Synthesis of compounds for the treatment of Chagas Disease within the MINDI consortium

Abstract

The work proposal for the postdoctoral fellowship involves collaboration with the Medicines for Neglected Diseases initiative (DNDi, www.dndi.org), a non-profit research and development organization that works to offer new treatments for neglected diseases, especially Chagas Disease, Leishmaniasis, sleeping sickness, Filariasis, and Pediatric HIV. The aim of the project is to investigate the synthesis of analogs of target molecules, sent by DNDi, as a starting point to discover a compound that meets the criteria for DNDi final candidates, aiming at the prevention and treatment of Chagas' Disease and Leishmaniasis. The duration of this project is 24 months. To overcome limited accessibility to molecules and reduced screening capacity, DNDi aims to catalyze research to discover new and small active molecules orally, with potential for future development. These publications are a huge resource for advancing drug discovery activities against Chagas' Disease and Leishmaniasis and redefine traditional rules on intellectual property. The postdoctoral student must perform the synthesis and biological evaluation of the following series: 3-cyanopyridine series: targets from the WHO/TDR and NIH/Broad Institute program: the 3-cyanopyridine series features a monocyclic system (WHO/TDR) and a bicyclic system (NIH/Broad Institute) and are under development. active against T. cruzi with sub-mM activity in vitro. The potency for this series is not due to CYP51 inhibition. The chemistry involved in the synthesis of these compounds is robust and scalable for preclinical development. Pyridipyrimidine series: targets from Pfizer/TDR and AbbVie: the pyridylpyrimidine series is active against L. donovani and T. cruzi and we will start an optimization program for this leader. In addition, new series derived from azaindoles and aminobenzimidazoles are available, and others will be available soon from DNDi's screening programs. (AU)