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

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-1<i>H</i>-pyrazole (<b>EH7</b>) 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 <b>EH7</b>) > -Cl (<b>EH6</b>) > -Br (<b>EH8</b>) > -H (<b>EH1</b>). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for <b>EH7</b> and <b>EH8</b> (IC₅₀ = 8.38 and 4.31 µM, respectively). <b>EH7</b> showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by <b>EH6</b> at > 55.8. <b>EH7</b> 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 <b>EH7</b> 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 <b>EH7</b> to MAO-B. Thus, <b>EH7</b> can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.