Neglected tropical diseases (NTDs) are a group of parasitic and bacterial diseases that are the source of massive suffering of nearly two billion people per year. NTDs majorly affect poverty-stricken areas where access to basic healthcare and eradication methods are not available. One such NTD is Chagas disease. Caused by T. cruzi, a protozoan parasite, the disease has two phases: acute and chronic. The acute phase can last weeks or months and presents very similarly to many common diseases: fever, fatigue, body aches, headaches. If not treated, the disease progresses to the lifelong chronic phase. The chronic phase is primarily asymptomatic, but heavily targets the digestive tract and heart, eventually leading to “Chagas heart disease.” When detected, Chagas disease can be treated with antiparasitics like nifurtimox and benznidazole. While effective, the side effects of the treatments tend to be more frequent and more severe with age, and neither are effective in the chronic phase of the illness. Due to the severity of the antiparasitic side effects, this research focuses on the synthesis of a library of drug candidates to treat Chagas disease. Squaramide-based drugs and transition metals have been shown to have anti-parasitic properties. Squaramides are bioisosteric replacements that serve as a substitutes for many functional groups such as guanidines, ureas, and amides. Additionally, they are far easier to functionalize than other functional groups. Starting with diethyl squarate (3,4- dihydroxycyclobut-3-ene-1,2-dione), amines and aminopyridines were attached to the scaffold made by diethyl squarate via addition/elimination reactions. Three monosquaramide compounds were initially synthesized (ranging from 77.25% to 85.97% yield) as precursors for 10 disquaramides (ranging from 43.1% to 71.14% yield). Each product was synthesized by addition/elimination reactions and was subsequently confirmed by 1H and 13C NMR spectroscopy. Our target disquaramides vary by number of pyridinyl rings depending on the group installed on the monosquaramide precursors. Current work entails installing a metal core (Cu, Zn, and Ni) between the nitrogen atoms of the pyridinyl rings.

Synthesis of dipyridynl disquaramides in route to new medications for Chagas disease

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