ChemInform Abstract: SPIROCYCLIC MEISENHEIMER COMPLEXES. V. INTRAMOLECULAR MEISENHEIMER 1,2‐COMPLEX FROM 1‐(β‐HYDROXYETHOXY)‐3,5‐DINITROBENZENE

Knyazev, V. N.; Drozd, V. N.; Klimov, A. A.

doi:10.1002/chin.197711231

Cited by 1 publication

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“…13 1-Bromo-3-methoxy-5-nitrobenzene (7). 17 To the solution of compound 6 (12 g, 48.6 mmol) in dry methanol (120 mL) was added sodium methoxide (3.24 g, 60 mmol). The mixture was boiled for 2 h and allowed to cool to room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…The crude product was purified by flash column chromatography on silica gel, eluting with a gradient of 2% ethyl acetate in hexane followed by 10-12% ethyl acetate in hexane to yield 9.25 g (82%) of 7 as a white solid, mp 86.9 °C (lit., 87.5 °C). 17 4′-Chloro-5-methoxy-3-nitro-biphenyl (8a). Method A.…”

Section: Methodsmentioning

confidence: 99%

“…Organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuum . The crude product was purified by flash column chromatography on silica gel, eluting with a gradient of 2% ethyl acetate in hexane followed by 10−12% ethyl acetate in hexane to yield 9.25 g (82%) of 7 as a white solid, mp 86.9 °C (lit., 87.5 °C) …”

Section: Methodsmentioning

confidence: 99%

“…16 3-Bromo-5-nitroanisole ( 7) was obtained by treatment of 6 with sodium methoxide in absolute methanol. 17 The coupling of bromoanisole 7 with the 4-chlorophenylboronic acid was achieved using a modified Suzuki method to afford substituted biaryl compound 8a in a good yield. 18 Two types of catalysts were used in the Suzuki coupling reaction to prepare compounds 8a and 8b.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Antimalarial Activity of New Isotebuquine Analogues

et al. 2007

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Amodiaquine (AQ) and tebuquine are 4-aminoquinoline antimalarials with Mannich base side chain and are highly effective against chloroquine (CQ)-resistant strains of Plasmodium falciparum. Clinical use of AQ has been severely restricted due to hepatoxicity and agranulocytosis side effects associated with its long term use. Lysosomal accumulation and bioactivation to generate reactive quinoneimine metabolite are implicated to be the cause of the observed AQ toxicities. To avoid the quinoneimine formation and thus the toxicity, a series of isotebuquine analogues and their N ω -oxides with hydroxy group meta to the amino rather than in para position of the aniline moiety were prepared. The new Mannich bases are highly active against both CQ-sensitive (D6) and -resistant (W2 and TM91C235) clones of P. falciparum with IC 50 in the range of 0.3-120 ng/mL. New compounds are1000-fold less toxic (IC 50 ) 0.7-6 µg/mL) to mouse macrophage cell line than to parasite cell lines. Mono-Mannich bases are more active than bis-Mannich bases. Mono-Mannich base 1a (IC 50 ) 0.3 ng/mL) is 20-fold more active than the corresponding trifluoromethyl analogue 1b. No appreciable difference in either toxicity or efficacy were observed between the new Mannich bases (m-hydroxyaniline derivatives) 1a or 2a and the corresponding p-hydroxyaniline derivatives. IntroductionMalaria is one of the most widespread diseases in many regions of the world, exposing millions of people to risk of infection and death. The 4-aminoquinolines such as chloroquine (CQ) are the most important and widely used class of drugs for treatment of malaria. Chloroquine has been the drug of choice for malaria treatment since the early 1950s, providing effective and safe treatment for millions of Plasmodium falciparum infected patients a year. Development of drug resistance to chloroquine in malaria has become a major health concern in malaria endemic areas, which has prompted a search for alternative antimalarials against the CQ-resistant strains. 1,2 As a result, several new classes of antimalarial drugs were developed; none has reached the same status of recognition as the drug of choice in malaria therapy as CQ.Amodiaquine (AQ), a new Mannich base 4-aminoquinoline, is effective against chloroquine-resistant strains of P. falciparum. 3 However, the clinical use of AQ has been severely restricted because of the hepatoxicity and agranulocytosis side effects associated with its long term use. 4,5 Recent reports indicate that AQ was metabolized by cytochrome P-450 oxidation to form reactive quinoneimine metabolite with subsequent conjugate addition of glutathione or cysteinyl function of the enzymes. 6,7 Lysosomal accumulation and bioactivation of reactive quinoneimine metabolite are implicated to be the cause of the observed AQ in vivo toxicity. 8,9 To avoid the quinoneimine metabolite formation, a series of isoquine and related analogues were reported in the literature. 10-12 Isoquine (IQ) is an analogue of AQ, in which the 4′-hydroxy group on the aniline ring of AQ is int...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%