Selected aryl thiosemicarbazones as a new class of multi-targeted monoamine oxidase inhibitors

MedChemComm
2018.0

Abstract

A series of 13 phenyl substituted thiosemicarbazones (<b>SB1-SB13</b>) were synthesized and evaluated for their inhibitory potential towards human recombinant monoamine oxidase A and B (MAO-A and MAO-B, respectively) and acetylcholinesterase. The solid state structure of <b>SB4</b> was ascertained by the single X-ray diffraction technique. Compounds <b>SB5</b> and <b>SB11</b> were potent for MAO-A (IC<sub>50</sub> 1.82 ± 0.14) and MAO-B (IC<sub>50</sub> 0.27 ± 0.015 μM), respectively. Furthermore, <b>SB11</b> showed a high selectivity index (SI > 37.0) for MAO-B. The effects of fluorine orientation revealed that <b>SB11</b> (<i>m</i>-fluorine) showed 28.2 times higher inhibitory activity than <b>SB12</b> (<i>o</i>-fluorine) against MAO-B. Furthermore, inhibitions by <b>SB5</b> and <b>SB11</b> against MAO-A and MAO-B, respectively, were recovered to near reference levels in reversibility experiments. Both <b>SB5</b> and <b>SB11</b> showed competitive inhibition modes, with <i>K</i> <sub>i</sub> values of 0.97 ± 0.042 and 0.12 ± 0.006 μM, respectively. These results indicate that <b>SB5</b> and <b>SB11</b> are selective, reversible and competitive inhibitors of MAO-A and MAO-B, respectively. Compounds <b>SB5</b>, <b>SB7</b> and <b>SB11</b> showed moderate inhibition against acetylcholinesterase with IC<sub>50</sub> values of 35.35 ± 0.47, 15.61 ± 0.057 and 26.61 ± 0.338 μM, respectively. Blood-brain barrier (BBB) permeation was studied using the parallel artificial membrane permeation assay (PAMPA) method. Molecular docking studies were carried out using AutoDock 4.2.

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