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  2. Halogenated class of oximes as a new class of monoamine oxidase-B inhibitors for the treatment of Parkinson's disease: Synthesis, biochemistry, and molecular dynamics study

Halogenated class of oximes as a new class of monoamine oxidase-B inhibitors for the treatment of Parkinson's disease: Synthesis, biochemistry, and molecular dynamics study

  • Comput Biol Chem. 2023 Aug;105:107899. doi: 10.1016/j.compbiolchem.2023.107899.
Della Grace Thomas Parambi 1 Jong Min Oh 2 Sunil Kumar 3 Sachithra Thazhathuveedu Sudevan 3 Omnia Magdy Hendawy 4 Mohamed A Abdelgawad 5 Arafa Musa 6 Mohammad M Al-Sanea 5 Iqrar Ahmad 7 Harun Patel 8 Hoon Kim 9 Bijo Mathew 10
Affiliations

Affiliations

  • 1 College of Pharmacy, Department of Pharmaceutical Chemistry, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia. Electronic address: dellajesto@ju.edu.sa.
  • 2 Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
  • 3 Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India.
  • 4 College of Pharmacy, Department of Clinical Pharmacology, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia.
  • 5 College of Pharmacy, Department of Pharmaceutical Chemistry, Jouf University, Sakaka 72341, Al Jouf, Saudi Arabia.
  • 6 College of Pharmacy, Department of Pharmacognosy, Jouf University, Sakaka, 72341, Al Jouf, Saudi Arabia.
  • 7 Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule 424002, Maharashtra, India.
  • 8 Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur 425405, Maharashtra, India.
  • 9 Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea. Electronic address: hoon@sunchon.ac.kr.
  • 10 Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India. Electronic address: bijovilaventgu@gmail.com.
Abstract

Oximes are the promising structural scaffold for inhibiting Monoamine Oxidase (MAO)-B. Eight chalcone-based oxime derivatives were synthesized by microwave-assisted technique, and their ability to inhibit human MAO (hMAO) Enzymes were tested. All compounds showed higher inhibitory activity of hMAO-B than hMAO-A. In the CHBO subseries, CHBO4 most potently inhibited hMAO-B with an IC50 value of 0.031 μM, followed by CHBO3 (IC50 = 0.075 μM). In the CHFO subseries, CHFO4 showed the highest inhibition of hMAO-B with an IC50 value of 0.147 μM. Compound CHBO4 had the highest selectivity index (SI) value of 1290.3. However, CHBO3 and CHFO4 showed relatively low SI values of 27.7 and 19.2, respectively. The -Br substituent in the CHBO subseries at the para-position in the B-ring showed higher hMAO-B inhibition than the -F substituent in the CHFO subseries. In both series, hMAO-B inhibition increased with the substituents at para-position in A-ring (-F > -Br > -Cl > -H in order). Compound CHBO4 (-F in A-ring and -Br in B-ring) was 12.6-times potent than the substituents-reversed compound CHFO3 (-Br in A-ring and -F in B-ring; IC50 = 0.391 μM). In the kinetic study, Ki values of CHBO4 and CHFO4 for hMAO-B were 0.010 ± 0.005 and 0.040 ± 0.007 μM, respectively, with competitive inhibitions. Reversibility experiments showed that CHBO4 and CHFO4 were reversible hMAO-B inhibitors. In the cytotoxicity test using the Vero cells by the MTT technique, CHBO4 had low toxicity with an IC50 value of 128.8 µg/mL. In H2O2-induced cells, CHBO4 significantly reduced cell damage by scavenging Reactive Oxygen Species (ROS). Molecular docking and dynamics showed the stable binding mode of the lead molecule CHBO4 on the active site of hMAO-B. These results suggest that CHBO4 is a potent reversible, competitive, and selective hMAO-B inhibitor and can be used as a treatment agent for neurological disorders.

Keywords

Cytotoxicity; HMAO-B inhibition; Kinetics; Molecular dynamics; ROS assay; Reversibility; chalcone-based oximes.

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