Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors

CAN N. Ö., OSMANİYE D., LEVENT S., SAĞLIK B. N., KORKUT ÇELİKATEŞ B., ATLI EKLİOĞLU Ö., ...Daha Fazla

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.144, ss.68-81, 2018 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 144
  • Basım Tarihi: 2018
  • Doi Numarası: 10.1016/j.ejmech.2017.12.013
  • Dergi Adı: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Index Chemicus (IC)
  • Sayfa Sayıları: ss.68-81
  • Anahtar Kelimeler: Thiazole, Hydrazine, hMAO enzymes, Enzyme inhibition, Docking, MONOAMINE-OXIDASE-B, HUMAN-MAO-B, THIAZOLE DERIVATIVES, MECHANISM, SCAFFOLD, IDENTIFICATION, PREDICTION, HYDRAZONE, OXIDATION, FLUORINE
  • Bilecik Şeyh Edebali Üniversitesi Adresli: Hayır

Özet

In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC50 values of 0.012 mu M and 0.011 mu M and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound. (C) 2017 Elsevier Masson SAS. All rights reserved.