Planejamento e investigação de metodologias sintéticas para a obtenção de derivados diimidazolínico-pirazólicos com potencial ação tripanocida

Abstract

Chagas Disease (CD), a n illness discovered by Carlos Chagas 11 5 years ago, remains a great public health problem . It has been reported 30 thousand new cases annually and causing 14 thousand deaths during the same period of time . Currently, two drugs only are used in the chemotherapy , benznidazol e (B Z) and nifurtimox (NF). T he former is the unique commercially available in Brazil, but its major issue is a high treatment dropout rate around 20% due to severe side effects and long periods of administration, in addition to its lack of efficacy in the chronic phase of CD. In the search for new cand idates with potential trypanocidal effect , our research group has been synthesizing several heterocyclic systems for their antiparasitic evaluation. In this work, the aim is to synthesize and evaluate the trypanocidal activity of 9 new 1 aryl 3 --(methyl(4,5 dihydro 1 H imidazol 2 yl)) 4 --(4,5 dihydro 1 H imidazol 2 yl) 1 H p yrazoles derivatives 1( a i )). Eighteen key intermediates were synthesized: 5 amine 1 aryl 4 cyane 3 --( 1 H pyrazoles 2( a i 1 aryl 4 cyane 3 --( 1 H pyrazoles 3( a c,e i )), 2 amine 1,1,3 tricyaneprop 2 en e 4 , isolated in 31 85% yields . Regard to synthesis of the desired compounds 1(a i)i), eleven methodologies were evaluated in attempt to obtain 1a and none of them generated this compound . However, when it was employed classical methodology involving ethylenediamine (EDA) and carbon disulfide (CS 2 ), an unexpected compound was obtained: 8 phenyl 2,3 dihydro 8 H imidazo[1,2 a ]pyrazolo[4,3 c ]pyridine 5 thiol 6a , in 29% yield From similar experimental procedure more three compounds were obtained, 6(e,f,h) h), in 11 87% yields. All compounds had it structure confirmed by Fourier Transform Infrared (FT IR) Spectroscopy, High Resolution Mass Spectrometry (HRMS), and Nuclear Magnetic Resonance (NMR) analysis