Review For reprint orders, please contact: reprints@future-science.com Malaria transmission-blocking drugs: implications and future perspectives Ishan Wadi 1 , Pargat Singh 1 , Mahendra Nath 1 , Anupkumar R Anvikar 2 & Abhinav Sinha* ,2 1 Department of Chemistry, University of Delhi, Delhi, 110007, India 2 ICMR-National Institute of Malaria Research, Dwarka, New Delhi, 110077, India *Author for correspondence: aspsm2003@yahoo.co.in Since the world is inching toward malaria elimination, the scientific community worldwide has begun to realize the importance of malaria transmission-blocking interventions. The onus of breaking the life cycle of the human malaria parasite Plasmodium falciparum predominantly rests upon transmission-blocking drugs because of emerging resistance to commonly used schizonticides and insecticides. This third part of our review series on malaria transmission-blocking entails transmission-blocking potential of preclinical transmission-blocking antimalarials and other non-malaria drugs/experimental compounds that are not in clinical or preclinical development for malaria but possess transmission-blocking potential. Collective analysis of the structure and the activity of these experimental compounds might pave the way toward generation of novel prototypes of next-generation transmission-blocking drugs. First draft submitted: 24 January 2020; Accepted for publication: 18 February 2020; Published online: 7 May 2020 Keywords: antimalarials • drugs • endectocide • gametocyte • gametocytocidal • Plasmodium falciparum • sporon- tocidal • transmission blocking Malaria, one of the most devastating tropical diseases on this planet, is caused by the parasites of genus Plasmodium. Out of the malaria parasitic species infecting humans, Plasmodium falciparum is the most lethal [1–4] and is responsible for causing maximum mortality and morbidity [5]. One of the primary reasons that we have not been able to eradicate this disease is the complexity in the life cycle of the parasite and the existence of numerous proteomically distinct parasite stages. When an infected female Anopheles mosquito takes a blood meal from a vertebrate host, it introduces sporozoites (haploid parasitic forms competent of invading liver cells) into the extravascular spaces inside the dermis of the host. These sporozoites find their way into the bloodstream and eventually reach the liver and invade the hepatocytes, in which they complete asexual exo-erythrocytic growth and development. Merozoites released into the circulation, after completion of an asexual exo-erythrocytic cycle, start asexual erythrocytic cycle by invading erythrocytes. Asexual multiplication of these malaria parasites continue until they commit and differentiate into sexually dimorphic haploid forms known as gametocytes [6]. These male and female gametocytes constitute the terminal parasitic stage inside the vertebrate host and are taken up by definitive host, the mosquito, during a blood meal. Inside the mosquito’s midgut, the male and the female gametocytes convert into male and female gametes, to initiate sporogonic development or sporogony. The male gamete fuses with the female gamete to form the zygote that eventually matures to form the ookinete, which is a much elongated and motile form of the parasite. The ookinete migrates through the blood bolus and invades the wall of the mosquito’s midgut and emerges from the basal side (facing hemocoel) to finally settle beneath the basal lamina and develops into a multinucleated oocyst. The oocyst undergoes further maturation and finally ruptures to release thousands of sporozoites into the hemocoel. The sporozoites at this stage possess gliding motility and migrate through the hemolymph into the salivary glands. The sporozoites undergo maturation inside the salivary glands and stay there to further perpetuate the life cycle [7–10]. Although integrated vector management (IVM) approaches are strongly driving malaria elimination campaigns, global malaria elimination still remains a formidable challenge [11,12]. One of the primary reasons of not being able to eliminate malaria from the endemic countries of sub-Saharan Africa is the continuous emergence and rapid spread of resistance in malaria parasites and their vectors to commonly used antimalarials and insecticides, respectively. Future Med. Chem. (Epub ahead of print) ISSN 1756-8919 10.4155/fmc-2020-0026 C  2020 Newlands Press