BibTex RIS Kaynak Göster

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

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.

Kaynakça

  • Reynolds GP. Developments in the drug treatment of schizophrenia. Trends Pharmacol Sci 1992; 13:116-21.
  • Seeman P. Brain dopamine receptors. Pharmacol Rev 1980; 32:229-313.
  • Gudelsky GA, Nash JF, Berry SA, Meltzer HY. Basic biology of clozapine: electrophysiological and neuroendocrinological studies. Psychopharmacology (Berl) 1989; 99:S13–7.
  • Rang HP, Ritter JM, Dale MM, Moore PK. Pharmacology. Reed Elsevier India (p) Ltd., New Delhi. 2006.
  • Hawas UW, Al-Omar MA, Galil AE, Amr AGE, Hammam AEG. Synthesis of some thiopyrimidine and thiazolopyrimidines starting from 2,6-dibenzylidene-3-methylcyclohexanone and its antimicrobial activities. Arab J Chem 2012; 5:509-15.
  • Salem MA, Thabet HKH, Helal MH, Abdelaal AS, Ammar YA. Synthesis and pharmacological evaluation of some pyrazoles, thiazolopyrimidine, triazolopyrimidine, pyridone and 2-iminochromene containing naproxenoyl moiety as NSAIDs. Chem Sci 2011; 2:1-12.
  • Mohamed SF, Flefel EM, Galil AE, Amr AEE, El-Shafy DNA. AntiHSV-1 activity and mechanism of action of some new synthesized substituted pyrimidine, thiopyrimidine and thiazolopyrimidine derivatives. Eur J Med Chem 2010; 45: 1494–501.
  • Balkan A, Uma S, Ertan M, Wiegrebe W. Thiazolo[3,2-a]pyrimidine derivatives as calcium antagonists. Pharmazie 1992; 47:687-88.
  • Abu-Hashem AA, Youssef MM, Husseina AR. Synthesis, antioxidant, antitumor activities of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolopyrrolothiazolopyrimidines derivatives. J Chin Chem Soc 2011; 58:41-8.
  • Awadallah FM. Synthesis, Pharmacophore modeling, and biological evaluation of novel 5H-thiazolo[3,2-a]pyrimidin-5-one derivatives as 5-HT2A receptor antagonists. Sci Pharm 2008; 76:415–38.
  • Prashantha Kumar BR, Sankar G, Nasir Baig RB, Chandrashekaran S. Novel Biginelli dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study. Eur J Med Chem 2009; 44:4192–8.
  • Ashok M, Holla BS, Kumari NS. Convenient one pot synthesis of some novel derivatives of thiazolo [2, 3-b] dihydropyrimidinone possessing 4-methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities. Eur J Med Chem 2007; 42:380-5.
  • Arora P, Das S, Arora N, Gawai A, Baghel US. Synthesis and screening of some novel 7-Hydroxy 4-Methyl Coumarin derivatives for antipsychotic activity. Int J Pharm Life Sci 2010; 1:113-8.
  • Kaur H, Kumar S, Kumar A. Synthesis, antipsychotic and anticonvulsant activity of some new pyrazolinyl/isoxazolinylindol-2ones. Int J ChemTech Res 2010; 2: 1010-9.
  • Arruda MOV, Soares PM, Honorio JER, Lima RC de S, Chaves EMC, Lobato R de FG, Martin AL de AR, Sales GTM, Carvalho K de M, Assreuy AMS, Brito EM, Vasconcelos SMM. Activities of the antipsychotic drugs haloperidol and risperidone on behavioural effects induced by ketamine in mice. Sci Pharm 2008; 76:673–87.
  • QSAR plus molecular design suit [MDS]. VLife Sciences Technology Pvt. Ltd. Pune. Halgren TA. Merck molecular force field III, Molecular geometries and vibrational frequencies. J Comput Chem 1996; 17:553–86.
  • Chakraborti AK, Gopalakrishnan B, Sobhia ME, Malde A. 3D-QSAR studies of indole derivatives as phosphodiesterase IV inhibitors. Eur J Med Chem 2003; 38: 975-82.
  • Puratchikody A, Nagalakshmi G, Doble M. Experimental and QSAR studies on antimicrobial activity of benzimidazole derivatives. Chem Pharm Bull 2008; 56: 273-81.
  • Tropsha A, Gramatica P, Gombar VK. The importance of being Earnest: Validation is the absolute essential for successful application and interpretation of QSPR models. QSAR Comb Sci 2003; 22:69-77.
  • Golbraikh A, Tropsha A. Beware of q2!. J Mol Graph Model 2002; 20:269-76.
  • Afantitis Α, Melagraki G, Sarimveis H, Igglessi–Markopoulou O, Kollias G. A novel QSAR model for predicting the inhibition of CXCR3 receptor by 4-N-aryl-[1,4] diazepane ureas. Eur J Med Chem 2009; 44:877-84.
  • Ravichandran V, Mourya VK, Agrawal RK. QSAR prediction of HIV–1 reverse transcriptase inhibitory activity of benzoxazinone derivatives. Internet Electron J Mol Des 2007; 6:363-74.

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

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

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

Kaynakça

  • Reynolds GP. Developments in the drug treatment of schizophrenia. Trends Pharmacol Sci 1992; 13:116-21.
  • Seeman P. Brain dopamine receptors. Pharmacol Rev 1980; 32:229-313.
  • Gudelsky GA, Nash JF, Berry SA, Meltzer HY. Basic biology of clozapine: electrophysiological and neuroendocrinological studies. Psychopharmacology (Berl) 1989; 99:S13–7.
  • Rang HP, Ritter JM, Dale MM, Moore PK. Pharmacology. Reed Elsevier India (p) Ltd., New Delhi. 2006.
  • Hawas UW, Al-Omar MA, Galil AE, Amr AGE, Hammam AEG. Synthesis of some thiopyrimidine and thiazolopyrimidines starting from 2,6-dibenzylidene-3-methylcyclohexanone and its antimicrobial activities. Arab J Chem 2012; 5:509-15.
  • Salem MA, Thabet HKH, Helal MH, Abdelaal AS, Ammar YA. Synthesis and pharmacological evaluation of some pyrazoles, thiazolopyrimidine, triazolopyrimidine, pyridone and 2-iminochromene containing naproxenoyl moiety as NSAIDs. Chem Sci 2011; 2:1-12.
  • Mohamed SF, Flefel EM, Galil AE, Amr AEE, El-Shafy DNA. AntiHSV-1 activity and mechanism of action of some new synthesized substituted pyrimidine, thiopyrimidine and thiazolopyrimidine derivatives. Eur J Med Chem 2010; 45: 1494–501.
  • Balkan A, Uma S, Ertan M, Wiegrebe W. Thiazolo[3,2-a]pyrimidine derivatives as calcium antagonists. Pharmazie 1992; 47:687-88.
  • Abu-Hashem AA, Youssef MM, Husseina AR. Synthesis, antioxidant, antitumor activities of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolopyrrolothiazolopyrimidines derivatives. J Chin Chem Soc 2011; 58:41-8.
  • Awadallah FM. Synthesis, Pharmacophore modeling, and biological evaluation of novel 5H-thiazolo[3,2-a]pyrimidin-5-one derivatives as 5-HT2A receptor antagonists. Sci Pharm 2008; 76:415–38.
  • Prashantha Kumar BR, Sankar G, Nasir Baig RB, Chandrashekaran S. Novel Biginelli dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study. Eur J Med Chem 2009; 44:4192–8.
  • Ashok M, Holla BS, Kumari NS. Convenient one pot synthesis of some novel derivatives of thiazolo [2, 3-b] dihydropyrimidinone possessing 4-methylthiophenyl moiety and evaluation of their antibacterial and antifungal activities. Eur J Med Chem 2007; 42:380-5.
  • Arora P, Das S, Arora N, Gawai A, Baghel US. Synthesis and screening of some novel 7-Hydroxy 4-Methyl Coumarin derivatives for antipsychotic activity. Int J Pharm Life Sci 2010; 1:113-8.
  • Kaur H, Kumar S, Kumar A. Synthesis, antipsychotic and anticonvulsant activity of some new pyrazolinyl/isoxazolinylindol-2ones. Int J ChemTech Res 2010; 2: 1010-9.
  • Arruda MOV, Soares PM, Honorio JER, Lima RC de S, Chaves EMC, Lobato R de FG, Martin AL de AR, Sales GTM, Carvalho K de M, Assreuy AMS, Brito EM, Vasconcelos SMM. Activities of the antipsychotic drugs haloperidol and risperidone on behavioural effects induced by ketamine in mice. Sci Pharm 2008; 76:673–87.
  • QSAR plus molecular design suit [MDS]. VLife Sciences Technology Pvt. Ltd. Pune. Halgren TA. Merck molecular force field III, Molecular geometries and vibrational frequencies. J Comput Chem 1996; 17:553–86.
  • Chakraborti AK, Gopalakrishnan B, Sobhia ME, Malde A. 3D-QSAR studies of indole derivatives as phosphodiesterase IV inhibitors. Eur J Med Chem 2003; 38: 975-82.
  • Puratchikody A, Nagalakshmi G, Doble M. Experimental and QSAR studies on antimicrobial activity of benzimidazole derivatives. Chem Pharm Bull 2008; 56: 273-81.
  • Tropsha A, Gramatica P, Gombar VK. The importance of being Earnest: Validation is the absolute essential for successful application and interpretation of QSPR models. QSAR Comb Sci 2003; 22:69-77.
  • Golbraikh A, Tropsha A. Beware of q2!. J Mol Graph Model 2002; 20:269-76.
  • Afantitis Α, Melagraki G, Sarimveis H, Igglessi–Markopoulou O, Kollias G. A novel QSAR model for predicting the inhibition of CXCR3 receptor by 4-N-aryl-[1,4] diazepane ureas. Eur J Med Chem 2009; 44:877-84.
  • Ravichandran V, Mourya VK, Agrawal RK. QSAR prediction of HIV–1 reverse transcriptase inhibitory activity of benzoxazinone derivatives. Internet Electron J Mol Des 2007; 6:363-74.
Toplam 22 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Bölüm Makaleler
Yazarlar

Ramesh Sawant

Supriya Ramdın Bu kişi benim

Jyoti Wadekar Bu kişi benim

Yayımlanma Tarihi 12 Eylül 2014
Yayımlandığı Sayı Yıl 2014 Cilt: 18 Sayı: 3

Kaynak Göster

APA Sawant, R., Ramdın, S., & Wadekar, J. (2014). Synthesis, QSAR and docking studies of 5HT2A receptor antagonising thiazolo[3,2-a]pyrimidines as antipsychotic agents. Marmara Pharmaceutical Journal, 18(3), 109-119. https://doi.org/10.12991/mpj.2014187237
AMA Sawant R, Ramdın S, Wadekar J. Synthesis, QSAR and docking studies of 5HT2A receptor antagonising thiazolo[3,2-a]pyrimidines as antipsychotic agents. mpj. Kasım 2014;18(3):109-119. doi:10.12991/mpj.2014187237
Chicago Sawant, Ramesh, Supriya Ramdın, ve Jyoti Wadekar. “Synthesis, QSAR and Docking Studies of 5HT2A Receptor Antagonising thiazolo[3,2-a]pyrimidines As Antipsychotic Agents”. Marmara Pharmaceutical Journal 18, sy. 3 (Kasım 2014): 109-19. https://doi.org/10.12991/mpj.2014187237.
EndNote Sawant R, Ramdın S, Wadekar J (01 Kasım 2014) Synthesis, QSAR and docking studies of 5HT2A receptor antagonising thiazolo[3,2-a]pyrimidines as antipsychotic agents. Marmara Pharmaceutical Journal 18 3 109–119.
IEEE R. Sawant, S. Ramdın, ve J. Wadekar, “Synthesis, QSAR and docking studies of 5HT2A receptor antagonising thiazolo[3,2-a]pyrimidines as antipsychotic agents”, mpj, c. 18, sy. 3, ss. 109–119, 2014, doi: 10.12991/mpj.2014187237.
ISNAD Sawant, Ramesh vd. “Synthesis, QSAR and Docking Studies of 5HT2A Receptor Antagonising thiazolo[3,2-a]pyrimidines As Antipsychotic Agents”. Marmara Pharmaceutical Journal 18/3 (Kasım 2014), 109-119. https://doi.org/10.12991/mpj.2014187237.
JAMA Sawant R, Ramdın S, Wadekar J. Synthesis, QSAR and docking studies of 5HT2A receptor antagonising thiazolo[3,2-a]pyrimidines as antipsychotic agents. mpj. 2014;18:109–119.
MLA Sawant, Ramesh vd. “Synthesis, QSAR and Docking Studies of 5HT2A Receptor Antagonising thiazolo[3,2-a]pyrimidines As Antipsychotic Agents”. Marmara Pharmaceutical Journal, c. 18, sy. 3, 2014, ss. 109-1, doi:10.12991/mpj.2014187237.
Vancouver Sawant R, Ramdın S, Wadekar J. Synthesis, QSAR and docking studies of 5HT2A receptor antagonising thiazolo[3,2-a]pyrimidines as antipsychotic agents. mpj. 2014;18(3):109-1.