Synthesis of 1,2,4-Oxadiazin-5(6<i>H</i>)-One Derivatives and Their Biological Investigation as Monoamine Oxidase Inhibitors
Sofia I. Presnukhina,
Valentina D. Kotlyarova,
Anton A. Shetnev,
Sergey V. Baykov,
Rakhymzhan Turmanov,
Nurbol Appazov,
Rakhmetulla Zhapparbergenov,
Leilya Zhussupova,
Nurila Togyzbayeva,
Stephanus J. Cloete,
Mikhail K. Korsakov,
Vadim P. Boyarskiy,
Anél Petzer,
Jacobus P. Petzer
Affiliations
Sofia I. Presnukhina
Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab., 7/9, 199034 Saint Petersburg, Russia
Valentina D. Kotlyarova
Pharmaceutical Technology Transfer Centre, Yaroslavl State Pedagogical University Named after K.D. Ushinsky, Respublikanskaya St., 108, 150000 Yaroslavl, Russia
Anton A. Shetnev
Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, 29 Aiteke Bi Str., Kyzylorda 120014, Kazakhstan
Sergey V. Baykov
Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab., 7/9, 199034 Saint Petersburg, Russia
Rakhymzhan Turmanov
Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, 29 Aiteke Bi Str., Kyzylorda 120014, Kazakhstan
Nurbol Appazov
Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, 29 Aiteke Bi Str., Kyzylorda 120014, Kazakhstan
Rakhmetulla Zhapparbergenov
Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, 29 Aiteke Bi Str., Kyzylorda 120014, Kazakhstan
Leilya Zhussupova
Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, 29 Aiteke Bi Str., Kyzylorda 120014, Kazakhstan
Nurila Togyzbayeva
Laboratory of Engineering Profile “Physical and Chemical Methods of Analysis”, Korkyt Ata Kyzylorda University, 29 Aiteke Bi Str., Kyzylorda 120014, Kazakhstan
Stephanus J. Cloete
Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa
Mikhail K. Korsakov
Pharmaceutical Technology Transfer Centre, Yaroslavl State Pedagogical University Named after K.D. Ushinsky, Respublikanskaya St., 108, 150000 Yaroslavl, Russia
Vadim P. Boyarskiy
Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab., 7/9, 199034 Saint Petersburg, Russia
Anél Petzer
Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa
Jacobus P. Petzer
Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa
Monoamine oxidase (MAO) plays a key role in the pathogenesis of central nervous system disorders, and MAO inhibitors have been used in the treatment of depression and Parkinson’s disease. In the search for new classes of MAO inhibitors, the present study investigated a series of 1,2,4-oxadiazin-5(6H)-one derivatives. This study provides the first optimization of the reaction conditions for the condensation of amidoximes with alkyl 2-halocarboxylates to yield the desired 1,2,4-oxadiazin-5(6H)-ones. The results of the in vitro MAO inhibition studies showed that the 1,2,4-oxadiazin-5(6H)-ones were indeed inhibitors of human MAO with the most potent inhibition observed for 5f (IC50 = 0.900 µM) and 7c (IC50 = 0.371 µM). It was concluded that, with appropriate substitution, 1,2,4-oxadiazin-5(6H)-one derivatives would act as good potency MAO-B inhibitors and lead compounds for the development of antiparkinsonian drugs. In Parkinson’s disease, MAO-B inhibitors enhance central dopamine levels and reduce MAO-mediated production of hydrogen peroxide and resultant oxidative injury. This study represents one of few works to investigate synthetic approaches and biological activities of the 1,2,4-oxadiazin-5(6H)-one class of heterocycles.
