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2553 17

(A)

, : ** : , (A) ,

,

indo-methacin A esters amide acid-catalyzed esterification coupling reaction conc.H2SO4 DCC, DMAP

methyl ester, ethyl ester, phenyl ester N-

phenyl amide 72, 72, 86 23

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indomethacin reduction LiAlH4

reduced indomethacin indole (5-methoxy-2-methyl indole-3 acetic acid) p-chlorobenzaldehyde

FT-IR, LC-

MS 1H-NMR A Thioflavin T assay indomethacin curcumin esters amides 5-methoxy-2-methyl indole-3 acetic acid

(88 %) 150 M indomethacin molecular docking

SYLBYL 8.1 A fragment 25-35 (A25-35) (pdb code: 1QWP)

Autodock 4.0 carbonylgroup aromatic indole ring indomethacin thiol (Compound 6) bindingenergy -7.43 kcal/mol inhibitionconstant 3.56 M

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A

Academic year 2010Project 17

Synthesis of indomethacin analogues forevaluation as

amyloid-beta (A) plaques lowering

Sawinee Chokchalermwong, Sarochin SantiwarangkoolProject advisor: Kittisak Sripha** Department of Pharmaceutical Chemistry, Faculty ofPharmacy, Mahidol University

Keyword : Indomethacin, Amyloid-beta (A

) plaques, Anti-aggregation, Molecular docking

The purpose of this work aimed to synthesizeand design new indomethacin derivatives as potentialof anti-A plaques formation. Ester and amide

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derivatives were synthesized by acid-catalyzedesterification, using conc. H2SO4 and coupling reaction,

using DCC and DMAP as the catalysts, respectively.% Yield of obtaining synthesized indomethacinderivatives, i.e., methyl ester, ethyl ester, phenyl ester,N-phenyl amide were 72, 72, 86, and 23, respectively.Reduction of indomethacin by LiAlH4 was additionally

investigated. Unfortunately, no reduced form ofindomethacin was achieved. Under our reducedconditions, the amide bond was broken to give indolepart (5-methoxy-2-methyl indole-3 acetic acid) and p-chlorobenzaldehyde. Identification of the all synthesized

structures was characterized by FT-IR, LC-MS, and1H-NMR. The anti-A plaques formation could betested by Thioflavin T assay comparing withindomethacin and curcumin and it was found that theester and amide derivatives of indomethacin exhibited

no activity whereas 5-methoxy-2-methyl indole-3 aceticacid showed a good inhibitory activity (88%) at aconcentration of 150 M. Furthermore, in this work, amolecular docking was employed to design newindomethacin derivatives. All desired structures were

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drawn by SYBYL 8.1 and docked with A fragment25-35 (A25-35) (pdb code: 1QWP) by using Autodock

4.0. It was noticed that replacing of carbonyl groupbetween aromatic and indole ring of indomethacin withthiol group (Compound 6) showed the lowest bindingenergy at -7.43 kcal/mol with an inhibition constant of3.56 M. This compound will be synthesized and

investigated for the anti-A plaques formation in theupcoming future.