2. Academic Validation
  3. Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease

Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease

  • Molecules. 2023 Aug 21;28(16):6167. doi: 10.3390/molecules28166167.
Amritha Manoharan 1,  Jong Min Oh 2,  Feba Benny 1,  Sunil Kumar 1,  Mohamed A Abdelgawad 3 4,  Mohammed M Ghoneim 5 6,  Mohamed E Shaker 7 8,  Mohamed El-Sherbiny 9 10,  Hailah M Almohaimeed 11,  Prashant Gahtori 12,  Hoon Kim 2,  Bijo Mathew 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India.
  • 2 Department of Pharmacy, Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
  • 3 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
  • 4 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 5 Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia.
  • 6 Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
  • 7 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
  • 8 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 9 Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh 11597, Saudi Arabia.
  • 10 Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 11 Department of Basic Science, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia.
  • 12 School of Pharmacy, Graphic Era Hill University, Dehradun 248002, India.
PMID: 37630420 DOI: 10.3390/molecules28166167
Abstract

Monoamine Oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 μM, followed by IHC2 (IC50 = 16.934 μM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the Others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the Other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and Enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B Inhibitor that can be used to treat neurological diseases.

Keywords

indole-based phenylallylidene derivatives; kinetics; molecular docking; monoamine oxidase inhibitors; neurological diseases; neuroprotection; reversibility.

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