Influenza is an acute respiratory disease causing hundreds of thousands hospitalized each year worldwide. Vaccination plays a major role in the prevention of influenza, but due to constant antigenic drift and the ever-present potential for antigenic shift of the virus and an associated pandemic, antiviral therapy has an important role in the management of influenza.
Oseltamivir (Tamiflu®) is the ethyl ester prodrug of oseltamivir carboxylate, a potent and selective inhibitor of the influenza virus enzyme neuraminidase. Oseltamivir is extensively converted to oseltamivir carboxylate by hepatic esterases and eliminated entirely in the urine. Neuraminidase is a surface glycoprotein of influenza viruses that cleaves terminal sialic acids from carbohydrates. This enzyme is critical for viral release from infected cells, prevents virus aggregation and facilitates viral spread in the respiratory tract.
In this thesis it was synthesized a few novel promoieties from coumarin, which could be used as potential amine prodrugs of oseltamivir carboxylate. Different strategies for these synthesis were studied and attempted. By synthesizing these prodrugs the binding to albumin might increase and a passive targeting effect to inflamed tissue can be obtained. Synthesizing different esters of cis-2-hydroxycinnamic acid as pro moiety takes advantages of the fast breakdown from esterases in vivo and a spontaneous lactonization which regenerates the coumarin unit. Since coumarin has been studied for many years, the toxicity profile is well known, and it is found be nontoxic. The conversion or activation of a prodrug to the parent drug molecule in the body is a result of enzyme mediated cleavage or pH dependent hydrolysis of the established prodrug linkage. The human body is rich in enzymes that are capable of quickly hydrolyzing these ester bonds, they are ubiquitous distributed and several types are found in the blood, liver, and other organs and tissues. The rate of hydrolytic breakdown of prodrug is also dependent of steric effects/hindrance within the pro moiety and the percentage of protein binding.
The active metabolite oseltamivir carboxylate was hydrolyzed from oseltamivir phosphate under acid condition. Crystals was attempted grown from both oseltamivir phosphate and oseltamivir carboxylate to obtain the x-ray crystal structure. The crystals grown were needle shaped and very small, less then 10 m in diameter. The needle grains had also connected with each other to form a continuous network. To obtain single-crystal x-ray crystallographic data the crystals had to be three times larger and these crystals could therefore not be used.