Antimetaboliten des Coenzyms Q. Möglichkeiten ihrer Anwendung als Antimalaria‐Mittel

Porter, Thomas H.; Folkers, Karl

doi:10.1002/ange.19740861705

Cited by 12 publications

(5 citation statements)

References 41 publications

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“…P. vivax infections could be cured in single patients, but only by parenteral application of high doses. [291] The availability of the cheap and effective chloroquine (8) during that time resulted in a lack of interest in this class of compounds. With the occurrence of chloroquine resistance, interest in hydroxynaphthoquinones was renewed in the 1960s.…”

Section: Development Of 2-hydroxynaphthoquinonesmentioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

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Section: Development Of 2-hydroxynaphthoquinonesmentioning

confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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“…2.3-Dimethoxy-5-methyl-4-pyridinol (5). The 4-aminopyridine 17 (895 mg, 5.33 mmol), dissolved in 30 mL of 6 N H2SO4, was diazotized at 0 °C with sodium nitrite (387 mg, 5.6 mmol) in 3.5 mL of water.…”

Section: Experimental Section22mentioning

confidence: 99%

“…4-Benzyloxy-2,3-dimethoxy-5-methylpyridine (18). The 4-pyridinol 5 (148 mg, 0.877 mmol) and O-benzyldiisopropylurea (217 mg, 0.92 mmol) were mixed and kept at 110 °C for 2 h, 2 mL of CCI4 was then added, the mixture was filtered, and the product was isolated from the filtrate by preparative TLC (III). Distillation (Kugelrohr, 100 °C (0.5 Torr)) gave 18 as an oil: yield 160 mg, 0.63 mmol, 71%; NMR 2.03 (s, C-5 CH3), 3.83 (s, C-3 OCH3), 3.95 (s, C-2 OCH3), 4.83 (s, CH2Ar), 7.39 (s, C6H5), 7.65 (s, C-6 H).…”

Section: Experimental Section22mentioning

confidence: 99%

“…4 It is also suggestive of a potential as an antimalarial, along with other antimetabolites of coenzyme Q. 5 Piericidin is highly toxic2-3 and this property has restricted its broader application. Thus we have undertaken the synthesis of piericidin relatives in which the coenzyme Q antagonist activity is retained and the toxicity decreased.…”

mentioning

confidence: 99%

“…Nuclei of the 4-hydroxy-2-pyridone (3) type were to be avoided at all stages to circumvent any tautomeric ambiguity and possible isomeric mixtures. Thus our specific objectives became 2,3-dimethoxy-5,6-dimethyl-4-pyridinol (4) and 2,3-dimethoxy-5-methyl-4-pyridinol (5). The former offered the potential of 3 4 5 adding the side chain via a carbanionic or otherwise functionalized intermediate derived from the acidic hydrogens of the -methyl group; the latter, via its 6-halo and 6-metallo derivative, offered the possibility of attaching the side chain by coupling with the necessary allylic bromide, a procedure which has given excellent yields in the synthesis of menaquinones.…”

mentioning

confidence: 99%

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Polyprenylpyridinols. Synthesis of piericidin analogs

Schmidtchen¹,

Rapoport²

1977

J. Am. Chem. Soc.

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Piericidin A, isolated from S. mobaraensis, is a specific antagonist of coenzyme Q. Its unusual structure consists of a 2,3-dimethoxy-5-methyl-4-pyridinol nucleus with a polyunsaturated side chain at C-6. We have prepared this nucleus and attached conventional polyprenyl side chains for structure-activity studies on coenzyme Q inhibitors. To prepare the nucleus, 3-methoxyacetylamino-2-methylacrylonitrile was cyclized to a 4-amino-2-pyridone which trimethyloxonium fluoroborate converted to the 4-amino-2,3-dimethoxypyridine. Bromination of the acylated amine formed the 6-bromo derivative in which the 4-amino was then replaced by hydroxy and the latter blocked by conversion to its benzyl ether with a benzylisourea. Transmetalation now gave the 6-lithio compound which was coupled with various prenyl bromides, leading to introduction of all trans polyprenyl side chains. The final 4-pyridinols were formed on selective debenzylation with butyl mercaptide. All the polyprenylpyridinols inhibited coenzyme Q electron transport to some extent, with the farnesyl analogue having the same activity as piericidin A.Piericidin A is a powerful insecticidal and antimicrobial principle isolated, along with piericidin B, from the soil microorganism Streptomyces mobaraensis. Its structure and stereochemistry have been established as all-trans-2,3-dimethoxy-5-methyl-6-[ lO(S)-hydroxy-3,7,8,9(S), 1 l-pentamethyl-2,5,7,11 -tridecatetraenyl]-4-pyridinol (la), and piericidin B is the corresponding methyl ether lb.3The striking structural resemblance between piericidin A (as its pyridone tautomer) and coenzymes Q (ubiquinones, 2) suggested that piericidin might be acting as a coenzyme Q antagonist. This has been confirmed by the finding that piericidin is a specific and potent inhibitor to coenzyme Q in the mitochondrial electron transport chain.4 It is also suggestive of a potential as an antimalarial, along with other antimetabolites of coenzyme Q.5Piericidin is highly t o x i~~,~ and this property has restricted its broader application. Thus we have undertaken the synthesis of piericidin relatives in which the coenzyme Q antagonist activity is retained and the toxicity decreased. In considering candidate structures, we determined to retain the 4-pyridinol (or 4-pyridone) portion of the molecule since this moiety seems to mimic the quinone structurally without its parallel oxidation-reduction properties. For the unusual side chain, we proposed to substitute prenyl units of various lengths which would reflect exactly the side chains in the naturally occurring, biologically active quinones.Our synthetic strategy then focused primarily on the unusual pyridine nucleus with its three contiguous oxygen atoms, two present as methyl ethers and one as an OH group. Nuclei of the 4-hydroxy-2-pyridone (3) type were to be avoided a t all stages to circumvent any tautomeric ambiguity and possible isomeric mixtures. Thus our specific objectives became 2,3-dimethoxy-5,6-dimethyl-4-pyridinol (4) and 2,3-dimethoxy-5-methyl-4-pyridinol ( 5 ) . The former off...

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ChemInform Abstract: ANTIMETABOLITEN DES COENZYMS Q, MOEGLICHKEITEN IHRER ANWENDUNG ALS ANTIMALARIA-MITTEL

Porter¹,

Folkers²

1974

Chemischer Informationsdienst

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Antimetaboliten des Coenzyms Q. Möglichkeiten ihrer Anwendung als Antimalaria‐Mittel

Cited by 12 publications

References 41 publications

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Polyprenylpyridinols. Synthesis of piericidin analogs

ChemInform Abstract: ANTIMETABOLITEN DES COENZYMS Q, MOEGLICHKEITEN IHRER ANWENDUNG ALS ANTIMALARIA-MITTEL

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