Propiedades químicas estructurales de compuestos que actúan contra el Trypanosoma brucei

Abstract

This article summarizes the tireless work that for twelve years has been conducted in the framework of a multicenter project, led by Prof. Jörg hacker, Ulrike Holzgrabe and Gerhard Bringmann from the University of Würzburg in Germany. More than 12 university laboratories distributed in the Faculties of Chemistry, Medicine, Pharmacy and Biology, a central laboratory to analyze the synthesized compounds and over 100 people interacting to design and test compounds against 11 pathogens, including trypanocidal compounds. My summary emphasizes the work on trypanocidal compounds, which together with the leishmanicidals were the ones with which I worked mostly. Trypanosomiasis is a vectorborne disease, fatal if untreated. Although in the human disease the annual incidence used to be very high, it has recently been reduced to less than 10,000 cases per year. This statement has been used to assert that "it is not necessary to invest in the development of new drugs against sleeping sickness". The disease, however, can return as it has done in the past, increasingly aggressive. Two drugs are being clinically studied by the DNDi initiatives (for its acronym in English, Drugs for Neglected Diseases initiative), and nonprofit associations. Since the survival rate of drug candidates is extremely low, two is a very small number of compounds, none is in phase three of clinical evaluation. The potency of a compound (reflected in its IC50), not necessarily translates into the "best drug to market level". In addition to the activity that molecules must have against the selected organism, its properties of absorption, distribution, metabolism and excretion, are essential for the selection of candidates to enter in pharmacological and preclinical animal studies. In this work, and with the aim of using transport properties across membranes, as a tool to refine the selection of lead compounds to enter preclinical studies, the correlation established between trypanocidal activity of molecules of different structural classes, synthesized under a broad spectrum platform with polar surface area (PSA), has been analyzed. The data suggest a sigmoidal correlation between PSA and trypanocidal activity of the compounds and confirms that this parameter may be useful for understanding the relationship between the power of a compound and its chemical characteristics.