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Download Author Version (PDF) RSC Advances This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. This Accepted Manuscript will be replaced by the edited, formatted and paginated article as soon as this is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/advances Page 1 of 50 PleaseRSC do not Advances adjust margins Journal Name ARTICLE Structure guided drug-discovery approach towards identification of Plasmodium Inhibitors Received 00th January 20xx, Babita Aneja a, Bhumika Kumar a, Mohamad Aman Jairajpuri b, Mohammad Abid a* Accepted 00th January 20xx DOI: 10.1039/x0xx00000x Rapidly increasing resistance to the currently available antimalarial drugs has drawn attention globally for the www.rsc.org/ search of more potent novel drugs with high therapeutic index. The genome sequencing of human malarial parasite Plasmodium falciparum has provided extensive information to understand potential target pathways and efforts are being made to develop lead inhibitors with a hope to eliminate the disease. This review is focused on brief description of key biochemical targets identified from the genome sequence of P. falciparum . This review also summarized the work undertaken by different scientific groups since last five years to develop inhibitors from natural, semisynthetic or synthetic sources, which will be valuable to the medicinal chemists to develop novel antimalarial agents. Manuscript Keywords : Plasmodium falciparum ; malaria; genome sequence; targets; inhibitors Accepted Advances RSC This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins PleaseRSC do not Advances adjust margins Page 2 of 50 ARTICLE Journal Name Introduction (quinine, artemisinin) (e) use of drug resistance reversers (verapamil. desipramine, trifluoperazine) 8 (f) in vitro whole cell parasitic assay Despite global efforts to control and eradicate malaria, it is one (KAE609 (formerly known as NITD609) and KAF156 under phase of the most widespread and deadliest parasitic diseases affecting II clinical trials). 9 The most recent approach is the identification and more than 40% of the world’s population. 1 World Health validation of novel molecular targets and the development of Organization (WHO) factsheet for 2014 reveals more than 198 inhibitors active against these targets. The accessibility of whole million cases with an estimated 584000 fatalities. The severity of genome sequence of P. falciparum has facilitated the identification this disease is prevalent in WHO African region with an estimated of potential targets for the development of new drugs and also shed 90% mortality rate, affecting mainly the children under the age of 5, light on the mechanism of action of older drugs. The validation of who account for 78% of all deaths. 2 This disease is mainly identified target is crucial for this approach and is carried out by attributable to five species of malaria parasite i.e. Plasmodium which repeated antiparasitic activity of different lead compounds against are known to infect humans - P. falciparum , P. vivax , P. ovale , P. that particular target. Identification of potentially active compounds malariae and P. knowlesi. Out of these, P. falciparum and P. vivax and their optimization subsequently results in lead candidates that are biggest threat to public health. While P. vivax is widely are further taken to pre-clinical and clinical investigations. 10 Since distributed geographically, P. falciparum is reportedly more fatal. 3 the qualitative information of all the identified lead compounds and Though a number of antimalarial drugs such as quinine, potential drug targets imparts impetus to the drug discovery artemisinin, artemether, artesunate, dihyroartemisinin, atovaquone, programmes, this review aims to provide the same for antimalarial chloroquine, cinchonine, chlorproguanil, mefloquine, research boon. In this review, the antimalarial potential of various Manuscript pyrimethamine, primaquine, piperaquine, sulfadoxine, amodiaquine, natural, semi-synthetic as well as synthetic compounds reported lumefantrine (Fig. 1) are available, these drugs are rapidly losing during the last 5 years (2010-2015) are compiled and discussed in their therapeutic potential due to emerging drug resistance in target-oriented manner, which will provide a stand to medicinal Plasmodium . 4,5 The parasitic mutations associated with resistance to chemists for the development of better antimalarial therapeutics. antimalarial drugs primarily contributes to the re-emergence of the CH3 H H O disease and its spread to new places and populations. Although CH3 H H C H 3 O O O O HO O H N H C O 3 O artemisinin-based combination therapy has been recommended by H O H O O H O H H CH3 H O O CH HO Accepted WHO as the first-line of treatment for multi-drug resistant P. N 3 O O O falciparum infection which is non-responsive to quinoline and Quinine Artemisinin Artemether Artesunate O 6 H HO antifolate based drugs, but the frequent use of artemisinin and its O H N HN HO O N O H O derivatives has also resulted in resistance to this class of drugs and H O H Cl N the first signs of resistance have emerged in South-East Asian OH Cl N Dihydroartemisinin Atovaquone Chloroquine Cinchonine 2,7 countries. Thus, there is an urgent need to develop new HN HO therapeutic agents with novel mode of action to save people from the Cl O H Cl N N N N N grasp of this deadly disease and to reduce morbidity and mortality. N CF3 NH NH2 NH2 H2N N NH2 H2N Cl CF3 Advances Different approaches adopted till now by the scientific Chlorproguanil Mefloquine Pyrimethamine Primaquine communities for antimalarial drug discovery are mainly based upon Cl OH N N O O H N N N O N (a) combination of existing drugs (artemether-lumefantrine, S HN N N O NN H2N amodiaquine-artesunate, dihyroartemisinin-piperaquine) (b) Cl N Cl RSC chemical modification of known drugs and compound classes ( Piperaquine Sulfadoxine Amodiaquine Cl mefloquine, primaquine, chloroquine, artesunate) (c) “piggy back Cl approach” for the compounds active against other diseases N HO (antifolates, tetracyclines, atovaquone) (d) use of natural products Cl a Medicinal Chemistry Lab, Department of Biosciences, Jamia Millia Islamia (A Central Lumefantrine University), Jamia Nagar, New Delhi 110025, India bProtein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Fig. 1 Structure of commonly used antimalarial drugs Islamia (A Central University), Jamia Nagar, New Delhi 110025, India [email protected]; (Phone):- +91-8750295095; (Fax): +91-11-26980229 2 | J. Name ., 2012, 00 , 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 50 PleaseRSC do not Advances adjust margins Journal Name ARTICLE Target insights of antimalarial inhibitors Drug targets which have been identified and characterized Inhibiting either of these may prove lethal to the parasite thus against malaria can be classified on the basis of their locations targeting these enzymes will be a powerful strategy in the malaria within the malaria parasite. The enzymes that are crucial for parasite eradication campaign. The key targets and their inhibitors along with growth and survival are the strategic targets of these inhibitors. their locations in the parasite are summarised in Table 1. Table 1 Antimalarial drug targets and their inhibitors along with their location in P. falciparum Target Pathway/ mechanism Target enzyme Inhibitors References location Parasite Merozoite invasion Apical membrane antigen 1(AMA1) N-methylated 20-residue peptide, R1 198 invasion and release Merozoite egress Subtilisin-like protease 1 ( Pf SUB1) Chloroisocoumarin JCP104, 199 difluorostatone based inhibitors 20 Food vacuole Hemoglobin Plasmepsin (PM) Allophenylnorstatine-based inhibitor 42 degradation Falcipain (FP) Cyanopyrimidine based analogues 45 Aminopeptidase Bestatin analogues, phosphonic acid 88, 89, 91 arginine mimetics, hydroxamate derivatives Dipeptidyl aminopeptidase (DPAP) Dipeptide based analogues 94 Manuscript Nucleus Nucleic acid regulation Histone deacetylase (HDAC) Apicidin, WR301801, 200, 201 aryltriazolylhydroxamates based 98 derivatives Cyclin dependent protein kinase Oxindole derivatives 202 (CDK) Mitochondria Electron transport Cytochrome bc 1 complex ELQ-300 113 system Dihydroorotate dehydrogenase Phenyl-substituted triazolopyrimidines 121 (DHODH) NADH: ubiquinone oxidoreductase SL-2-25 134 (Pf NDH2) Accepted Apicoplast Type II fatty acid Pf FabZ NAS91 203 biosynthesis Pf FabI Coumarin-based triclosan analogues 142 Pf FabG (-)-catechin gallate 204 Isoprenoid biosynthesis DOXP reductoisomerase (DXR) Fosmidomycin, FR-900098 150 Protein myristoylation N-myristoyltransferase (NMT) Benzo[ b]thiophene derivatives 159
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