound to the KRIT1 FERM domain confirmed the primary screening results and ultimately led to the identification of a fragment-like inhibitor (HKi002), which occupies the HEG1 pocket producing comparable activity. These findings suggest that these inhibitors block the interaction by competing with the HEG1 for binding to KRIT1 FERM domain. Moreover, our results demonstrate that HKi002 upregulates KLF2/4 gene expression in two types of human ECs. These results reveal an unexpected role of inhibiting the HEG1-KRIT1 interaction and provide a proof-of-concept that pharmacological manipulation of this complex may offer new opportunities to induce expression of KLF2/4 as vasoprotective factors

Microtubule-stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as candidate therapeutics for neurodegenerative disease: Matched molecular pair analyses and computational studies reveal new structure-activity insights

Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer’s disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure–activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity

Synthesis of Multi-Target-Directed Ligands against Alzheimer's Disease

National audienc

Synthesis of Multi-Target-Directed Ligands against Alzheimer's Disease

National audienc

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

The 1,2,4-triazolo[1,5-a]pyrimidine (TP) heterocycle, in spite of its relatively simple structure, has proved to be remarkably versatile as evidenced by its use in many different applications reported over the years in different areas of drug design. For example, as the ring system of TPs is isoelectronic with that of purines, this heterocycle has been proposed as a possible surrogate of the purine ring. However, depending on the choice of substituents, the TP ring has also been described as a potentially viable bio-isostere of the carboxylic acid functional group and of the N-acetyl fragment of ε-N-acetylated lysine. In addition, the metal-chelating properties of the TP ring have also been exploited to generate candidate treatments for cancer and parasitic diseases. In the present review article, we discuss recent applications of the TP scaffold in medicinal chemistry, and provide an overview of its properties and methods of synthesis

Synthetic Route to Rare Isoindolones Derivatives

International audienceA shorter and more versatile synthetic route has been developed to prepare tetrahydropyrido[2,1‐a]isoindolone and superior analogues. The key step of this synthesis is the formation of the lactam ring by a cyclization using Shibasaki's conditions.The isoindolone scaffold is present in many biologically active compounds. Here, we have developed a shorter and more efficient synthesis of tetrahydropyrido[2,1‐a]isoindolone. The key step of this approach is a cyclization to form the γ‐lactam ring under Shibasaki's conditions. Thus, tetrahydropyrido[2,1‐a]isoindolone and superior analogues, namely hexahydroazepino[2,1‐a]isoindolone and hexahydroazocino[2,1‐a]isoindolone, have been prepared in only three steps in 39, 25, and 19 % overall yields, respectively. This novel strategy offers a shorter alternative to existing procedures