Derivatives of guanidine-based DNA minor groove binders as antiprotozoal agents

Infectious diseases are one of the main causes of mortality worldwide. Parasitic diseases caused by microorganisms of the genus Trypanosoma (human African trypanosomiasis-HAT), Leishmania (leishmaniasis) and Plasmodium (malaria) cause some of the deadliest human infections in tropical and subtropical areas of the world. According to the WHO, in 2018, there were approximately 228 million cases of malaria with death rates of 405,000. In addition, in sub-Saharan Africa, HAT has an overwhelming risk population of 65 million people and 700,000 - 1 million cases of Leishmaniasis annually. Still no definitive cure has been found for these infectious diseases due to poor patient compliance, severe side effects and the increasing emergence of drug resistance to current therapeutics. Hence, there is a need for the development of new drug therapies.

Within the past 20 years, the Rozas group has developed a series of guanidine based DNA minor groove binders that have displayed potent in vitro and in vivo anti-trypanosomal and antimalarial activity. Hence, based on previous results this project focuses on the development of a new series of guanidine based DNA minor groove binders. Our objective is to computationally and biophysically study the interaction of these molecules with DNA and assess their ability as potential anti-protozoal agents.