Class Of Antimalarials Research Articles

Design, synthesis and biological evaluation of functionalized phthalimides: A new class of antimalarials and inhibitors of falcipain-2, a major hemoglobinase of malaria parasite

Phthalimides functionalized with cyclic amines were synthesized, characterized and screened for their in vitro antimalarial efficacy against Plasmodium falciparum (Pf3D7). Of all the listed phthalimides evaluated, 14 and 24 were identified as potent antimalarial agents as advocated by assessment of their ability to inhibit [3H] hypoxanthine incorporation in the nucleic acid of parasites. In addition, phthalimides 14 and 24 were incubated for 60 and 90h and an enhanced antimalarial effect was noticed with increase in time to great extent. A reduction in IC50 values was observed with increase in exposure time of the parasite to the compounds. A symmetric phthalimide, 24 possessing piperazine as linker unit was identified as the most potent antimalarial agent with IC50 values of 5.97±0.78, 2.0±1.09 and 1.1±0.75μM on incubation period of 42, 60 and 90h, respectively. The abnormal morphologies such as delay in developmental stages, growth arrest and condensed nuclei of parasite were observed with the aid of microscopic studies upon exposure with 14 and 24. The evaluation of 14 and 24 against chloroquine resistant strain, (Pf7GB) of P. falciparum afforded IC50 values, 13.29±1.20 and 7.21±0.98μM, respectively. The combination of 24 with artemisinin (ART) showed enhanced killing of parasite against Pf3D7. Further, all phthalimides were evaluated for their activity against falcipain-2 (FP2), a major hemoglobinase of malarial parasite. The enzymatic assay afforded 6 as most active member against FP2. To the best of our knowledge this is the initial study represents phthalimide protected amino acids functionalized with cyclic amines as potent antimalarial agents.

Molecular modelling based target identification for endo-peroxides class of antimalarials.

The emerging cases of artemisinin and endoperoxide drug resistance are becoming a challenge to antimalarial drug discovery and therapy. The exact mode of action of this class of antimalarials is still unknown which presents a bottleneck for the understanding of drug resistance as well as designing new lead molecules of this class. To address this issue, the molecular docking and scoring studies of a homogeneous and structurally diverse dataset of artemisinin derived trioxanes have been performed on each of the two plausible targets of this class viz. heme and PfATP6. Since the crystal structure of PfATP6 is unknown, its homology model was built utilizing the human SERCA1 protein crystallized structure as a template. The binding energies of the heme binding site of the docked artemisinin derivatives showed very good correlation with the antimalarial activity (r(2) = 0.69), whereas the same study with the binding site of pfATP6 showed a very poor correlation (r(2) = 0.12), suggesting heme to be the possible target of artemisinin derived endoperoxides.

Salinipostins A-K, long-chain bicyclic phosphotriesters as a potent and selective antimalarial chemotype.

Despite significant advances in antimalarial chemotherapy over the past 30 years, development of resistance to frontline drugs remains a significant challenge that limits efforts to eradicate the disease. We now report the discovery of a new class of antimalarials, salinipostins A-K, with low nanomolar potencies and high selectivity indices against mammalian cells (salinipostin A: Plasmodium falciparum EC50 50 nM, HEK293T cytotoxicity EC50 > 50 μM). These compounds were isolated from a marine-derived Salinospora sp. bacterium and contain a bicyclic phosphotriester core structure, which is a rare motif among natural products. This scaffold differs significantly from the structures of known antimalarial compounds and represents a new lead structure for the development of therapeutic targets in malaria. Examination of the growth stage specificity of salinipostin A indicates that it exhibits growth stage-specific effects that differ from compounds that inhibit heme polymerization, while resistance selection experiments were unable to identify parasite populations that exhibited significant resistance against this compound class.

Fixed drug eruption at a dermatology clinic in Lagos, Nigeria

Background: Fixed drug eruption (FDE) is common cutaneous drug eruption characterized by the development of one or more annular, oval, erythematous, and hyperpigmented patches as a result of systemic exposure to a drug. Drugs causing FDE vary with prevailing diseases and prescription pattern in different parts of the world. This study is aimed at reviewing cases of FDE seen at the dermatology outpatient clinic of Lagos University Teaching Hospital (LUTH) over a 9-year period, highlighting the spectrum of drugs implicated and the clinical characteristics. Materials and Methods: Data were obtained from the clinic records and patients' case notes. These included the demographic details, duration of presentation, drugs implicated, and clinical characteristics. Results: FDE was diagnosed in 1.8% (295/16,160) of patients seen. There was a slight female preponderance. Antimalarials were the commonest group of medications implicated (51.0%) followed by antibiotics (27.9%); analgesics (10.2%), herbal toothpaste (6.1%), and oral hypoglycemic agents (4.1%). Sulfonamides were the commonest group of drugs found in 78 patients (53.1%) predominantly as sulfadoxine/pyrimethamine antimalarials and trimethoprim/sulfamethoxazole antibiotics (co-trimoxazole). Conclusion: Concerted efforts are needed to discourage over-the-counter sales and purchase of nonprescription sulfonamide-based medications. A change in prescription pattern from sulfonamides to other classes of antimalarials and antibiotics is desirable and/or recommended. Patients should inform their caregivers at any point of care about their reaction to drugs. It is advised that they have a list of common implicating drugs and they wear a medic alert or carry an ID card bearing this information.

Antimicrobial peptides: a new class of antimalarial drugs?

A range of antimicrobial peptides (AMP) exhibit activity on malaria parasites, Plasmodium spp., in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity, and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs.

Crystal structure and solution characterization of the thioredoxin-2 from Plasmodium falciparum, a constituent of an essential parasitic protein export complex

Survival of the malaria parasite Plasmodium falciparum when it infects red blood cells depends upon its ability to export hundreds of its proteins beyond an encasing vacuole. Protein export is mediated by a parasite-derived protein complex, the Plasmodium translocon of exported proteins (PTEX), and requires unfolding of the different cargos prior to their translocation across the vacuolar membrane. Unfolding is performed by the AAA+protein unfoldase HSP101/ClpB2 and the thioredoxin-2 enzyme (TRX2). Protein trafficking is dramatically impaired in parasites with defective HSP101 or lacking TRX2. These two PTEX subunits drive export and are targets for the design of a novel class of antimalarials: protein export inhibitors. To rationalize inhibitor design, we solved the crystal structure of Pfal-TRX2 at 2.2-Å resolution. Within the asymmetric unit, the three different copies of this protein disulfide reductase sample its two redox catalytic states. Size exclusion chromatography and small-angle X-ray scattering (SAXS) analyses demonstrate that Pfal-TRX2 is monomeric in solution. A non-conserved N-terminal extension precedes the canonical thioredoxin-fold; although it is not observed in our structure, our solution analysis suggests it is flexible in contrast to Plasmodium thioredoxin-1. This represents a first step towards the reconstitution of the entire PTEX for mechanistic and structural studies.

PfalDB: an integrated drug target and chemical database for Plasmodium falciparum.

Plasmodium falciparum is one of the deadliest protozoan parasite species among those that cause malaria. Uncontrolled use of antimalarial drugs has resulted in evolutionary selection pressure favoring high levels of resistance to antimalarials; currently P.falciparum shows resistance to all classes of antimalarials. Therefore it is essential to identify novel drug targets, and design selective anti-malarials which can overcome resistance. While many drug targets are freely available in various public domain resources, a single comprehensive source of data containing easily searchable and retrievable information is currently lacking. To facilitate the total integration and mining of data emerging from different drug consortia and also to prioritize drug targets for structure-based drug design, an open-access, inclusive comprehensive database for Plasmodium falciparum was established. Meta data of known/modeled structures along with binding site parameters of drug targets have been included in the database. Additionally, chemical compounds showing a positive inhibitory assay against Plasmodium falciparum or known drug targets have also been provided. The database is accessible at http://pfaldb.jnu.ac.in. The database provides diverse information regarding the structure, sequence, stage specific gene expression, pathway, action mechanism, essentiality and druggability for each drug target, and literature to assess the validation status of individual drug targets. It also includes information on individual anti-malarials with their activity and bioassay.

Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials.

Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target.

Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Malaria in Children in Zaire and Uíge Provinces, Angola

The development of resistance to antimalarials is a major challenge for global malaria control. Artemisinin-based combination therapies, the newest class of antimalarials, are used worldwide but there have been reports of artemisinin resistance in Southeast Asia. In February through May 2013, we conducted open-label, nonrandomized therapeutic efficacy studies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in Zaire and Uíge Provinces in northern Angola. The parasitological and clinical responses to treatment in children with uncomplicated Plasmodium falciparum monoinfection were measured over 28 days, and the main outcome was a PCR-corrected adequate clinical and parasitological response (ACPR) proportion on day 28. Parasites from treatment failures were analyzed for the presence of putative molecular markers of resistance to lumefantrine and artemisinins, including the recently identified mutations in the K13 propeller gene. In the 320 children finishing the study, 25 treatment failures were observed: 24 in the AL arms and 1 in the DP arm. The PCR-corrected ACPR proportions on day 28 for AL were 88% (95% confidence interval [CI], 78 to 95%) in Zaire and 97% (91 to 100%) in Uíge. For DP, the proportions were 100% (95 to 100%) in Zaire, and 100% (96 to 100%) in Uíge. None of the treatment failures had molecular evidence of artemisinin resistance. In contrast, 91% of AL late-treatment failures had markers associated with lumefantrine resistance on the day of failure. The absence of molecular markers for artemisinin resistance and the observed efficacies of both drug combinations suggest no evidence of artemisinin resistance in northern Angola. There is evidence of increased lumefantrine resistance in Zaire, which should continue to be monitored.

Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence

Artemisinin derivatives are the mainstay of antimalarial treatment, both for uncomplicated malaria and for severe disease. Artemisinins are known for their rapid onset of action, good tolerability, and safety. However, besides the sporadic but worrying reports of delayed parasite clearance after treatment with artemisinins, there have been an increasing number of reports of acute haemolytic anaemia following their use and the safety of this class of antimalarials is being questioned. In this systematic review, all reports of patients experiencing haemolysis following the use of artemisinins for the treatment of malaria were identified and collated into an electronic database. Summary statistics were calculated to characterize the epidemiology and clinical features of this safety concern related to artemisinin derivatives. A total of 37 patients were identified suffering from haemolysis following the treatment of severe malaria with artemisinin derivatives. Thirty-one cases had received intravenous artesunate, while the remaining cases were attributed to other parenteral or oral regimens of artemisinin derivatives. The majority of patients were returning travellers (n=30), and six clinical cases had been reported in paediatric patients. The median onset of haemolysis was 15 (interquartile range (IQR) 13-15) days after the initiation of treatment for the 'delayed-onset' pattern and 17 (IQR 13-22) days for the 'persistent' haemolysis pattern. The median reduction in haemoglobin due to haemolysis was 6 g/dl (IQR 4-8 g/dl). The estimated proportion of patients suffering from severe malaria experiencing haemolysis after treatment with artemisinin derivatives was 13% (95% confidence interval 9-18%), and 73% of these (i.e., 9% of the total population) required blood transfusions. No fatal outcome has been reported in the literature to date. Haemolysis is commonly associated with the class of artemisinin drugs when used for the treatment of severe malaria. Potential causes of this safety issue are discussed. Although no deaths attributed to haemolysis have been reported so far, this safety issue may lead to life-threatening anaemia and is particularly worrying for regions where safe blood products are not readily available.

An analysis of the sponge Acanthostrongylophora igens' microbiome yields an actinomycete that produces the natural product manzamine A.

Sponges have generated significant interest as a source of bioactive and elaborate secondary metabolites that hold promise for the development of novel therapeutics for the control of an array of human diseases. However, research and development of marine natural products can often be hampered by the difficulty associated with obtaining a stable and sustainable production source. Herein we report the first successful characterization and utilization of the microbiome of a marine invertebrate to identify a sustainable production source for an important natural product scaffold. Through molecular-microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, we provide the first report of a sponge-associated bacterium (Micromonospora sp.) that produces the manzamine class of antimalarials from the Indo-Pacific sponge Acanthostrongylophora ingens (Thiele, 1899) (Class Demospongiae, Order Haplosclerida, Family Petrosiidae). These findings suggest that a general strategy of analysis of the macroorganism's microbiome could significantly transform the field of natural products drug discovery by gaining access to not only novel drug leads, but the potential for sustainable production sources and biosynthetic genes at the same time.

Cytotoxic effect of carotenoid phytonutrient lycopene on P. falciparum infected erythrocytes

Resistance to almost all class of antimalarial drugs has emerged as one of the greatest challenges to malaria control. Strategies to limit the advent and spread of drug-resistant malaria include development of new drugs and its combination with existing drugs. In this work we provide a strong evidence for phytonutrient lycopene, a non-provitamin A carotenoid, to be effective against Plasmodium falciparum growth in vitro. Consistent with the previous findings in mammalian cells, lycopene's prooxidant activity promoted the production of reactive oxygen species (ROS) in P. falciparum. Also a significant loss of mitochondrial functionality and thus, the loss of the membrane potential was observed in lycopene treated schizonts. Taken together, our results indicated that the generation of ROS and loss of mitochondrial membrane potential accounted for lycopene's cytotoxicity against P. falciparum growth in vitro. These insights will help in the design of new treatment strategies to combat malaria.

In vitro and in vivo antimalarial activity of amphiphilic naphthothiazolium salts with amine-bearing side chains.

Because of emerging resistance to existing drugs, new chemical classes of antimalarial drugs are urgently needed. We have rationally designed a library of compounds that were predicted to accumulate in the digestive vacuole and then decrystallize hemozoin by breaking the iron carboxylate bond in hemozoin. We report the synthesis of 16 naphthothiazolium salts with amine-bearing side chains and their activities against the erythrocytic stage of Plasmodium falciparum in vitro. KSWI-855, the compound with the highest efficacy against the asexual stages of P. falciparum in vitro, also had in vitro activity against P. falciparum gametocytes and in vivo activity against P. berghei in a murine malaria model.

Improving access to malaria medicine through private-sector subsidies in seven African countries.

Improving access to quality-assured artemisinin combination therapies (ACTs) is an important component of malaria control in low- and middle-income countries. In 2010 the Global Fund to Fight AIDS, Tuberculosis, and Malaria launched the Affordable Medicines Facility--malaria (AMFm) program in seven African countries. The goal of the program was to decrease malaria morbidity and delay drug resistance by increasing the use of ACTs, primarily through subsidies intended to reduce costs. We collected data on price and retail markups on antimalarial medicines from 19,625 private for-profit retail outlets before and 6-15 months after the program's implementation. We found that in six of the AMFm pilot programs, prices for quality-assured ACTs decreased by US$1.28-$4.34, and absolute retail markups on these therapies decreased by US$0.31-$1.03. Prices and markups on other classes of antimalarials also changed during the evaluation period, but not to the same extent. In all but two of the pilot programs, we found evidence that prices could fall further without suppliers' losing money. Thus, concerns may be warranted that wholesalers and retailers are capturing subsidies instead of passing them on to consumers. These findings demonstrate that supranational subsidies can dramatically reduce retail prices of health commodities and that recommended retail prices communicated to a wide audience may be an effective mechanism for controlling the market power of private-sector antimalarial retailers and wholesalers.

In vitro antiplasmodial activity of cepharanthine.

BackgroundNew classes of anti-malarial drugs are needed to control the alarming Plasmodium falciparum resistance toward current anti-malarial therapy. The ethnopharmacological approach allows the discovery of original chemical structures from the vegetable biodiversity. Previous studies led to the selection of a bisbenzylisoquinoline, called cepharanthine and isolated from a Cambodian plant: Stephania rotunda. Cepharanthine could exert a mechanism of action different from commonly used drugs. Potential plasmodial targets are reported here.MethodsTo study the mechanism of action of cepharanthine, a combined approach using phenotypic and transcriptomic techniques was undertaken.ResultsCepharanthine blocked P. falciparum development in ring stage. On a culture of synchronized ring stage, the comparisons of expression profiles showed that the samples treated with 5 μM of cepharanthine (IC90) were significantly closer to the initial controls than to the final ones. After a two-way ANOVA (p-value < 0.05) on the microarray results, 1,141 probes among 9,722 presented a significant differential expression.A gene ontology analysis showed that the Maurer’s clefts seem particularly down-regulated by cepharanthine. The analysis of metabolic pathways showed an impact on cell-cell interactions (cytoadherence and rosetting), glycolysis and isoprenoid pathways. Organellar functions, more particularly constituted by apicoplast and mitochondrion, are targeted too.ConclusionThe blockage at the ring stage by cepharanthine is described for the first time. Transcriptomic approach confirmed that cepharanthine might have a potential innovative antiplasmodial mechanism of action. Thus, cepharanthine might play an ongoing role in the progress on anti-malarial drug discovery efforts.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-327) contains supplementary material, which is available to authorized users.

Exploring prodrug approaches for albitiazolium and its analogues.

Choline analogues such as bis-thiazolium salts are thought to inhibit choline transport into Plasmodium-infected erythrocytes, thus preventing parasite PC biosynthesis, and also to interact with plasmodial haemoglobin degradation in the food vacuole. This new and multiple mode of action is a major asset of these new class of antimalarials, as they could help delay resistance development. We synthesized and designed various sets of analogues, notably prodrugs, since the oral bioavailability of bis-thiazolium salts is relatively low. The chemistry underlying this synthesis relies on inexpensive and readily available starting materials and is straightforward. This is essential since the ultimate objective is to obtain affordable and orally available drugs for uncomplicated malaria treatment.

Overcoming drug-resistant malaria through rational drug design in cytochrome bc1

Over three billion people live in regions affected by malaria and there are over one million deaths each year [1]. Malaria is caused by the Plasmodium parasite and various drugs are currently used in both treatment and prophylaxis but resistant strains are rapidly emerging. One of the most commonly used anti-malarial drugs is Atovaquone, a hydroxynapthoquinone that is currently used in combination with Proguanil and sold as Malarone™. Atovaquone targets cytochrome bc1 (Complex III, ubiquinol-cytochrome c oxidoreductase), a multi subunit electron transfer protein complex embedded in the inner mitochondrial membrane [2]. Drug resistance rises through a single point mutation in cytochrome b at the Qo site, one of two quinone binding sites. By visualising compounds bound to cytochrome bc1 through x-ray crystallography, it may be possible to modify the compounds to both bind stronger and more specifically. We have worked on compounds that recently failed phase I clinical trials due to cross-reactivity with human cytochrome bc1 [3]. Our structural studies have shown that these compounds appear to bind at the Qi site, which would overcome current drug-resistant strains. Further work here could produce a novel class of anti-malarial drug.

Identification of inhibitors of Plasmodium falciparum RuvB1 helicase using biochemical assays.

Human malaria is a major parasitic infection, and the situation has worsened mainly due to the emergence of resistant malaria parasites to several anti-malarial drugs. Thus, an urgent need to find suitable drug targets has led to the development of newer classes of anti-malarial drugs. Helicases have been targeted to develop therapeutics for viral, bacterial, and other microorganism infections. Recently, Plasmodium falciparum RuvB ATPases/helicases have been characterized and proposed as a suitable antimalarial drug target. In the present study, the screening of various compounds was done and the results suggest that PfRuvB1 ATPase activity is inhibited considerably by the novobiocin and partially by cisplatin and ciprofloxacin. Helicase assay of PfRuvB1 in the presence of various compounds suggest novobiocin, actinomycin, and ethidium bromide as potent inhibitors. Novobiocin inhibits the helicase activity of PfRuvB1 possibly by blocking the ATPase activity of PfRuvB1. This study is unique in respect to the identification of novobiocin as inhibitor of PfRuvB1, partially by competing with ATP binding at its active site and provides evidence for PfRuvB1 as target of novobiocin after DNA gyrase-B and HSP90. These studies will certainly help the pharmacologist to design and develop some novel inhibitor specific to PfRuvB1, which may serve as suitable chemotherapeutics to target malaria.

Tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials.

The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.

Design, economical synthesis and antiplasmodial evaluation of vanillin derived allylated chalcones and their marked synergism with artemisinin against chloroquine resistant strains of Plasmodium falciparum

The in vitro blood stage antiplasmodial activity of a series of allylated chalcones based on the licochalcone A as lead molecule was investigated against chloroquine (CQ) sensitive Pf3D7 and CQ resistant PfINDO strains of Plasmodium falciparum using SYBR Green I assay. Of the forty two chalcones tested, eight showed IC50 ≤ 5 μM. Structure–activity relationship (SAR) studies revealed 9 {1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-en-1-yloxy)phenyl]-prop-2-en-1-one} as the most potent (IC50: 2.5 μM) against Pf3D7 with resistance indices of 1.2 and 6.6 against PfDd2 and PfINDO strains, respectively. Later on, the synergistic effects 9 with standard antimalarials {artemisinin (ART) and chloroquine (CQ)} were studied in order to provide the basis for the selection of the best partner drug. In vitro combinations of 9 with ART showed strong synergy against PfINDO (ΣFIC50: 0.31–0.72) but additive to slight antagonistic effects (ΣFIC50: 1.97–2.64) against Pf3D7. ΣFIC50 0.31 of ART+9 combination corresponded to a 320 fold and 3 fold reduction in IC50 of 9 and ART, respectively. Similar combinations of 9 with CQ showed synergy to additivity to mild antagonism against the two strains {ΣFIC50: 0.668–2.269 (PfINDO); 1.45–2.83 (Pf3D7)}. Drug exposure followed by drug withdrawal indicated that 9 taken alone at IC100 killed rings, trophozoites and schizonts of P. falciparum. The combination of ART and 9 (1X ΣFIC100) selectively inhibited the growth of rings while the 2X ΣFIC100 combination of the same caused killing of rings without affecting trophozoites and schizonts. In contrast, the 1X combination of CQ and 9 (ΣFIC100: 0.5) killed rings and trophozoites. DNA fragmentation and loss of mitochondrial membrane potential (ΔΨm) in the 9 treated P. falciparum culture indicated apoptotic death in malaria parasites. Prediction of ADME properties revealed that most of the molecules did not violate Lipinski's parameters and have low TPSA value suggesting good absorption. The results suggest the promising drug-like properties of 9 against CQ resistant Pf and propensity for synergy with classical antimalarial drugs together with easy and economical synthesis.