Abstract
Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of –F (in EH7) > –Cl (EH6) > –Br (EH8) > –H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.
Highlights
Monoamine oxidases (MAOs) are the principal metabolizing enzymes responsible for the oxidative degradation of various biogenic amines that are related to diverse cognitive functions of the central nervous system (CNS) [1]
The enzyme inhibition results obtained in the current study revealed that all of the halogenated pyrazoline derivatives showed good selective MAO-B inhibitory activity
The results revealed that EH7 had comparatively higher probability of blood–brain barrier (BBB)
Summary
Monoamine oxidases (MAOs) are the principal metabolizing enzymes responsible for the oxidative degradation of various biogenic amines that are related to diverse cognitive functions of the central nervous system (CNS) [1]. Aldehyde, and hydrogen peroxide are the major intermediate products formed during MAO-based catalyzed oxidative deamination [3]. These can produce substantial issues, such as astrocyte swelling, unbalancing of the signaling process in the neurotransmission, neuronal loss, and mitochondrial dysfunctions [4]. These toxic by-products can lead to numerous neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [5]. Selegiline is a selective/irreversible MAO-B inhibitor used as an adjuvant therapy with L -DOPA, which is considered a safe therapy for PD [6,7]. In 2017, safinamide, as the first selective and reversible MAO-B inhibitor approved by the USFDA for PD treatment, along with levodopa, has promising neuroprotective effects on MPTP-treated mice [9,10]
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