David D. N’Da

Synthesis, characterization and antimalarial activity of quinoline–pyrimidine hybrids

The aim of this study was to synthesize a series of quinoline-pyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a two-step nucleophilic substitution process involving quinoline and pyrimidine moieties. They were screened alongside chloroquine (CQ), pyrimethamine (PM) and fixed combinations thereof against the D10 and Dd2 strains of Plasmodium falciparum. The cytotoxicity was determined against the mammalian Chinese Hamster Ovarian cell line. The compounds were all active against both strains. However, hybrid (21) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain, and possessed a moderately superior potency over CQ against the Dd2 strain (IC(50): 0.157 vs 0.417 μM, ∼threefold), and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains.

Recent progress in the development of anti-malarial quinolones

Available anti-malarial tools have over the ten-year period prior to 2012 dramatically reduced the number of fatalities due to malaria from one million to less than six-hundred and thirty thousand. Although fewer people now die from malaria, emerging resistance to the first-line anti-malarial drugs, namely artemisinins in combination with quinolines and arylmethanols, necessitates the urgent development of new anti-malarial drugs to curb the disease. The quinolones are a promising class of compounds, with some demonstrating potent in vitro activity against the malaria parasite. This review summarizes the progress made in the development of potential anti-malarial quinolones since 2008. The efficacy of these compounds against both asexual blood stages and other stages of the malaria parasite, the nature of putative targets, and a comparison of these properties with anti-malarial drugs currently in clinical use, are discussed.

Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids.

Dihydroartemisinin (DHA) was coupled to different aminoquinoline moieties forming hybrids 9-14, which were then treated with oxalic acid to form oxalate salts (9a-14a). Compounds 9a, 10a, 12, 12a, and 14a showed comparable potency in vitro to that of chloroquine (CQ) against the chloroquine sensitive (CQS) strain, and were found to be more potent against the chloroquine resistant CQR strain. Hybrids 12 and its oxalate salt 12a were the most active against CQR strain, being 9- and 7-fold more active than CQ, respectively (17.12 nM; 20.76 nM vs 157.9 nM). An optimum chain length was identified having 2 or 3 Cs with or without an extra methylene substituent.

Antimalarial and anticancer activities of artemisinin-quinoline hybrid-dimers and pharmacokinetic properties in mice

Malaria, one of the three most important life-threatening infectious diseases, is recommended to be treated with ACT (artemisinin combination therapy) against which Plasmodium falciparum already displayed resistance. Two artemisinin-4-amino-quinoline hybrid-dimers (1 and 2), previously synthesized, possessed low nanomolar in vitro antiplasmodial activity, while poorly toxic against mammalian cells. They are here investigated to ascertain whether this antimalarial activity would be carried on in vivo against Plasmodium vinckei. During the four day treatment, parasitemia of less than 1% were observed on day 5 after doses from 2.5 mg/kg ip and 50 mg/kg po for hybrid-dimer 1, and from 7.5 mg/kg ip and 25 mg/kg po for hybrid-dimer 2. Snapshot pharmacokinetic analysis demonstrated that the antiplasmodial activity of these C-10-acetal artemisinin dimers may be due to active metabolites, which were confirmed by in silico findings. Hybrid-dimer 1 also displayed potent in vitro activity against tumor cells and was found to be more active than etoposide against TK10, UACC62 and MCF7 cell lines (TGI values 3.45 vs. 43.33 μM, 2.21 vs. 45.52 μM and 2.99 vs. >100 μM, respectively). The 1,3-diaminopropane linker, present in hybrid-dimer 1, was therefore identified as the optimum linker.

Synthesis, antimalarial activity and cytotoxicity of 10-aminoethylether derivatives of artemisinin

In this study, a series of 11 10-aminoethylether derivatives of artemisinin were synthesised and their antimalarial activity against both the chloroquine sensitive (D10) and resistant (Dd2) strains of Plasmodium falciparum was determined. The compounds were prepared by introducing aliphatic, alicyclic and aromatic amine groups with linkers of various chain lengths through an ethyl ether bridge at C-10 of artemisinin using conventional and microwave assisted syntheses, and their structures were confirmed by NMR and HRMS. All derivatives proved to be active against both strains of the parasite. The highest overall activity was displayed by the short chain aromatic derivative 8 (IC(50)=1.44nM), containing only one nitrogen atom, while long chain polyamine derivatives were found to have the lowest activity against both strains. An interesting correlation between the IC(50), pK(a) values and resistance index (RI) was found.

Antimalarial activity of 10-alkyl/aryl esters and -aminoethylethers of artemisinin.

A series of n-alkyl/aryl esters were synthesized and their in vitro antiplasmodial activity was measured alongside that of previously synthesized aminoethylethers of artemisinin ozonides against various strains of Plasmodium falciparum. The cytotoxicity against human cell lines was also assessed. The esters were synthesized in a one-step reaction by derivatization on carbon C-10 of dihydroartemisinin. Both classes were active against both the 3D7 and K1 strains of P. falciparum, with all compounds being significantly more potent than artemether against both strains. The majority of compounds possessed potency either comparable or more than artesunate with a high degree of selectivity towards the parasitic cells. The 10α-n-propyl 11 and 10α-benzyl 18 esters were the most potent of all synthesized ozonides, possessing a moderate (~3-fold) and significant (22- and 12-fold, respectively) potency increases against the 3D7 and K1 strains, respectively, in comparison with artesunate.

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.

Accessible and distinct decoquinate derivatives active against Mycobacterium tuberculosis and apicomplexan parasites

The quinolone decoquinate is coadministered with feed for treatment of parasites which cause coccidiosis in poultry. However, from a drug-development perspective, the biological activity is often not adequately exploited due to poor physicochemical properties. Here we convert decoquinate into N-alkyl quinolone amides that, in contrast to decoquinate, are active against the tuberculosis bacterium with MIC90 values ranging from 1.4 to 3.64 µM, and quinoline O-carbamates active against apicomplexan parasites that cause malaria, toxoplasmosis, and neosporosis with IC50 values of 0.32–1.5 nM for the best derivative. Uniquely for the TB-active amides, disruption of cell wall homoeostasis is identified as one target. With IC50 values against fetal lung fibroblast cells of 40 to >100 μM, the derivatives are selective for the pathogens. Structures of the most active derivatives are determined by NMR spectroscopy and X-ray crystallography. Analogues lacking the decyl side chain of decoquinate are inactive.Decoquinate is a drug used in veterinary practice, which displays antimalarial activity in vitro but has poor bioavailability. Here, the authors convert decoquinate into more soluble amide and carbamate derivatives and assess their efficacy against tuberculosis bacteria and apicomplexan parasites.