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

Beteck, Richard M.; Coertzen, Dina; Smit, Frans J.; Birkholtz, Lyn‐Marié; Haynes, Richard K.; N’Da, David D.

doi:10.1016/j.bmcl.2016.05.024

Cited by 16 publications

(21 citation statements)

References 26 publications

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“…As part of a large-scale international interdisciplinary research program involving the design and development of new triple-drug combinations for the treatment of malaria, tuberculosis, and toxoplasmosis, we are evaluating the utility of combinations of oxidant (16)(17)(18) and redox (or pro-oxidant) drugs (19)(20)(21) coupled with a third partner drug with a different mechanism of action. The third partner drug being considered in the first instance incorporates a 4(1H)-quinolone scaffold (22). Quinolones are used clinically for the treatment of tuberculosis (23); selected examples have acquired lead status as antimalarial drugs (24)(25)(26) and display potent dual target effects when combined with the appropriate drug partner (25).…”

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confidence: 99%

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

Coertzen

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Watt

et al. 2018

Antimicrob Agents Chemother

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The emergence of resistance toward artemisinin combination therapies (ACTs) by the malaria parasite 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 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.

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

Coertzen

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Watt

et al. 2018

Antimicrob Agents Chemother

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“…Here we describe the conversion of the ethyl ester unit in DQ into more polar alkoxy esters and less readily metabolized amides 16,[36][37][38] , and attach groups to the quinolone nucleus at N-1 or O-4. In the last case, we focus here on carbamate derivatives: the role of carbamates in enhancing bioavailability of drugs is established 39,40 .…”

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

et al. 2018

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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 MIC 90 values ranging from 1.4 to 3.64 µM, and quinoline O-carbamates active against apicomplexan parasites that cause malaria, toxoplasmosis, and neosporosis with IC 50 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 IC 50 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.

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“…The starting quinolones 2 were synthesized from the synthetically accessible compounds 1 as previously described in literature. 34…”

Section: General Methodsmentioning

confidence: 99%

“…), DBU (320 µL, 0.33 g, 2.1 mmol), an appropriate amine (5 eq. ), and chloroform (15 mL) in a 100 mL round-bottom flask was stirred under reflux for 24-30 h. 34 Upon reaction completion as indicated by TLC, the mixture was evaporated to dryness and resultant crude subjected to silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (10:1). Fractions containing the desired product were combined, evaporated to dryness and recrystallized from ethanol.…”

Section: General Methods For the Preparation Of Amides 4a-jmentioning

confidence: 99%

Synthesis, in vitro Cytotoxicity and Trypanocidal Evaluation of Novel 1,3,6-Substituted Non-fluoroquinolones

Beteck¹,

Isaacs²,

Hoppe³

et al. 2018

S.Afr.j.chem.

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Sleeping sickness (trypanosomiasis) is a neglected tropical disease that affects mostly the poorest communities in sub-Saharan Africa. Toxic side effects associated with the use of current anti-trypanosomal drugs, which in some cases kill faster than the disease itself, necessitate the search for new drugs with better safety margins. To this effect, a small library bearing different substituents at position-1,-3, and-6 of the quinolone nucleus were synthesized and evaluated in vitro against HeLa cell lines and Trypanosoma brucei brucei for cytotoxicity and trypanocidal potentials, respectively. While most of these compounds showed no cytotoxic effect, they exhibited moderate to weak anti-trypanosomal activities. The SAR studies of this series provide new information worth considering in future exploration of the quinolone scaffold in search of more potent and safe trypanocidal agents.

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

Cited by 16 publications

References 26 publications

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

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

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

Synthesis, in vitro Cytotoxicity and Trypanocidal Evaluation of Novel 1,3,6-Substituted Non-fluoroquinolones

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