Abstract
A library of dihydropyrimidinones was synthesized via a “one-pot” three component Biginelli reaction using different aldehydes in combination with β-dicarbonyl compounds and urea. Selected 2-thiooxo and 2-imino analogs were also obtained with the Biginelli reaction from thiourea and guanidine hydrochloride, respectively. The products were screened in vitro for their β-secretase inhibitory activity. The majority of the compounds resulted to be active, with IC50 in the range 100 nM–50 μM.
Highlights
TThhee vvaarriieeddaaccttiivvitityyooffDDHHPPMMs,s,cocommbibninededwwithiththtehierisrysnytnhtehtiectiaccacecscseisbsiilbitiylitaynadntdhethpeospsoibssiliibtyilittoy rtaopriadplyidalyssaesmsebmlebdleivdeirvseersseusbustbitsutietuntesntosnonthtehehehteetreorcoyccylciclicscsacfafffooldldinin aa ssiinnggllee mmuullttiiccoommppoonneenntt rreeaaccttiioonn, mmaakkeeththeeBiBgiingeinlleilrlei arcetaiocntioann aatntraactttirvaectaipvperoaapcphrofoarchthefodristchoevedriyscoofvneerwy boifolnoegwicalbaiocltoivgiitcieasl. aMctuivltiitcioems. pMonueltnitcoremacptoionnesn,tinrepaacrttiiocunlsa,r,inshpoawrtgicruealatrp,rsohmoiwse ignrethaet dpirsocmovieseryionf tshmealdlimscoolveceuryleopfrostmeaaslel inhibitors possessing better pharmacological properties than peptidomimetic inhibitors [14,15,16]
BACE-1 is an aspartyl protease involved in the proteolytic degradation of the β-amyloid precursor protein (APP) to form amyloid-β peptide (Aβ), a small protein with a high tendency to form aggregates that are found in the Alzheimer’s Disease (AD) brain [19]
In this work we report on the synthesis and preliminary evaluation of a set of dihydropyrimidinones and their thia and aza analogues (Scheme 1, X=S, NH) as BACE-1 inhibitors
Summary
TThhee 3,4-DDiihhyyddrroo--22--ppyyrriimmiiddiinnoonneess((DDHHPPMMss)),,rreeaaddiillyyaacccceessssiibblleeiinnaa ssiinnggllee sstteepp vviiaa thee Biginelli reaction [1,2,3] ((SScchheemmee 11,, XX ==OO)),,hhaavveerreecceennttllyyaattttrraacctteeddccoonnssiiddeerraabblleeaatttteennttiioonn ffoorr tthheeiirr mmuullttiifaceted pharrmmaaccoollooggiiccaall propeerrttiieess [4,5]. DHPMs possess neighboring hydrogen bond donor and acceptor groups; we decided to explore the potential of the Biginelli reaction for the synthesis of new β-secretase inhibitors. In this work we report on the synthesis and preliminary evaluation of a set of dihydropyrimidinones and their thia and aza analogues (Scheme 1, X=S, NH) as BACE-1 inhibitors. The cyclic urea motif embedded in the DHMP scaffold and its thiourea and guanidine analogues are in principle capable to establish multiple hydrogen bond interactions with the dyad of catalytic aspartates (Asp 32, Asp 228), while it is possible to introduce diversity at R1 and R2 (Scheme 1), to allow interactions at least with the closer subsites S1 (wider) and S1 (narrow), which are both hydrophobic.
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