Kemal YELEKÇI, Begüm EVRANOS AKSÖZ, Gülberk UÇAR

2-pirazolin yapısındaki yeni bir bileşiğin sentezi, moleküler modellemesi ve monoaminoksidaz inhibitörü etkisinin araştırılması

Amaç: Nöromediatörlerin yıkımından sorumlu olanmonoamin oksidaz (MAO) enziminin izoformlarının(MAO-A ve -B) birçok hastalık ile yakından ilişkili olduğu;MAO inhibitörlerinin depresyon, Parkinson ve Alzheimerhastalığı gibi hastalıkların tedavisinde kullanıldığıbilinmektedir. Grubumuzca daha etkin, tersinir ve az yanetkili yeni bir MAO inhibitörü (SH2U bileşiği) sentezlenmişve bu bileşiğin insan MAO enzimini (hMAO) inhibe etmeyeteneği incelenmiştir. Ayrıca bu yeni bileşiğin hMAO ileetkileşimi, moleküler modelleme çalışmaları ile detaylıbir şekilde araştırılmıştır. Sentezlenen yeni bileşiğinhMAO’yu kuvvetli bir şekilde yarışmalı ve tersinir olarakinhibe ettiği bulunmuştur. Söz konusu bileşiğin Parkinsonve Alzheimer hastalıklarının tedavisinde ümit verici birilaç etken maddesi olabileceği düşünülmektedir.Yöntem: 3’,5’-Dikloro-2’-hidroksi asetofenonile p-tolualdehit’in metanol içinde KOH varlığındareaksiyona girmesiyle 1-(3,5-dikloro-2-hidroksifenil)-3-p-tolil prop-2-en-1-on (3’,5’-Dikloro-2’-hidroksi-4-metil şalkon) bileşiği sentez edilmiştir. Daha sonraelde edilen bu bileşiğin etanol içerisinde geri çevirensoğutucu altında izonikotinik asit hidrazit ile muameleedilmesiyle [3-(3,5-dikloro-2-hidroksifenil)-5-p-tolil-4,5-dihidropirazol-1-il] (piridin-4-il) metanon bileşiği sentezedilmiştir. Yapısı doğrulanan bu bileşiğin hMAO enzimi ileetkileşimi, ticari tayin kiti kullanılarak fluorometrik biryöntemle incelenmiştir. Ayrıca, söz konusu yeni bileşikile hMAO arasındaki etkileşimler, moleküler modellemeçalışmaları ile aydınlatılmıştır.Bulgular: Sentezlenen bileşiğin yapısı, IR, Mass,1H-NMR ve elemental analiz yöntemleri kullanılarakdoğrulanmıştır. Yapısı doğrulanan bu bileşiğin etkin,seçici, tersinir, toksik olmayan bir hMAO-B inhibitörüolduğu ve inhibisyonun yarışmalı olduğu görülmüştür.Moleküler yerleştirme programı kullanılarak bileşiğinhMAO-B enziminin aktif bölgesinde hangi amino asit yanzincirleri ile ne tür girişimleri yaptığı belirlenmiştir.Sonuç: Yeni sentezlenen SH2U bileşiği, hMAO-Benzimini kuvvetle, seçici, yarışmalı ve tersinir olarakinhibe etmiştir. Sentezlediğimiz bileşik, bilinen seçiciama tersinmez MAO-B inhibitörü olan selejilin’den dahaetkin ve seçici, tersinir olarak hMAO-B enzimini inhibeetmiştir ve Parkinson ile Alzheimer hastalığı tedavisindekullanılabilecek bir ilaç etken maddesi olarak ümitvadetmektedir.

Investigation of synthesis, molecular modelling and monoaminoxidase inhibitor activity of a new 2-pyrazoline compound

Objective: Isoforms of monoamine oxidase (MAO-A and -B) which are responsible for the degradation of neuromediators are involved in many diseases, and MAO inhibitors are used for the treatment of some diseases such as depression, Alzheimer’s and Parkinson’s diseases. Thus, a novel compound, SH2U was synthesized and its ability for the inhibition of human MAO (hMAO) activity was investigated by our group. In addition, the interaction of SH2U with hMAO isoforms have been investigated in detail using molecular modelling technics. It has been found that SH2U inhibited hMAO-B potently, selectively, competitively and reversibly suggesting that the novel compound may be a promising drug agent for the treatment of Parkinson’s and Alzheimer’s diseases. Methods: 1-(3,5-dichloro-2-hydroxyphenyl)-3- p-tolylprop-2-ene-1-on (3’,5’-Dichloro-2’-hydroxy4-methyl chalcone) was prepared via the reaction of p-tolualdehyde and 3’,5’-Dichloro-2’-hydroxy acetophenone in methanol in the presence of KOH. Then, the obtained chalcone was treated with isonicotinic acid hydrazide under reflux in ethanol to give (3-(3,5-Dichloro-2-hydroxy phenyl)-5-p-tolyl4,5-dihydropyrazol-1-yl) (pyridin-4-yl) methanone. The interaction of SH2U with hMAO isoforms was investigated fluorometrically using commercial kits. The interaction between SH2U and hMAO was also analyzed using AutoDock 4.2.6 program. Results: The structure of compound SH2U was confirmed using IR, Mass, 1 H-NMR and elemental analysis methods. SH2U appeared as a potent, selective, reversible and nontoxic hMAO-B inhibitor. Mode of inhibition was found to be competitive. Interactions of the new compound with the active site of hMAO-B were clarified using molecular modelling studies. Conclusion: Compound SH2U inhibited hMAO-B potently, selectively, competitively and reversibly. The synthesized compound is found to be more potent and selective than selegiline, the known irreversible MAO-B inhibitor, indicating that SH2U appears as a promising active molecule to be used in the treatment of Parkinson’s and Alzheimer’s diseases.

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