N,Nʼ -Cyclic azomethine imines as precursors in the synthesis of novel derivatives of pyrazolopyrazolones

Apstrakt: N,N′-Biciklični heterocikli poput pirazolopirazolona su čest strukturni fragment brojnih farmaceutskih, agrohemijskih i drugih biološki aktivnih jedinjenja. Jedna od najefikasnijih strategija za sintezu ovog tipa jedinjenja se zasniva na 1,3- dipolarnoj cikloadiciji azometinimina. Iako su proučavane brojne cikloadicije azometinimina sa različitim dipolarofilima, nismo naišli na radove o primeni enona koji sadrže vinil-grupu kao dipolarofil. Reakcija različitih vinil-enona i N,N′-cikličnih azometinimina sa AlCl3 kao katalizatorom se pokazala kao odličan način za sintezu serije 6-acil-5- feniltetrahidropirazolo[1,2-a]pirazol-1(5H)-ona u umerenim do odličnim prinosima (do 98%). Kako je dobro poznato da uvođenje ferocenske grupe u molekul, može poboljšati biološku aktivnost kod nekih jedinjenja, u nastavku istraživanja smo proučavali cikloadiciju akriloilferocena sa različitim N,N’-cikličnim azometiniminima. Dobijena je serija tetrahidropirazolopirazolona koji sadrže ferocen u dobrim prinosima (do 70%). Sva novosintetisana jedinjenja su okarakterisana spektroskopskim tehnikama ( 1H NMR, 13C NMR i IR), a četiri proizvoda su bila pogodna i za kristalografska ispitivanja. Takođe, ispitivana je i antimikrobna aktivnost svih jedinjenja, a pirazoloni sa ferocenom su proučavani i u pogledu antioksidativne aktivnosti, elektrohemijskih svojstava i interakcije sa COX-2 pomoću studija molekulskog dokovanja. Odlična aktivnost neutralisanja DPPH• i ABTS•+ radikala je primećena kod većine testiranih jedinjenja, a studije molekulskog dokovanja su pokazale da neka jedinjenja imaju potencijal da postanu vodeći molekuli u procesu stvaranja novih lekova.Abstract: Numerous pharmaceuticals, agrochemicals, and other biologically active compounds have N,N′-bicyclic heterocycles such as pyrazolopyrazolones in the role of a frequent structural fragment. One of the most efficient strategies for the construction of such fused skeletons relies on the 1,3-dipolar cycloadditions of azomethine imines. Despite the wide range of the investigated cycloadditions of azomethine imines with various dipolarophiles, we have not found any report on the usage of enones that contain vinyl group. The reaction of different vinyl enones and N,N′-cyclic azomethine imines with AlCl3 as catalyst proved to be an excellent way to synthesize series of 6-acyl-5- phenyltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-ones in moderate to excellent chemical yields (up to 98%). Moreover, it is well known that the presence of ferrocene moiety increases a bioactivity of some compounds and consequently we decided to explore the cycloaddition of acryloylferrocene with various N,N’-cyclic azomethine imines. A series of ferrocene-containing tetrahydropyrazolopyrazolones was obtained in good yields (up to 70%). All the newly synthesized compounds are characterized by spectroscopic techniques (1H NMR, 13C NMR and IR), and four examples were suitable for the crystallographic examinations. Antifungal and antibacterial activity were inspected for all products, and ferrocene-containing pyrazolones were also investigated in terms of antioxidant activity, electrochemical properties, and interaction with COX-2 by molecular docking studies. An excellent DPPH• and ABTS•+ radical scavenging activity were observed for majority of tested compounds and molecular docking studies revealed that some compounds have potential to become leading molecules in drug discovery process