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. 2016 Mar 1;7(5):502-7.
doi: 10.1021/acsmedchemlett.6b00039. eCollection 2016 May 12.

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

Tarek Mohamed  1 , Arash Shakeri  1 , Gary Tin  1 , Praveen P N Rao  1
Affiliations

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

Tarek Mohamed et al. ACS Med Chem Lett. .

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 IC50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (Aβ40 IC50 = 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 IC50 = 1.7 μM). However, compound 4k exhibited superior inhibition of Aβ42 aggregation (Aβ42 IC50 = 1.7 μM) compared to compound 3k (Aβ42 IC50 = 14.8 μM) and was ∼1.8-fold more potent compared to curcumin (Aβ42 IC50 = 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: Alzheimer’s disease; Aβ aggregation; Quinazolines; amyloid.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of naturally occurring and synthetic amyloid aggregation inhibitors and the DAQ scaffold.
Scheme 1
Scheme 1
Reagents and conditions: (a) Alkyl- or aromatic halides, NaH, DMSO, 0 °C to r.t. 14 h. (b) Alkyl- or aromatic halides, potassium carbonate, DMA, r.t. to 85 °C, 5 h.
Figure 2
Figure 2
(a) Amyloid aggregation kinetics study. Panels A and B: 5 μM Aβ40 with varying concentrations (1, 5, or 25 μM) of DAQ derivatives 3j and 3k, respectively. Panels C and D: 5 μM Aβ42 with varying concentrations (1, 5, or 25 μM) of DAQ derivatives 4j and 4k, respectively. Aggregation kinetics were monitored by ThT-fluorescence spectroscopy (excitation = 440 nm, emission = 490 nm) for 24 h at 37 °C in phosphate buffer at pH 7.4. Results are based on three independent experiments in triplicate measurements. (b) Amyloid morphology analysis using transmission electron microscopy (TEM) after 24 h incubation at 37 °C in phosphate buffer at pH 7.4. Panel A, 25 μM Aβ40 control; Panel B, 25 μM Aβ40 with 25 μM of DAQ derivative 3k; Panel C, 25 μM Aβ42 control; Panel D, 25 μM Aβ42 with 25 μM of DAQ derivative 4k. Scale: black/white bars represent 500 nm.
See this image and copyright information in PMC

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