**6. Drug development research in during 2010–2019**

There is continuous efforts has been given after resistance toward existing drug chloroquine, mefloquine, piperaquine, sulphadoxine-pyrimethamine, artemisinin derivatives, in Southeast Asia. Resistance to the partner drug, not artemisinin, is the primary driver for failure of ACT. Hence along with combination therapy of artemisinin second alternative drug is needed. Medicine of malaria venture is a non governmental organization which support collaborations with a library of antimalarial leads drug discovery (www.mmv.org.in). Clinically used antimalarial combination dose described in (**Table 2**).

A study of literature peformed to find out the new leads and their clinical stage along with survey on www.mmv.org, www.mpmp.huji, and ClinicalTrials. gov website (https://www.clinicaltrials.gov/). Major new drugs focus the blood schizonticide stage of uncomplicated *P. falciparum*. These potential inhibitor of plasmodium cycle must be single dose with minimum exposure and minimized toxicity in pregnant women and children with quite affordability to common people of minimum income.

There are at least 13 agents in clinical development (**Table 3**). Krintafel (tafenoquine) developed by Glaxosmith in collaboration with MMV has the potential to clear hypnozoites is approved for a single dose by regulatory authorities as a treatment for *Plasmodium vivax* relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. Cipargamin (KAE609), developed by Novartis in collaboration with MMV. Cipargamin targets a cell membrane channel in the parasite, which is the new molecular target for malaria in more than 20 years. 75 mg for over 8 days require killing parasite in blood, and also having malaria transmission blocking. Intravenous formulation for severe malaria is also planned for 2020. One of the leading pipeline combinations are artefenomel (OZ439)–ferroquine and lumefantrine-KAF156, both in Phase 2b. Artefenomel is nonartemisinin based drug which has been designed by joint sanofi and mmv effort for children and to allow for oncedaily. The combination is currently in a phase IIb trial, which is completed in the 2018. A novel trioxane 97/78, contains 1,2,4-trioxane nucleus similar to artemisinin developed by Central Drug Research Institute (CDRI), India, has shown promising antimalarial activity and is currently in clinical trials phase I. This 97/78 target, plasmodial phospholipid metabolism responsible for their pharmacological activity. Firstly 97/63 was synthesized but, due to its poor bioavailability, it was resynthesized as a hemisuccinate derivative and coded as 97/78. Upon administration of 97/78 it gets converted into its active *in vivo* metabolite 97/63. The concentrations of 97/63 and 97/78 can be measured by validated LC–MS/MS method [44].
