Novel 1,3,4-thiadiazole compounds as potential MAO-A inhibitors - design, synthesis, biological evaluation and molecular modelling

• Published in: MedChemComm 2020-09, Vol.11 (9), p.163-174
• Main Authors: Sa l k, Begüm Nurpelin, Kaya Çavu o lu, Betül, Acar Çevik, Ulviye, Osmaniye, Derya, Levent, Serkan, Özkay, Yusuf, Kaplanc kl, Zafer As m
• Format: Article
• Language: English
• Subjects: Amine oxidase (flavin-containing); Amines; Chemical synthesis; Inhibitors; Modelling; Molecular modelling; Neurological diseases; Organic compounds; Pharmacokinetics; Selectivity; Therapeutic targets; Thiadiazoles
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/d0md00150c

Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against h MAO-A than h MAO-B. The half maximal inhibitory concentration (IC 50 ) values of most of the compounds were lower than that of the common drug moclobemide (IC 50 = 4.664 μM) and compound 6b was proven to be the most active compound (IC 50 = 0.060 μM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC 50 = 0.048 μM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors. Compound 6b is a reversible and competitive h MAO-A inhibitor.