Exploring the structure activity relationship of antiplasmodial compounds identified from the MMV Pathogen Box.

Abstract

Over 200 million new infections are caused by malaria-causing plasmodium species. This results in over 500 000 annual deaths. These deaths are mostly young children under the age of five years. As there is an emergence of resistance to primitive first-line treatments, there is an increasing need for the development of new targets with novel scaffolds. For such advancements, we have to consider the structure-activity of antiplasmodial compounds. The Pathogen Box is a concept modelled on the Malaria Box, except the 400 drug-like compounds it contains are a diverse range of compounds which are active against numerous neglected diseases of interest, and is readily accessible. It unpacks 125 compounds of antiplasmodial activity, a lot of which have been identified from phenotypic screening of the GSK Tres Cantos Anti-Malarial Set (TCAMS). Upon request, select researchers around the globe receive a set of compounds from the Pathogen Box to help in the advancements towards neglected disease drug discovery. In turn, the researchers are requested to present, in the public domain, any data they will have generated in their work within two years. This presents an opportunity for a collaborative space for neglected disease drug research. In this project, compound MMV023227 was found to have promising antiplasmodial activity. We have therefore designed and synthesized some analogues of the hit compound with the purpose of identifying an SAR. We initiated the synthesis of the designed analogues of compound MMV023227 by successfully synthesising the three imidazole compounds that are 2-(3-bromophenyl)-4,5-dimethyl-1H-imidazole (3.1), 2-(3-bromophenyl)-4-methyl-1H-imidazole (3.2), and 2-(3-bromophenyl)-1H-imidazole (3.3) in yields between 33 – 42 %. We moved these compounds towards the desired final compounds through several stages, but we could only go as far as producing compounds N-(2-chlorobenzyl)-3-(1-(ethoxymethyl)-1H-imidazol-2-yl)aniline (3.9), N-(2 chlorobenzyl)-3-(1-(ethoxymethyl)-4-methyl-1H-imidazol-2-yl)aniline (3.10) and N-(2-chlorobenzyl)-3-(1-(ethoxymethyl)-5-methyl-1H-imidazol-2-yl)aniline (3.11) in yields between 7 – 41 %.