Title:Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 Inhibitor: Plausible Lead for Alzheimer’s Disease
Volume: 17
Issue: 10
Author(s): Priti Jain*, Pankaj K. Wadhwa and Hemant R. Jadhav
Affiliation:
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi,India
Keywords:
Alzheimer's disease, BACE-1, Substituted pyrimidine, Docking simulation, Claisen-Schmidt reaction, FRET
assay.
Abstract:
Alzheimer’s disease is one of the most common neurodegenerative disorder afflicting a
large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway
considered responsible for Alzheimer’s disease (AD). Since it catalyzes the rate-limiting step of
Aβ-42 production from amyloid precursor protein (APP), its inhibition is considered a viable therapeutic
strategy. We have reported the design of small molecular weight compounds supposed to be
blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the
previously designed series from our research group.
Objective: Design and synthesis of 2,4,6-substituted pyrimidine derivatives has been reported. In
vitro FRET-based screening of synthesized derivatives was performed to evaluate the BACE-1 inhibition
profile.
Methods: Based on the docking simulation studies, a library of derivatives was designed, synthesized
and evaluated for BACE-1 inhibition in-vitro. The docking studies were performed on Glide
(Schrodinger suite) and Molegro virtual docker. Theoretical toxicity was predicted using Osiris
Property Explorer. The synthesized compounds were tested for BACE-1 inhibition using in vitro
assay based on Fluorescence Resonance Energy Transfer technique. The percent inhibition was calculated
as a measure of activity.
Results: The designed compounds revealed strong interactions with the desired amino acids of
BACE-1 active sites. The aromatic rings placed at the fourth and sixth position of the pyrimidine ring
occupied S1 and S3 substrate-binding clefts while the amino group formed hydrogen bonding interactions
with Asp32 and Asp228. In silico data ensured that the compounds were orally bioavailable
and brain permeable. The in vitro testing showed that the compounds inhibited BACE-1 at 10μM
concentration.
Conclusion: Compounds substituted with m-benzyloxy on one aromatic ring and o,p-di-chloro on
another aromatic ring displayed maximum BACE-1 inhibition. Compound 2.13A displayed high
docking score and was found to be most potent with IC50 of 6.92μM. The series displayed a good
correlation between the docking score and BACE-1 inhibition profile.
