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Selected aryl thiosemicarbazones as a new class of multi-targeted monoamine oxidase inhibitors
Mathew, Bijo,Baek, Seung Cheol,Grace Thomas Parambi, Della,Pil Lee, Jae,Joy, Monu,Annie Rilda, P. R.,Randev, Rugma V.,Nithyamol, P.,Vijayan, Vijitha,Inasu, Sini T.,Mathew, Githa Elizabeth,Lohidakshan, The Royal Society of Chemistry 2018 MedChemComm Vol.9 No.11
<P>A series of 13 phenyl substituted thiosemicarbazones (SB1-SB13) were synthesized and evaluated for their inhibitory potential towards human recombinant monoamine oxidase A and B (MAO-A and MAO-B, respectively) and acetylcholinesterase. The solid state structure of SB4 was ascertained by the single X-ray diffraction technique. Compounds SB5 and SB11 were potent for MAO-A (IC50 1.82 ± 0.14) and MAO-B (IC50 0.27 ± 0.015 μM), respectively. Furthermore, SB11 showed a high selectivity index (SI > 37.0) for MAO-B. The effects of fluorine orientation revealed that SB11 (<I>m</I>-fluorine) showed 28.2 times higher inhibitory activity than SB12 (<I>o</I>-fluorine) against MAO-B. Furthermore, inhibitions by SB5 and SB11 against MAO-A and MAO-B, respectively, were recovered to near reference levels in reversibility experiments. Both SB5 and SB11 showed competitive inhibition modes, with <I>K</I>i values of 0.97 ± 0.042 and 0.12 ± 0.006 μM, respectively. These results indicate that SB5 and SB11 are selective, reversible and competitive inhibitors of MAO-A and MAO-B, respectively. Compounds SB5, SB7 and SB11 showed moderate inhibition against acetylcholinesterase with IC50 values of 35.35 ± 0.47, 15.61 ± 0.057 and 26.61 ± 0.338 μM, respectively. Blood-brain barrier (BBB) permeation was studied using the parallel artificial membrane permeation assay (PAMPA) method. Molecular docking studies were carried out using AutoDock 4.2.</P>
Inhibition of monoamine oxidases by benzimidazole chalcone derivatives
Krishna Athulya,Lee Jiseong,Kumar Sunil,Sudevan Sachithra Thazhathuveedu,Uniyal Prerna,Pappachen Leena K.,Kim Hoon,Mathew Bijo 한국응용생명화학회 2023 Applied Biological Chemistry (Appl Biol Chem) Vol.66 No.-
Ten benzimidazole chalcone derivatives were synthesized, and their monoamine oxidase (MAO) inhibitory activity was evaluated. Most compounds showed higher inhibitory activity against MAO-B than MAO-A. Compound BCH2 exhibited an IC50 value of 0.80 μM, thereby showing the most potent inhibition amongst all. In addition, BCH2 showed the highest MAO-B selectivity index (SI) with an SI value of 44.11 compared to MAO-A. Among the substituents, the halogen group showed the best MAO-B inhibition, and the ortho-position of the B ring showed better inhibitory activity than the para-site. In comparison with ortho-substituents, the inhibitory activity increased in the order, -Cl > -Br > -F > -H. BCH2 was found to be a competitive inhibitor of the enzyme with optimum inhibition kinetics, where Ki was found to be 0.25 ± 0.014 μM. In the reversibility experiment, BCH2 showed a recovery pattern after MAO-B inhibition, similar to that of lazabemide. Thus, BCH2 is a potent, reversible, and selective MAO-B inhibitor and has been suggested as a candidate for the treatment of neurological disorders.
Peedikayil Arshida Thottile,Lee Jiseong,Abdelgawad Mohamed A.,Ghoneim Mohammed M.,Shaker Mohamed E.,Selim Samy,Kumar Sunil,Dev Sanal,Kim Hoon,Mathew Bijo 한국응용생명화학회 2023 Applied Biological Chemistry (Appl Biol Chem) Vol.66 No.-
Monoamine oxidases (MAOs) regulate neurotransmitters, and changes in their regulation lead to neurogenerative diseases (NDs). Therefore, MAO inhibitors are used to treat NDs. Ferulic acid, a phenolic compound found in various plant species, has been demonstrated to have a variety of biological functions, including anti-inflammatory, anticancer, and neuroprotective effects. In this study, ten ferulic acid hydrazide derivatives (FA1–FA10) were synthesized, and their ability to inhibit monoamine oxidase (MAO) enzymes was tested. Six candidates demonstrated a more pronounced pattern of inhibitory action against MAO-B than against MAO-A. FA3 had the highest inhibitory efficacy in MAO-B inhibition (IC50 value of 1.88 μM), followed by FA9 (2.08 μM). FA3 has a Ki of 1.92 ± 0.73 μM. A reversibility experiment of MAO-B inhibition by FA3 was conducted using dialysis, and the recovery pattern showed FA3 was a reversible MAO-B inhibitor with a similar recovery to safinamide, a reversible reference inhibitor. These results indicate that FA3 is an effective reversible MAO-B inhibitor. In molecular dynamics and docking, FA3 paired with pi-pi stacking helped stabilize the protein ligand in the active site of MAO-B. According to this study, lead compounds can be used as therapeutic agents to treat neurological conditions, such as Parkinson's disease (PD).
Lee Jiseong,Parmbil Saranya Kattil,Pandit Nagendar Kumar,Kumar Sunil,Syed Asad,Elgorban Abdallah M.,Wong Ling Shing,Ranjana,Kim Hoon,Mathew Bijo 한국응용생명화학회 2024 Applied Biological Chemistry (Appl Biol Chem) Vol.67 No.-
Nine morpholine-derived halogenated chalcone derivatives (MHC1-MHC9) were synthesized, and their inhibitory activity against monoamine oxidase (MAO) was evaluated. MHC5 showed the highest inhibitory activity against MAO-B with an IC50 value of 0.065 μM, followed by MHC7 (IC50=0.078 μM) and MHC6 (IC50=0.082 μM). The para-F substituent MHC4 was also potent (IC50=0.095 μM). The selectivity index values of all the compounds were high for MAO-B over MAO-A, and the values for MHC5 and MHC4 were 66.15 and 80.11, respectively. MHC5 and MHC4 were competitive MAO-B inhibitors with Ki values of 0.024±0.00062 and 0.041±0.0028 μM, respectively. In reversibility tests, the changes in residual activity before and after the dialysis of MHC5 and MHC4 were similar to those of safnamide, a reversible MAO-B reference inhibitor. Additionally, molecular docking and dynamic simulations predicted that the lead molecules MHC5 and MHC4 could strongly bind to the MAO-B active site with docking scores of –10.92±0.08 and –10.64±0.14 kcal/mol, respectively. Additionally, MHC4 and MHC5 exhibited favorable ADME features, including blood–brain barrier permeability. The experiments confrmed that MHC5 and MHC4 are reversible and potent selective inhibitors of MAO-B and are promising candidates for the treatment of neurodegenerative diseases (human health).