Synthesis, QSAR and docking studies of 5HT2A receptor antagonising thiazolo[3,2-a]pyrimidines as antipsychotic agents

Yıl 2014, Cilt: 18 Sayı: 3, 109 - 119, 12.09.2014

Ramesh Sawant , Supriya Ramdın Jyoti Wadekar

Öz

A series of twenty two compounds containing thiazolo[3,2-a]

pyrimidine carboxamide nucleus was synthesized by using

microwave. Substituted acetoacetanilide was condensed with

thiourea and substituted benzaldehydes in the presence of

p-toluenesulfonic acid as catalyst in ethanol to get 2-thioxo-

1,2,3,4-tetrahydropyrimidine carboxamide. In the second step,

1,2,3,4-tetrahydropyrimidine carboxamides were treated with

chloroacetic acid, anhydrous sodium acetate and glacial acetic

acid to yield the title compounds. The reaction progress and

purity of the synthesized compounds were monitored by TLC

using silica gel G and by determining their melting points.

Structures of title compounds were confirmed by elemental

analysis, IR, 1H NMR and mass spectral data. The

antipsychotic activity for title compounds was performed using

albino mice by rotarod and tail suspension method.

Compounds have shown antipsychotic activity comparable

with the standard risperidone. The 2D, 3D QSAR and

molecular docking studies were performed using VLife MDS

3.5 software. The molecular modelling studies reveals that

more potent antipsychotics from this series can be generated

by substituting electronegative group at para and meta position

of N-phenyl ring and less bulky group at 5-phenyl ring of

thiazolo[3,2-a]pyrimidine-6-carboxamide nucleus.

Keywords: Molecular docking, QSAR, Schizophrenia,

Thiazolo[3,2-a]pyrimidine, 5HT2A receptor antagonist.

Anahtar Kelimeler

Molecular docking, QSAR, Schizophrenia, Thiazolo[3, 2-a]pyrimidine, 5HT2A receptor antagonist.

Tiyazolo[3,2-a]pirimidin türevi 5HT2A reseptör antagonisti antipsikotiklerin sentezi, yapı-etki ilişkileri ve docking çalışmaları

Öz

Mikrodalga yöntemi kullanılarak tiyazolo[3,2-a]pirimidin
karboksamit yapılı 22 yeni madde sentezlenmiştir. Sübstitüe
asetoasetanilit’lerin, tiyoüre ve substitüe benzaldehitler’le
etanol içerisinde ve p-toluensülfonik asit katalizörlüğünde
tepkimesinden 2-tiyokso-1,2,3,4-tetrahidropirimidin-2-
karboksamit’ler elde edilmiştir. Elde edilen ürün, buzlu asetik
asit içerisinde ve susuuz sodyum asetat varlığında klororasetik
asit’le muamele edilerek hedef bileşikler kazanılmıştır.
Tepkime takibi ve bileşiklerin saflıklarının belirlenmesi için
ince tabaka kromatografisi yöntemi (sabit faz; silikkajel G)
uygulanmış ve bileşiklerin erime noktaları saptanmıştır.
Saflıkları elementel analiz ile doğrulanan bileşiklerin, yapıları,
IR, 1H NMR spektroskopisi ve kütle spektrometrisi
yöntemleriyle aydınlatılmıştır. Bileşiklerin antipsikotik etkileri
albino fareler kullanılarak rotarod ve kuyruk süspansiyon
testleri ile saptanmıştır. Bileşiklerin risperidon’la kıyaslanabilir
antipsikotik etki gösterdiği bildirilmiştir. 2D, 3D QSAR ve
moleküler modelleme çalışmaları VLife MDS 3.5 yazılımı
kullanılarak gerçekleştirilmiştir. Moleküler modelleme
çalışmaları sonucunda en yüksek antipsikotik etkinin N-fenil
halkasının para ve meta konumlarına elektronegatif grupların
eklenmesi ile ve tiyazolo[3,2-a]pirimidin-6-karboksamit’in 5.
konumuna fenil yerine daha küçük hacimli gruplar getirilmesi
ile elde edilebileceği bildirilmiştir

Anahtar Kelimeler

Moleküler Modelleme, QSAR, Tiyazolo[3, 2-a]pirimidin, Şizofreni, 5HT2A reseptör antagonisti.

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