Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach.

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-1-pyrazole () showed the highest potency against MAO-B with an IC value of 0.063 µM. The potencies against MAO-B were increased in the order of -F (in ) > -Cl () > -Br () > -H (). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for and (IC = 8.38 and 4.31 µM, respectively). showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by at > 55.8. 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 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 to MAO-B. Thus, can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.