Design and Synthesis of New Benzothiazole Compounds As Selective Hmao-B Inhibitors

molecules Article Design and Synthesis of New Benzothiazole Compounds as Selective hMAO-B Inhibitors Sinem Ilgın 1, Derya Osmaniye 2,3, Serkan Levent 2,3, Begüm Nurpelin Sa˘glık 2,3, Ulviye Acar Çevik 2,3, Betül Kaya Çavu¸so˘glu 2, Yusuf Özkay 2,3,* and Zafer Asım Kaplancıklı 2 ID 1 Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Anadolu Universty, 26470, Eski¸sehir, Turkey; [email protected] 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu Universty, 26470, Eski¸sehir, Turkey; [email protected] (D.O.); [email protected] (S.L.); [email protected] (B.N.S.); [email protected] (U.A.Ç.); [email protected] (B.K.Ç.); [email protected] (Z.A.K.) 3 Doping and Narcotic Compounds Analysis Laboratory, Faculty of Pharmacy, Anadolu Universty, 26470, Eski¸sehir, Turkey * Correspondence: [email protected]; Tel.: +90-222-335-0580 (ext. 3603) Received: 15 November 2017; Accepted: 8 December 2017; Published: 9 December 2017 Abstract: In the current work a new class of novel benzothiazole-hydrazone derivatives was designed and synthesized as hMAO-B inhibitors. Structures of the obtained compounds (3a–3j) were characterized by IR, 1H-NMR, 13C-NMR, and HRMS spectroscopic methods. The inhibitory activity of compounds (3a–3j) against hMAO-A and hMAO-B enzymes was evaluated by using an in vitro fluorometric method. According to activity results, some of the synthesized compounds displayed selective and significant hMAO-B enzyme inhibitor activity. Compound 3e was the most active derivative in the series with an IC50 value of 0.060 µM. Furthermore, cytotoxicity of compound 3e was investigated and found to be non-cytotoxic. Absorption, distribution, metabolism, and excretion (ADME) and blood-brain barrier (BBB) permeability predictions were performed for all compounds. It was determined that these compounds may have a good pharmacokinetic profiles. Bınding modes between the most active compound 3e and the hMAO-B enzyme were analyzed by docking studies. It was observed that there is a strong interaction between compound 3e and enzyme active site. Keywords: benzothiazole; hydrazone; MAO enzyme inhibition; docking study; cytotoxicity 1. Introduction Monoamine oxidase (MAO) is an important flavoenzyme existing in the outer mitochondrial membrane of neuronal, glial, and many other cells, and is responsible for the oxidative deamination of amines in the brain, as well as peripheral tissues to regulate their level. MAO exists in two isoforms: namely, MAO-A and MAO-B, which have been identified based on their amino acid sequences, three-dimensional structure, substrate preference, and inhibitor selectivity [1,2]. Monoamine oxidase enzyme inhibitors (MAOIs), in general, have inhibitory activity against both of MAO-A and MAO-B [3]. However, researchers have focused to develop a selective MAOI to avoid food–drug and drug–drug interactions of non-selective MAOIs, as well as their side effects [4,5]. Selective inhibition of MAO-A, which specifically metabolizes serotonin, norepinephrine, and tyramine is effective in the depression treatment, while selective inhibition of MAO-B, which specifically degrades dopamine, is effective in the treatment of Parkinson’s disease (PD) [5,6]. It is known that PD is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta [7,8]. Therefore, in the treatment of PD, it has been targeted to increase dopaminergic activity through dopamine supplementation, decrease dopamine breakdown, or activate dopaminergic receptors [9,10]. MAO-B inhibitors are useful in the treatment of the early stages of PD and, later, as an adjunct to Molecules 2017, 22, 2187; doi:10.3390/molecules22122187 www.mdpi.com/journal/molecules Molecules 2017, 22, 2187 2 of 13 Molecules 2017, 22, 2187 2 of 13 activity through dopamine supplementation, decrease dopamine breakdown, or activate dopaminergic receptors [9,10]. MAO-B inhibitors are useful in the treatment of the early stages of PD andother, later drug, as therapies an adjunct [11 ,to12 other]. MAO-B drug inhibitorstherapies have[11,12 a]. good MAO safety-B inhibitors profile. have They a also good possess safety an profile. effect Theyin the also improvement possess an ofeffect motor in the symptoms improvement and, thus, of motor delay symptoms the need forand levodopa, thus, delay in the the treatment need for levodopaof PD. Furthermore, in the treatment studies of PD. have Further indicatedmore, that studies MAO-B have inhibitors indicated havethat MAO a neuroprotective-B inhibitors have effect a neuroprotectiveagainst neurodegeneration effect against [13]. Therefore,neurodegeneration the development [13]. Therefore, of novel, selective, the development and reversible of MAO-Bnovel, selective,inhibitors and with reversible fewer side MAO effects-B inhibitors is still necessary. with fewer side effects is still necessary. In terms terms of of crystal crystal structure, structure, the hhMAOMAO-B-B enzyme possesses two cavities connected by the amino amino acid ILE199. ILE199. The The entrance entrance cavity cavity has has a volume a volume of 290 of 290 Å 3 and, Å3 and, possesses possesses a hydrophobic a hydrophobic character. character. The secondThe second cavity, cavity, with with a volume a volume of 390 of 390 Å 3 Å, contains3, contains the the substrate substrate binding binding site site in in w whichhich coenzyme coenzyme FAD FAD is located. located. Crystallographic Crystallographic data data of of the the substrate substrate cavity cavity has has displayed displayed that that the the amino amino acid acid side side chains, chains, coating the cavity,cavity, areare very very hydrophobic hydrophobic and and favorable favorable to to interact interact with with an an amine amine moiety. moiety. The The FAD FAD and andtwo two closely-parallel closely-parallel tyrosyl tyrosyl residues residues (398 (398 and 435)and 435) constitute constitute an ‘aromatic an ‘aromatic cage’ cage’ [14,15 [14,15].]. The previous studies have shown that benzothiazole derivatives have potent and selective inhibitory activity activity against against the the MAO MAO-B-B enzyme enzyme [16 [16–19–19]. ].In In these these studies, studies, a similar a similar design design strategy strategy of targetof target compounds compounds has hasbeen been followed. followed. Synthesized Synthesized compounds compounds have havebeen beendesigned designed to possess to possess three essentialthree essential parts: parts: (i) a (i)2-mercapto a 2-mercapto-- or amino or amino-substituted-substituted benzothiazole benzothiazole core core;; (ii) (ii) an an aromatic aromatic or heteroaromatic ring sytem;sytem; and (iii) a linker, bearingbearing H-acceptorH-acceptor and/orand/or H H-donor-donor nitrogens, nitrogens, between the benzothiazole core and (hetero)aromatic ring system (Figure 11).). DockingDocking analysesanalyses havehave revealedrevealed that the benzothiazole core binds within the substrate cavity space, the the heteroaryl residue of the molecules is located in the en entrancetrance cavity space of MAO MAO-B-B enzyme, and nitrogen atoms of the linker are stabilizedstabilized byby hydrogen hydrogen bond bond interactions interactions with with amino amino acid acid residues residues of the of enzyme the enzyme active siteactive [16 ,site18]. [16,18In addition]. In addition to benzothiazole to benzothiazole derivatives, derivatives, hydrazine-based hydrazine compounds,-based compounds, which bear which an azomethine bear an -NHN=CH-azomethine functional-NHN=CH group,- functional have displayed group, have a selective displayed inhibitory a selective activity inhibitory against MAO-B activity [18 against,20,21]. MAOThe C=N-B [18,20,21 double]. bondThe C=N of hydrazone double bond and of thehydrazone terminal and nitrogen the terminal atom nitrogen significantly atom influence significantly the influencephysicaland the chemicalphysical and properties. chemical The properties. C-atom inThe hydrazone C-atom in has hyd bothrazone electrophilic has both electrophilic and nucleophilic and nucleophilicproperties [22 properties]. Due to MAO-B [22]. Due inhibitory to MAO potency-B inhibitory and the potency physicochemical and the physicochemical character of the character hydrazone of themoiety, hydrazone it has been moiety, preferred it has as been a linker preferred between as the a linker benzothiazole between core the andbenzothiazole the (hetero)aromatic core and ringthe (hetero)aromaticsystem in the design ring of system target in compounds the design asof outlinedtarget compounds in Figure1 .as outlined in Figure 1. In light of the above information, new benzothiazole derivatives consisting of of a hydrazone moiety were synthesized as as novel, novel, selective selective,, and and potent potent MAO MAO-B-B inhibitory inhibitory agents. agents. Additionally Additionally,, we we aimed aimed to determineto determine the in the vitroin vitro cytotoxiccytotoxic effect effectof compounds of compounds in case inthey case had they significant had significant enzyme inhibitory enzyme activity.inhibitory activity. Figure 1. 1. ExamplesExamples of structures of structures displaying displaying MAO-B MAO-B inhibitory inhibitory activity and activity the designed and the compound designeds (compounds3e–3j). (3e–3j). Molecules 2017, 22, 2187 3 of 13 Molecules 2017, 22, 2187 3 of 13 2. Results and Discussion 2. Results and Discussion 2.1. Chemistry 2.1. Chemistry The compounds 3a–3j were synthesized as summarized

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