Malaria is one of the major parasitic diseases in tropical and subtropical regions which is caused by the genus Plasmodium and transmitted to human beings through the bites of female Anopheles sp. mosquitoes. About 40% of the world’s population lives in malaria-endemic areas. It causes about 1 million deaths per year globally. The situation gets worsened by the widespread development of parasite lines becoming resistant to most of the commonly used antimalarial drugs. The use of chloroquine or fast-acting aminoquine has significantly controlled malaria in the last few decades, but due to the emergence of resistance to the drugs the world malaria eradication efforts are falling short. In these efforts, artemisinin-based combination therapies are being used clinically with the same mode of action in the parasite. Hence, there is a need to develop novel antimalarial drugs having a diverse mode of action inhibiting the resistance.
CSIR-National Chemical Laboratory (CSIR-NCL; www.ncl-india.org), Pune, reported the synthesis of artemisinin-peptidyl vinyl phosphonate hybrid molecules showing better efficacy than artemisinin alone against chloroquine-resistant as well as multidrug-resistant Plasmodium falciparum strains. A dual-targeting approach was employed by the team led by Dr Asish Bhattacharya from the Organic Chemistry Division of CSIR-NCL in collaboration with ICGEB, New Delhi. The objective was to provide a robust drug candidate for the treatment of infections due to parasites that have resistance to the antimalarial drugs including artemisinin.
The reported compounds effectively inhibited the survival of ring-stage parasite for laboratory-adapted artemisinin-resistant parasite lines as compared to artemisinin. These hybrid molecules showed complete parasite clearance in vivo using P. berghei-mouse malaria model. Further studies on the mode of action of hybrid molecules suggested that these artemisinin-peptidyl vinyl phosphonate hybrid molecules possessed dual activities such as inhibition of falcipain-2, a P. falciparum cysteine protease involved in haemoglobin degradation and blocked the hemozoin formation in the food-vacuole, a step shown to be blocked by earlier therapy of artemisinin alone.
The hybrid molecules blocked multiple steps of a pathway and showed synergistic efficacies and have less chance to induce resistance; hence these lead compounds can be used as an effective antimalarial to prevent the spread of resistance to current antimalarials.