hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole.

Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 µM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 µM; hERG IC50 = 0.63 µM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 µM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 µM, and liver-stage PbHepG2 IC50 = 2.30 µM), good microsomal metabolic stability (MLM CLint < 11 µL·min-1·mg-1, EH < 0.33), and solubility (150 µM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (log D7.4 = -0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.

Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against Mycobacterium abscessus and Malaria Parasites.

SQ109 is a tuberculosis drug candidate that has high potency against Mycobacterium tuberculosis and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca2+ homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against M. smegmatis, M. tuberculosis, M. abscessus, Bacillus subtilis, and Escherichia coli, as well as against the protozoan parasites Trypanosoma brucei, T. cruzi, Leishmania donovani, L. mexicana, and Plasmodium falciparum. Activity against the mycobacteria was generally less than with SQ109 and was reduced by increasing the size of the alkyl adduct, but two analogs were ∼4-8-fold more active than SQ109 against M. abscessus, including a highly drug-resistant strain harboring an A309P mutation in MmpL3. There was also better activity than found with SQ109 with other bacteria and protozoa. Of particular interest, we found that the adamantyl C-2 ethyl, butyl, phenyl, and benzyl analogs had 4-10× increased activity against P. falciparum asexual blood stages, together with low toxicity to a human HepG2 cell line, making them of interest as new antimalarial drug leads. We also used surface plasmon resonance to investigate the binding of inhibitors to MmpL3 and differential scanning calorimetry to investigate binding to lipid membranes. There was no correlation between MmpL3 binding and M. tuberculosis or M. smegmatis cell activity, suggesting that MmpL3 is not a major target in mycobacteria. However, some of the more active species decreased lipid phase transition temperatures, indicating increased accumulation in membranes, which is expected to lead to enhanced uncoupler activity.

Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and In Vivo Efficacy in a Plasmodium berghei Mouse Malaria Infection Model.

Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 (PfNF54 IC50 = 0.012 µM; PfK1 IC50 = 0.040 µM) displaying high microsomal metabolic stability (HLM CLint < 11.6 µL·min-1·mg-1) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei-infected mice at 4 × 50 mg·kg-1 oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.

The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple Plasmodium kinases and life cycle stages.

Compounds acting on multiple targets are critical to combating antimalarial drug resistance. Here, we report that the human "mammalian target of rapamycin" (mTOR) inhibitor sapanisertib has potent prophylactic liver stage activity, in vitro and in vivo asexual blood stage (ABS) activity, and transmission-blocking activity against the protozoan parasite Plasmodium spp. Chemoproteomics studies revealed multiple potential Plasmodium kinase targets, and potent inhibition of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4Kß) and cyclic guanosine monophosphate-dependent protein kinase (PKG) was confirmed in vitro. Conditional knockdown of PI4Kß in ABS cultures modulated parasite sensitivity to sapanisertib, and laboratory-generated P. falciparum sapanisertib resistance was mediated by mutations in PI4Kß. Parasite metabolomic perturbation profiles associated with sapanisertib and other known PI4Kß and/or PKG inhibitors revealed similarities and differences between chemotypes, potentially caused by sapanisertib targeting multiple parasite kinases. The multistage activity of sapanisertib and its in vivo antimalarial efficacy, coupled with potent inhibition of at least two promising drug targets, provides an opportunity to reposition this pyrazolopyrimidine for malaria.

Antimalarial and antitumour activities of the steroidal quinone-methide celastrol and its combinations with artemiside, artemisone and methylene blue.

Artemisinin, isolated from the traditional Chinese medicinal plant qing hao (Artemisia annua) and its derivatives are used for treatment of malaria. With treatment failures now being recorded for the derivatives and companion drugs used in artemisinin combination therapies new drug combinations are urgently required. The amino-artemisinins artemiside and artemisone display optimal efficacies in vitro against asexual and sexual blood stages of the malaria parasite Plasmodium falciparum and are active against tumour cell lines. In continuing the evolution of combinations of the amino-artemisinins with new drugs, we examine the triterpenoid quinone methide celastrol isolated from the traditional Chinese medicinal plant léi gong téng (Tripterygium wilfordii). This compound is redox active, and has attracted considerable attention because of potent biological activities against manifold targets. We report that celastrol displays good IC50 activities ranging from 0.50-0.82 µM against drug-sensitive and resistant asexual blood stage Pf, and 1.16 and 0.28 µM respectively against immature and late stage Pf NF54 gametocytes. The combinations of celastrol with each of artemisone and methylene blue against asexual blood stage Pf are additive. Given that celastrol displays promising antitumour properties, we examined its activities alone and in combinations with amino-artemisinins against human liver HepG2 and other cell lines. IC50 values of the amino-artemisinins and celastrol against HepG2 cancer cells ranged from 0.55-0.94 µM. Whereas the amino-artemisinins displayed notable selectivities (SI > 171) with respect to normal human hepatocytes, in contrast, celastrol displayed no selectivity (SI < 1). The combinations of celastrol with artemiside or artemisone against HepG2 cells are synergistic. Given the promise of celastrol, judiciously designed formulations or structural modifications are recommended for mitigating its toxicity.

The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside.

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5-2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro.

In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (PfNF54 IC50 = 0.025-0.043 µM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC50 = 0.6 ± 0.1 µM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 µM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.

Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and In Vivo Oral Efficacy Studies.

A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.

Benzimidazole Derivatives Are Potent against Multiple Life Cycle Stages of Plasmodium falciparum Malaria Parasites.

The continued emergence of resistance to front-line antimalarial treatments is of great concern. Therefore, new compounds that potentially have a novel target in various developmental stages of Plasmodium parasites are needed to treat patients and halt the spread of malaria. Here, several benzimidazole derivatives were screened for activity against the symptom-causing intraerythrocytic asexual blood stages and the transmissible gametocyte stages of P. falciparum. Submicromolar activity was obtained for 54 compounds against asexual blood stage parasites with 6 potent at IC50 < 100 nM while not displaying any marked toxicity against mammalian cells. Nanomolar potency was also observed against gametocytes with two compounds active against early stage gametocytes and two compounds active against late-stage gametocytes. The transmission-blocking potential of the latter was confirmed as they could prevent male gamete exflagellation and the lead compound reduced transmission by 72% in an in vivo mosquito feeding model. These compounds therefore have activity against multiple stages of Plasmodium parasites with potential for differential targets.

New Amidated 3,6-Diphenylated Imidazopyridazines with Potent Antiplasmodium Activity Are Dual Inhibitors of Plasmodium Phosphatidylinositol-4-kinase and cGMP-Dependent Protein Kinase.

Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive in vitro activity and in vivo efficacy in mouse models of malaria infection. Herein, we report the synthesis and antiplasmodium evaluation of a new series of amidated analogues and demonstrate that these compounds potently inhibit Plasmodium phosphatidylinositol-4-kinase (PI4K) type IIIß while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) activity in vitro. Using in silico docking, we predict key binding interactions for these analogues within the adenosine triphosphate (ATP)-binding site of PI4K and PKG, paving the way for structure-based optimization of imidazopyridazines targeting both Plasmodium PI4K and PKG. While several derivatives showed low nanomolar antiplasmodium activity (IC50 < 100 nM), some compounds, including piperazine analogue 28, resulted in strong dual PI4K and PKG inhibition. The compounds also demonstrated transmission-blocking potential, evident from their potent inhibition of early- and late-stage gametocytes. Finally, the current compounds generally showed improved aqueous solubility and reduced hERG (human ether-a-go-go-related gene) channel inhibition.

Poly(N-vinylpyrrolidone) Antimalaria Conjugates of Membrane-Disruptive Peptides.

The concepts of polymer-peptide conjugation and self-assembly were applied to antimicrobial peptides (AMPs) in the development of a targeted antimalaria drug delivery construct. This study describes the synthesis of α-acetal, ω-xanthate heterotelechelic poly(N-vinylpyrrolidone) (PVP) via reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization, followed by postpolymerization deprotection to yield α-aldehyde, ω-thiol heterotelechelic PVP. A specific targeting peptide, GSRSKGT, for Plasmodium falciparum-infected erythrocytes was used to sparsely decorate the α-chain ends via reductive amination while cyclic decapeptides from the tyrocidine group were conjugated to the ω-chain end via thiol-ene Michael addition. The resultant constructs were self-assembled into micellar nanoaggregates whose sizes and morphologies were determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro activity and selectivity of the conjugates were evaluated against intraerythrocytic P. falciparum parasites.

Antimalarial N 1,N 3-Dialkyldioxonaphthoimidazoliums: Synthesis, Biological Activity, and Structure-activity Relationships.

Here we report the nanomolar potencies of N 1,N 3-dialkyldioxonaphthoimidazoliums against asexual forms of sensitive and resistant Plasmodium falciparum. Activity was dependent on the presence of the fused quinone-imidazolium entity and lipophilicity imparted by the N1/N3 alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC50 < 1 µM. A representative analog with good solubility, limited PAMPA permeability, and microsomal stability demonstrated oral efficacy on a humanized mouse model of P. falciparum.

Facile Route to Targeted, Biodegradable Polymeric Prodrugs for the Delivery of Combination Therapy for Malaria.

A facile synthetic methodology has been developed to prepare multifaceted polymeric prodrugs that are targeted, biodegradable, and nontoxic, and used for the delivery of combination therapy. This is the first instance of the delivery of the WHO recommended antimalarial combination of lumefantrine (LUM, drug 1) and artemether (AM, drug 2) via a polymeric prodrug. To achieve this, reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization of N-vinylpyrrolidone (NVP) was conducted using a hydroxy-functional RAFT agent, and the resulting polymer was used as the macroinitiator in the ring-opening polymerization (ROP) of α-allylvalerolactone (AVL) to synthesize the biodegradable block copolymer of poly(N-vinylpyrrolidone) and poly(α-allylvalerolactone) (PVP-b-PAVL). The ω-end thiol group of PVP was protected using 2,2'-pyridyldisulfide prior to the ROP, and was conveniently used to bioconjugate a peptidic targeting ligand. To attach LUM, the allyl groups of PVP-b-PAVL underwent oxidation to introduce carboxylic acid groups, which were then esterified with ethylene glycol vinyl ether. Finally, LUM was conjugated to the block copolymer via an acid-labile acetal linkage in a "click"-type reaction, and AM was entrapped within the hydrophobic core of the self-assembled aggregates to render biodegradable multidrug-loaded micelles with targeting ability for combination therapy.

Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies-Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites.

We have demonstrated previously that amino-artemisinins including artemiside and artemisone in which an amino group replaces the oxygen-bearing substituents attached to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether and artesunate, display potent activities in vitro against the asexual blood stages of Plasmodium falciparum (Pf). In particular, the compounds are active against late blood stage Pf gametocytes, and are strongly synergistic in combination with the redox active drug methylene blue. In order to fortify the eventual selection of optimum amino-artemisinins for development into new triple combination therapies also active against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins based on the easily accessible and inexpensive DHA-piperazine. The latter was converted into alkyl- and aryl sulfonamides, ureas and amides. These derivatives were screened together with the comparator drugs DHA and the hitherto most active amino-artemisinins artemiside and artemisone against asexual and sexual blood stages of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins bearing aryl-urea and -amide groups are potently active against both asexual, and late blood stage gametocytes (IC50 0.4-1.0 nM). Although the activities are superior to those of artemiside (IC50 1.5 nM) and artemisone (IC50 42.4 nM), the latter are more active against the liver stage Pb sporozoites (IC50 artemisone 28 nM). In addition, early results indicate these compounds tend not to display reduced susceptibility against parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside and artemisone will enable the development of new combination therapies that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking capabilities and may be effective against artemisinin resistant falciparum malaria.

Synthesis, antimalarial activities and cytotoxicities of amino-artemisinin-1,2-disubstituted ferrocene hybrids.

Artemisinin-ferrocene conjugates incorporating a 1,2-disubstituted ferrocene analogous to that embedded in ferroquine but attached via a piperazine linker to C10 of the artemisinin were prepared from the piperazine artemisinin derivative, and activities were evaluated against asexual blood stages of chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf). The most active was the morpholino derivative 5 with IC50 of 0.86 nM against Pf K1 and 1.4 nM against Pf W2. The resistance indices were superior to those of current clinical artemisinins. Notably, the compounds were active against Pf NF54 early and late blood stage gametocytes - these exerted >86% inhibition at 1 µM against both stages; they are thus appreciably more active than methylene blue (∼57% inhibition at 1 µM) against late stage gametocytes. The data portends transmission blocking activity. Cytotoxicity was determined against human embryonic kidney cells (Hek293), while human malignant melanoma cells (A375) were used to assess their antitumor activity.

Artemisone and Artemiside Are Potent Panreactive Antimalarial Agents That Also Synergize Redox Imbalance in Plasmodium falciparum Transmissible Gametocyte Stages.

The emergence of resistance toward artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, the development of new artemisinins in combination with new drugs that impart activities toward both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular, those of resistant parasites, is urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives toward the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes, in the low-nanomolar range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displayed notable synergism. These data suggest that modulation of redox homeostasis is likely an important druggable process, particularly in gametocytes, and this finding thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.

Synthesis, in vitro antimalarial activities and cytotoxicities of amino-artemisinin-ferrocene derivatives.

Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC50 values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells.

Preliminary Evaluation of Artemisinin-Cholesterol Conjugates as Potential Drugs for the Treatment of Intractable Forms of Malaria and Tuberculosis.

To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin-cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50 ) against Pf drug-sensitive NF54, and drug-resistant K1 and W2 strains ranged from 0.03-2.6, 0.03-1.9, and 0.02-1.7 µm. Although the compounds are less active than the precursor artemisinin derivatives, the cholesterol moiety renders the compounds relatively insoluble in the culture medium, and variation in solubilities among the different compounds may reflect in the range of efficacies observed. Activities against Mtb H37Rv were assessed using a standardized colony-forming unit (CFU) assay after 24 h pretreatment of cultures with each of the compounds. Percentage inhibition ranged from 3-38 % and 18-52 % at 10 and 80 µm, respectively. Thus, in contrast to the comparator drug artemether, the conjugates display enhanced activities. The immediate aims include the preparation of conjugates with enhanced aqueous solubilities, assays against malaria and TB in vivo, and for TB, assays using an infected macrophage model and assessment of granuloma influx.

Activities of 11-Azaartemisinin and N-Sulfonyl Derivatives against Asexual and Transmissible Malaria Parasites.

Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use-artemether and artesunate-induces quiescence in ring-stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11-azaartemisinin 5 and selected N-sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug-sensitive Pf NF54 and drug-resistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC50 values <10.5 nm. The p-trifluoromethylbenzenesulfonyl-11-azaartemisinin derivative 11 [(4'-trifluoromethyl)benzenesulfonylazaartemisinin] was the most active, with IC50 values between 2 and 3 nm. The compounds were screened against Pf NF54 early and transmissible late intraerythrocytic-stage gametocytes using luciferase and parasite lactate dehydrogenase (pLDH) assays. The 2'-thienylsulfonyl derivative 16 (2'-thiophenesulfonylazaartemisinin) was notably active against late-stage (IV-V) gametocytes with an IC50 value of 8.7 nm. All compounds were relatively nontoxic to human fetal lung WI-38 fibroblasts, showing selectivity indices of >2000 toward asexual parasites. Overall, the readily accessible 11-azaartemisinin 5 and the sulfonyl derivatives 11 and 16 represent potential candidates for further development, in particular for transmission blocking of artemisinin-resistant parasites.

Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.

As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones.