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

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 & mu;M, followed by CHBO3 (IC50 = 0.075 & mu;M). In the CHFO subseries, CHFO4 showed the highest inhibition of hMAO-B with an IC50 value of 0.147 & mu;M. 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 substituentsreversed compound CHFO3 (-Br in A-ring and -F in B-ring; IC50 = 0.391 & mu;M). In the kinetic study, Ki values of CHBO4 and CHFO4 for hMAO-B were 0.010 & PLUSMN; 0.005 and 0.040 & PLUSMN; 0.007 & mu;M, 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 & mu;g/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.

Automated summary

Oximes are effective inhibitors of hMAO-B, with CHBO4 showing the highest potency and selectivity. The presence of -Br substituent at the para-position in the B-ring enhances the inhibition of hMAO-B in the CHBO subseries. The -F substituent in the A-ring also contributes to the increased hMAO-B inhibition.