Lead optimization for promising monoamine oxidase inhibitor from eugenol for the treatment of neurological disorder: synthesis and in silico based study

Abstract

Natural based inhibitors of monoamine oxidase are promising drug candidates for the treatment of several neurodegenerative and neuropsychological disorders including depression, anxiety, Parkinson’s disease and Alzheimer’s disease. In the present study we designed and synthesized the eugenol based derivatives and investigated them for human MAO inhibitory potential as promising candidates for therapeutics of neurological disorders. Moreover, radical scavenging activity of designed derivatives was tested by and H 2 O 2 and DPPH scavenging methods. Eugenol based derivatives were designed and synthesized for human MAO inhibitory action. The in silico and in vitro models were utilized for the evaluation of hMAO inhibition. The insight into molecular interactions among the compounds and both hMAO-A and hMAO-B active site was achieved by molecular docking studies. The two spectrophotometric titrations techniques were used to evaluate antioxidant potential. Compounds 5b and 16 were found as most active hMAO-A inhibitors with IC 50 values of 5.989 ± 0.007 µM and 7.348 ± 0.027 µM respectively, through an appreciable selectivity index value of 0.19 and 0.14 respectively. In case of hMAO-B inhibition compounds 13a and 13b were found as most active hMAO-B inhibitors with IC 50 values of 7.494 ± 0.014 µM and 9.183 ± 0.034 µM receptively and outstanding value of selectivity index of 5.14 and 5.72 respectively. Radical scavenging assay showed that compounds 5b , 5a , 9b , 9a were active antioxidants. The findings of present study indicated excellent correlation among dry lab and wet lab hMAO inhibitory experiments. Interestingly, the compounds exhibiting better MAO inhibition activity was also appeared as good antioxidant agents.

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

“…Obviously there are other plant-derived products that inhibit PrAO at much lower concentrations than theobromine such as the hydrolyzable tannin geraniin, which is reported to have an apparent inhibition constant, Ki, in the micromolar range [51]. Eugenol inhibits MAO-A and MAO-B activities with IC 50 values ranging between 5 and 25 µM [52]. Nevertheless, the methylxanthines, since they are the most widely ingested phytochemicals, can be considered as factors influencing amine oxidase activity in consumers.…”

Antidepressant activity of Spathodea campanulata in mice and predictive affinity of spatheosides towards type A monoamine oxidase

“…campanulata is rich in iridoids and spatheoside A and spatheoside B are two iridoids which are known to be present in S. campanulata (26,46) and that were identified in MESC following LC-MS analysis. In an effort to understand the possible mechanism of action for antidepressant activity of MESC, we sought to predict the binding affinity of these iridoids towards the MAO-A enzyme using a molecular docking approach (47,48). The latter is a mitochondrial enzyme responsible for the oxidative deamination of monoamines, mainly 5-HT, NA, DA (49).…”

Exploring Pharmacological Mechanisms of Essential Oils on the Central Nervous System

“…In addition to being analgesic, eugenol is also associated with antioxidant and antidepressant activity, as confirmed by Dhiman et al [ 86 ], who designed and synthesized eugenol-based derivatives, performed in vitro, in silico studies, and tested their MAO (A and B) inhibitory activity as agents for neurological disorders. Radical scavenging activity was also determined using H 2 O 2 and DPPH scavenging methods followed by spectrophotometric titrations.…”

“…All the synthesized compounds showed significant MAO inhibition through interaction with the MAO active site, as observed through molecular docking studies. Two synthesized compounds showed activity hMAO-A inhibition with IC 50 values of 5.989 ± 0.007 µM and 7.348 ± 0.027 µM with a selectivity index of 0.19 and 0.14, respectively, while two other synthesized compounds showed hMAO-B inhibitory activity with IC 50 values of 7.494 ± 0.014 µM and 9.183 ± 0.034 µM with a selectivity index of 5.14 and 5.72, respectively, indicating their potential antioxidant activity in antidepressant therapy and neurological disorders [ 86 ].…”