Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis, molecular modelling and in-silico ADME evaluation

Syed Mobasher Ali Abid, Hafiza Amna Younus, Mariya Al-Rashida, Zunaira Arshad, Tooba Maryum, Mazhar Amjad Gilani, Abdulrahman I. Alharthi, Jamshed Iqbal

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36 Scopus citations

Abstract

A series of sulfonyl hydrazones derived from 3-formylchromone was synthesized and discovered to be effective, non-selective inhibitors of monoamine oxidases (MAO-A and MAO-B). The compounds are easily (synthetically) accessible in high yields, by simple condensation of 4-methylbenzenesulfonohydrazide with different (un)substituted 3-formylchromones. All compounds had IC50 values in lower micro-molar range (IC50 = 0.33–7.14 μM for MAO-A, and 1.12–3.56 μM for MAO-B). The most active MAO-B inhibitor was N′-[(E)-(6-fluoro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3e) with IC50 value of 1.12 ± 0.02 μM, and N′-[(E)-(6-chloro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3f) was the most active MAO-A inhibitor with IC50 value of 0.33 ± 0.01 μM. From enzyme kinetic studies, the mode of inhibition against MAO-B was found to be competitive, whereas against MAO-A, it was found to be non-competitive. Molecular docking studies indicated a new binding pocket for non-competitive MAO-A inhibitors. The activity of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.

Original languageEnglish
Pages (from-to)291-302
Number of pages12
JournalBioorganic Chemistry
Volume75
DOIs
StatePublished - Dec 2017

Keywords

  • 3-Formylchromones
  • Molecular docking
  • Oral bioavailability
  • Sulfonohydrazide

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