The future of antimalarial drug discovery lies in innovative thinking and novel areas, some currently under exploration and some yet to be explored. the principal means of combating malaria. Over the past 60 to 70 years, since the introduction of synthetic antimalarials, only a small number of compounds, belonging to three broad classes, have been found LBH589 (Panobinostat) suitable for clinical usage [17,18]. These classes are described below. 1.2.1. Quinine and related drugs Quinine, originally extracted from cinchona bark in the early 1800s, along with its dextroisomer quinidine, is still one of the most important drugs for the treatment of uncomplicated malaria, and LBH589 (Panobinostat) often the drug of last resort for the treatment of severe malaria. Chloroquine (CQ), a 4-aminoquinoline derivative of quinine, has been the most successful, LBH589 (Panobinostat) inexpensive, and therefore the most widely used antimalarial drug since the 1940s. However, its usefulness has rapidly declined in those parts of the world where CQ-resistant strains of and have emerged and are now widespread. Amodiaquine, an analogue of CQ, is a pro-drug that relies on its active metabolite monodesethylamodiaquine, and is still effective in areas of Africa, but not in regions of South America. Other quinine-related, commonly used drugs include mefloquine, a 4-quinoline-methanol derivative of quinine, and the 8-aminoquinoline derivative, primaquine; the latter is specifically used for eliminating relapse causing, latent hepatic forms (hypnozoites) of and and has developed resistance to nearly all antimalarial drugs in current LBH589 (Panobinostat) use, although the LBH589 (Panobinostat) geographic distribution of resistance to any one particular drug varies greatly. In particular, Southeast Asia has a highly variable distribution of falciparum drug resistance; some areas have a high prevalence of complete resistance to multiple drugs, while elsewhere there is a spectrum of sensitivity to various drugs . Until 2009, no noticeable clinical resistance to artemisinin drugs was reported. However, as described below, a number of recent studies have raised concerns about the efficacy of ACTs, particularly in Southeast Asia. 1.4. Overview of Genetic Basis for Antimalarial Drug Resistance It is believed that the selection of parasites harboring polymorphisms, particularly point mutations, associated with reduced drug sensitivity, is the primary basis for drug resistance in malaria parasites [28,29]. Drug-resistant parasites are more likely to be selected if parasite populations are exposed to sub-therapeutic drug concentrations through (a) unregulated drug use; (b) the use of inadequate drug regimens; and/or (c) the use of long half-life drugs singly or in non-artemisinin combination therapies. In recent years, significant progress has been made to understand the genetic/molecular mechanisms underlying drug resistance in malaria parasites [30,31]. Chloroquine resistance (CQR) in is now linked to point mutations in the chloroquine resistance transporter (PfCRT [encoded by play a modulatory role in CQR, which appears to be a parasite strain-dependent phenomenon . Point mutations in the DHPS enzyme (encoded by DHFR domain (encoded by double mutant (437G with either 540E or 581G), combined with the triple mutant (108N_51I_59R), was found to be frequently associated with SP treatment failure [28,29]. Orthologues of ((((have been identified, and found to be polymorphic. However, associations of the mutant alleles of and with clinical resistance to CQ and SP, respectively, are unclear . 2.?Emergence of Artemisinin Resistance in malaria after artemisinin treatment are seen in some areas. Recrudescence, the reappearance of an infection after a period of quiescence, occurs in up to 30% of patients on artemisinin monotherapy, and in up to 10% of patients on ACTs [18,34]. The underlying mechanism of recrudescence after artemisinin treatment is unclear. As illustrated by recent studies, the MRK occurrence of parasite dormancy, where parasites enter a temporary growth-arrested state, may provide.