Plasmodium c-GMP dependent protein kinase inhibitors
Creators: name: Fondekar, Raheel
Publisher: name: No Publisher Supplied
Year: 2019

description: Malaria is an infectious parasitic disease affecting vertebrates such as birds and animals including humans. It is caused by unicellular eukaryotes belonging to the genus Plasmodium and is transmitted by the bite of the female Anopheles mosquitoes. Plasmodium are obligate parasites which means they require a vertebrate host and the insect vector to complete their lifecycle. According to one estimate, malaria may have claimed the lives of approximately half the people to have ever walked the face of the earth. The disease-causing Plasmodium species have been around for more than a million years. Malaria asserts a deep and harrowing socio-economic effect on malaria-endemic countries. This can be inferred from the fact that most of the malaria-endemic countries are under-developed. Hence, malaria is regarded as the worlds most devastating parasitic infection. The disease is endemic to countries close to the equator as the pathogen and the insect vector thrive particularly well in tropical climates. Five species of Plasmodium are known to infect humans  P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. Together, P. falciparum and P. vivax account for more than 90% of the human infections. The sporozoites of the parasite, introduced into the host body by the bite of the vector, find their way to the liver where they infect hepatocytes. They undergo multiplication and growth and exit hepatocytes as merozoites. Subsequently, the merozoites begin invading erythrocytes where they feast on the haemoglobin. After undergoing multiplication, the merozoites exit erythrocytes thus causing rupture and destruction of these cells. This phenomenon is attributed to high fever and chills associated with malaria patients.Malaria eradication relies heavily on pathogen and vector control. Vector control essentially aims to prevent spread of the disease by eliminating Anopheles mosquitoes. Pathogen control, on the other hand, is essential for disease treatment and prophylaxis. It is typically accomplished with the use of antimalarial drugs. The most effective antimalarial drug therapy as of today is artemisinin combination therapies (ACTs). However, with the recent rise in artemisinin resistance reported in several countries in Southeast Asia, the urgency to develop new antimalarial drugs is rapidly increasing. In addition, the parasites have long-developed resistance to most of the existing antimalarials like chloroquine, quinine and mefloquine which makes the fight against malaria even more grave.Plasmodium c-GMP dependent protein kinase (PKG) has been extensively researched in recent times as a potential means of pathogen control. The enzyme has been found to have a crucial role in each of the lifecycle stages of the parasite. Studies have shown that parasitic invasion of the hepatocytes, growth related schizogony in the erythrocytes and gametogenesis occurring in the mosquito cycle can all be linked to Plasmodium PKG. This makes parasitic PKG a very attractive target not only for malaria treatment, but also for prophylaxis. Trisubstituted pyrrole (TSP) has been identified as a potent and selective inhibitor of parasitic PKG. As a result, PKG inhibitors were synthesized to optimize the activity and selectivity of TSP and to generate a much-needed SAR in order to map the floor of the binding pocket of the enzyme. The optimization process involved introduction of a wide range of substituents at different locations of the TSP structure. A few new scaffolds were also investigated to evaluate activity and further SAR knowledge. In the biological assay performed, TSP (18 nM) and several potent analogues were identified.