Chapter 11 - Targeting DNA topoisomerases in parasitic protozoa by natural products: Chemical and biological perspectives

Abstract

Infections caused by parasitic protozoa pose significant health problems in vertebrates including humans. Unlike bacterial and viral pathogens, the clinical combat against protozoan pathogens is primarily aided by chemotherapeutics because of the unavailability of commercial vaccines to date. Extensive research has been channelized across the globe to identify and validate potential drug candidates against these parasites. A significant share of these lead molecules is held by natural agents. A large array of natural compounds from diverse chemical pedigree effective against these parasites has been investigated to date. However, a major concern with these therapeutic agents is their side effects upon the host. Specificity of the compounds toward pathogens without impacting the host physiology has always been an area of interest for researchers. Naturally, identifying suitable drug targets to ensure minimal adverse effects on hosts has always been a top priority. Contextually, DNA topoisomerases of protozoan parasites have emerged as significant drug targets. These ubiquitous enzymes associated with several nucleic acid transactions are highly conserved across all branches of life forms. But some “unique” features of these enzymes in the parasite lineage are extremely favorable in the quest of lead molecules. Large numbers of compounds derived from different natural sources have been well documented to target these enzymes leading to disturbed DNA metabolism eventually killing the parasites. Some of them have shown promising results in animal models. Structural features of these compounds have a leading role in governing their antitopoisomerase characteristics. Here we will discuss the chemical structures and isolation methodologies of several nature-derived compounds and their mode of functioning toward inhibition of protozoal DNA topoisomerases. We will also highlight the regulatory roles of the structures of these compounds associated with topoisomerase inhibition. Finally, the molecular mechanisms of cell death caused by these natural compounds will be briefly illustrated.