New anti- malarial treatment to fight against drug resistance.

Malaria is a life threatening disease caused by infected Anopheles mosquito bites. Control mainly depends on early diagnosis followed by treatment with anti-malarial drugs. However,  the treatment is severely hampered because of spread of drug resistant malaria parasites. Recently drug named DDD107498 beendeveloped and about to enter human trials with all properties of potentialmalaria drug. The properties include (i) it shows effect on multiple species of malaria parasites at several lifecycle stages, (ii) single dose effectiveness, (iii) Active gametocyte clearance,(iv) good pharmacokinetics all these characters proved this drug as a new- generation anti-malarial drug.To initiate the process of development of such a compound, the scientific team searched the chemical compound library at drug discovery unit (DDU) of University of Dundee that consists of around 4700 compounds and screened against blood stage asexual forms of the deadliest malaria parasite Plasmodium falciparum 3D7 strain. The screening process filtered out a compound class based on a 2,6- disubstituted quinoline-4-carboxamide scaffold, which seems to have activity against malaria 

parasite, although it shows poor physicochemical properties.

The research team further optimized the compound to attain drug-like properties through cycles of design, synthesis and testing. The significant optimization process included (i) Replacement of Bromine with Florine to reduce molecular mass and lipophilicity, (ii) Replacement of the 3-pyridyl substituent with an ethyl-pyrrolidine group and (iii) Addition of a morpholine group via methylene spacer. The final compound generated was named as DDD107498, and was experimented both in-vitro, in-vivo and ex-vivo methods using humanized mouse model and other model organisms against P.falciparum, P. vivax and P. berghei to confirm its efficacy. The compound was further evaluated for its drug-like properties, mode of action and safety measures. A comparative study with presently available drugs was also done to confirm its better efficacy, unique mechanism of action and ability to act at multiple stages of the parasite life cycle. Read more............