Trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic Acid: A New Lead Compound with Selective COX-2 Inhibitory Activity

Abdel-Rahman H. M., Ozadali K.

ARCHIV DER PHARMAZIE, cilt.345, sa.11, ss.878-883, 2012 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 345 Sayı: 11
  • Basım Tarihi: 2012
  • Doi Numarası: 10.1002/ardp.201200193
  • Dergi Adı: ARCHIV DER PHARMAZIE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.878-883
  • Hacettepe Üniversitesi Adresli: Evet

Özet

A novel series of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid derivatives was designed and synthesized by a new one-step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes in vitro. Among the synthesized compounds, the 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)acetic acid 4 emerged as the most potent COX-2 inhibitor (IC50 value: 150 nM) with the highest selectivity index (COX-1/COX-2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX-2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization.

A novel series of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole-1-acetic acid derivatives was designed and synthesized by a new one-step pathway. Structure elucidation of the synthesized compounds was confirmed by various spectral and elemental analyses. The prepared compounds were evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes in vitro. Among the synthesized compounds, the 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)acetic acid 4 emerged as the most potent COX-2 inhibitor (IC50 value: 150 nM) with the highest selectivity index (COX-1/COX-2 inhibition ratio: 570.6). Docking studies of compound 4 in the active site of COX-2 recognized its potential binding mode to the enzyme. Based on the preliminary results, compound 4 was considered as a lead compound for further optimization.