Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors

ALTINTOP M. D., SEVER B., OSMANİYE D., SAĞLIK B. N., ÖZDEMİR A.

ARCHIV DER PHARMAZIE, cilt.351, sa.7, 2018 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 351 Sayı: 7
  • Basım Tarihi: 2018
  • Doi Numarası: 10.1002/ardp.201800082
  • Dergi Adı: ARCHIV DER PHARMAZIE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Index Chemicus (IC)
  • Anahtar Kelimeler: docking, furan, Lipinski's rule of five, monoamine oxidase, pyrrole, MAO-B INHIBITORS, DRUG, FURANOCHALCONES, POTENT, N-(FURAN-2-YLMETHYL)-N-METHYLPROP-2-YN-1-AMINE, PERSPECTIVE, DISCOVERY, DOCKING, 3D-QSAR
  • Anadolu Üniversitesi Adresli: Evet

Özet

In an effort to develop potent monoamine oxidase (MAO) inhibitors, new pyrrole derivatives were obtained via the selective reduction of the CC bonds of 1-(1-methyl-1H-pyrrol-2-yl)-3-[5-(aryl)furan-2-yl]prop-2-en-1-ones through palladium catalyzed hydrogenation in ethanol. The synthesized compounds were screened for their inhibitory effects on MAO-A and MAO-B by an in vitro fluorometric method. The selectivity index (SI) value was given as the ratio of IC50 (MAO-A)/IC50 (MAO-B) for each compound. 3-(5-(4-Chlorophenyl)furan-2-yl)-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (6) was identified as the most selective MAO-A inhibitor in this series, with an IC50 value of 0.162 mu M and a SI value of 0.002. Kinetic studies were also carried out to assess the nature of MAO-A inhibition by compound 6. According to Lineweaver-Burk plots, compound 6 was found to be a competitive MAO-A inhibitor and the K-i value of compound 6 was determined as 0.1221M. Docking studies were performed for compound 6 and clorgyline using the human MAO-A crystal structure (PDB ID: 2Z5Y). The docking results showed that compound 6 presented similar interactions as clorgyline in the active center cavity of the enzyme. Molinspiration software was used to determine the physicochemical parameters of all compounds for an evaluation of their compliance to Lipinski's rule of five. Compound 6 did not violate Lipinski's rule, making it a potential orally bioavailable therapeutic agent.