Structure–Activity Relationship Studies of Isomeric 2,4-Diaminoquinazolines on β-Amyloid Aggregation Kinetics

Abstract

A library of isomeric 2,4-diaminoquinazoline (DAQ) derivatives were synthesized and evaluated for antiaggregation potential toward Aβ40/42. Structure−activity relationship data identified compound 3k (N 4 -(4-bromobenzyl)-quinazoline-2,4-diamine) with a 4-bromobenzyl substituent as the most potent inhibitor (Aβ40 IC 50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (Aβ40 IC 50 = 1.5 μM). The corresponding N 2 -isomer 4k (N 2 -(4-bromobenzyl)quinazoline-2,4-diamine) was also able to prevent Aβ aggregation (Aβ40 IC 50 = 1.7 μM). However, compound 4k exhibited superior inhibition of Aβ42 aggregation (Aβ42 IC 50 = 1.7 μM) compared to compound 3k (Aβ42 IC 50 = 14.8 μM) and was ∼1.8-fold more potent compared to curcumin (Aβ42 IC 50 = 3.1 μM). These results were supported by Aβ aggregation kinetics investigations and transmission electron microscopy studies, which demonstrate the suitability of DAQ ring system to develop antiamyloid agents as pharmacological tools to study Aβ aggregation. KEYWORDS: Quinazolines, amyloid, Aβ aggregation, Alzheimer's disease O ne of the most influential hallmarks of Alzheimer's pathology is the collapse of cellular amyloid management, leading to the progressive accumulation of neurotoxic Aβ-deposits. 1−4 While the mechanisms intertwining the amyloid pathway are vast and complex, a number of strategies to combat its neuronal insults have been proposed, researched, and evaluated in various preclinical and clinical settings. 5−7 An essential tool utilized by researchers to further understand the aggregation mechanisms of amyloidogenic peptides, such as Aβ, is to develop and evaluate aggregation modulators and inhibitors. 8,9 Not only is this beneficial in understanding the kinetics of amyloid aggregation but it may reveal potential therapeutic candidates.When it comes to developing drug candidates, nature plays an important role in highlighting ideas for potential core templates and scaffolds. Honing in on the case of Aβ with respect to aggregation modulators and inhibitors, compounds such as curcumin, a component of the spice turmeric, and resveratrol, a phytoalexin found in grapes and berries ( Figure 1), are considered as model compounds in this context. 10−13 The synthetic compound, orange G is a commonly used stain/ dye and, like curcumin and resveratrol, is used as a pharmacological tool in drug discovery due to its excellent activity against amyloid aggregation. 14,15From a chemical standpoint, these small molecules share structural features including aromaticity, conjugation, and planarity resulting in their ability to intercalate and disrupt the backbone hydrogen bonding interactions in the beta-sheet assembly thereby providing a framework to design small molecules as pharmacological tools to study Aβ aggregation and inhibition. 16,17 As part of our research program aimed at discovering and developing novel small-molecules as potential pharmacological tools to study Alzheimer's disease (AD) and

2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies

“…In addition, 17a exhibited superior inhibition of Aβ42 (IC 50 ~ 8 µM) compared to the corresponding C2 amino regioisomer 14b and was ~ 1.8-fold more potent compared to resveratrol (IC 50 = 15.3 µM) and ~ 1.2-fold more potent compared to curcumin (IC 50 = 3.3 µM). It should be noted that anti-Aβ activity of quinazoline derivatives 14b, 14d, 17a and 17b were previously reported by us [33].…”

“…The quinazoline derivative 11 was obtained from Sigma-Aldrich and the other quinazoline derivatives 8a-d, 14a-d, 17a and 17b were synthesized and characterized as per our previously reported methods [33,36,43]. Melting points (mp) were determined using a Fisher-Johns apparatus and are uncorrected.…”

Characterizing Structural Stability of Amyloid Motif Fibrils Mediated by Water Molecules

“…[15][16][17][18] It is important to characterize the cytotoxic mechanism of amyloid fibrils and their cytotoxicity resulting from their commons tructural andp hysicochemical features. [20][21][22][23][24][25][26] Although the conformations and physicochemical characteristics of amyloid fibrils have been widely studied, the detailed fibril forming mechanisms remain unclear because of the polymorphisms [27][28][29][30] and the complexity of formation mechanism. [20][21][22][23][24][25][26] Although the conformations and physicochemical characteristics of amyloid fibrils have been widely studied, the detailed fibril forming mechanisms remain unclear because of the polymorphisms [27][28][29][30] and the complexity of formation mechanism.…”

“…[19] Understanding of thesef eatures will enable the development of effective therapeutic compounds. [20][21][22][23][24][25][26] Although the conformations and physicochemical characteristics of amyloid fibrils have been widely studied, the detailed fibril forming mechanisms remain unclear because of the polymorphisms [27][28][29][30] and the complexity of formation mechanism. [5,31] Recently,a dvancede xperimental techniques [27,29,[32][33][34][35][36][37] that offer high-resolution structural features of amyloid fibrils have become avail-able.…”

Application of quinazoline and pyrido[3,2-d]pyrimidine templates to design multi-targeting agents in Alzheimer's disease

“…11,12 In this regard, dual inhibition of both AChE and BuChE is known to be benecial as BuChE can process ACh in advance stages of AD. 13 Building on our recent efforts on multi-targeting small molecules, herein we present the structure-activity relationship (SAR) studies of substituted quinazolines and its bioisostere, pyrido [3,2-d]pyrimidine ring template (Fig.…”