Synthesis and evaluation of 3,4-Dihydro-3-methyl-2(1H)-quinazolinone derivatives as monoamine oxidase inhibitors

Abstract

Parkinson’s disease (PD) is an age related neurodegenerative disorder. Loss of dopamine from the striatum is responsible for the motor symptoms of PD. This loss of dopamine is due to degeneration of the neurons of the substantia nigra in the brain. Mononamine oxidase B (MAO-B) is an enzyme in the brain that plays a key role in the catabolic pathway of dopamine. Inhibitors of MAO-B protect the striatum from the depletion of dopamine and the MAO-B enzyme is therefore an important target for the treatment of PD. Levodopa (L-dopa), the metabolic precursor of dopamine, is currently the treatment of choice in PD, and MAO-B are particularly useful as adjuvants to L-dopa since they may enhance the level of dopamine after administration of L-dopa. In the present study, a series of C6-substituted and N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives were synthesised and evaluated as inhibitors of recombinant human MAO-A and MAO-B. These quinazolinones are structurally related to a series of 3,4-dihydro-2(1H)-quinolinone derivatives, which has previously been reported to act as MAO-B inhibitors. The 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives substituted on C6 with benzoyl, or cinnamoyl moieties were successfully synthesised by reacting 3-methyl-3,4-dihydroquinazolin-2(1H)-one with acyl chloride/bromide in carbon disulphide or with an appropriate benzaldehyde in a mixture of hydrochloric acid and methanol. The N1-substituted derivatives were successfully synthesised by reacting 3-methyl-3,4-dihydroquinazolin-2(1H)-one with an appropriate alkyl bromide/chloride with dimethylformamide serving as a solvent. Twenty-six C6-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one and eleven N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives were synthesised. The structures of these compounds were verified with NMR and MS, and the purities were estimated by HPLC. The MAO inhibitory properties of the synthesised compounds were determined by using the recombinant human MAO-A and MAO-B enzymes. The inhibition potencies were expressed as the corresponding IC50 values. Lineweaver-Burk plots were constructed to determine the mode of MAO inhibition, while the reversibility of inhibition was examined by measuring the recovery of enzyme activity after dialysis of the enzyme-inhibitor mixtures. The results showed that the C6-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives are potent and selective MAO-B inhibitors and to a lesser extent inhibitors of MAO-A, while the N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives proved to be MAO-A inhibitors. The most potent MAO-B inhibitor, 3-methyl-6-[(2E,4Z)-5-phenylpenta-2,4-dienoyl]-3,4-dihydroquinazolin-2(1H)-one, displayed an IC50 of 0.269 μM. The results thus show that 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives are potent MAO inhibitors, with the C6-substituted derivatives being the most potent. With representative inhibitors, it was shown that these compounds are reversible inhibitors of MAO-A and MAO-B since dialysis of enzyme-inhibitor mixtures restores enzyme activity.

It may thus be concluded that the C6-substituted and N1-substituted 3-methyl-3,4-dihydroquinazolin-2(1H)-one derivatives are promising MAO inhibitors, and thus leads for the future therapy of PD.