TY - JOUR
T1 - Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B
T2 - Synthesis, molecular modelling and in-silico ADME evaluation
AU - Abid, Syed Mobasher Ali
AU - Younus, Hafiza Amna
AU - Al-Rashida, Mariya
AU - Arshad, Zunaira
AU - Maryum, Tooba
AU - Gilani, Mazhar Amjad
AU - Alharthi, Abdulrahman I.
AU - Iqbal, Jamshed
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/12
Y1 - 2017/12
N2 - 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.
AB - 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.
KW - 3-Formylchromones
KW - Molecular docking
KW - Oral bioavailability
KW - Sulfonohydrazide
UR - http://www.scopus.com/inward/record.url?scp=85032855238&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2017.10.001
DO - 10.1016/j.bioorg.2017.10.001
M3 - Article
C2 - 29065322
AN - SCOPUS:85032855238
SN - 0045-2068
VL - 75
SP - 291
EP - 302
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
ER -