Synthesis and antimalarial assessment of a new series of orally active amino-functionalized spiro 1,2,4-trioxanes (1)

Journal of Medicinal Chemistry

Volumn 53, Issue 21, 2010, Pages 7587-7598

  Singh, Chandan ^a   Hassam, Mohammad ^a   Naikade, Niraj Krishna ^a   Verma, Ved Prakash ^a   Singh, Ajit Shankar ^a   Puri, Sunil K ^a  

^a CENTRAL DRUG RESEARCH INSTITUTE   (India)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 TRIOXANE DERIVATIVE; ALCOHOL; ANTIMALARIAL AGENT; SPIRO COMPOUND;

AMINATION; ANIMAL EXPERIMENT; ANTIMALARIAL ACTIVITY; ARTICLE; DRUG SYNTHESIS; MOUSE; MULTIDRUG RESISTANCE; NONHUMAN; PLASMODIUM YOELII; REDUCTION; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANILINE COMPOUNDS; ANIMALS; ANTIMALARIALS; DRUG RESISTANCE; HETEROCYCLIC COMPOUNDS, 2-RING; KETONES; MALARIA; MICE; NAPHTHALENES; PARASITIC SENSITIVITY TESTS; PLASMODIUM YOELII; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 78149256497     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100678p     Document Type: Article

References (51)

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46. 6 P. yoelii nigeriensis (MDR) parasites on day zero, and treatment was administered to a group of five mice at each dose, from day 0 to 3, in two divided doses daily. The drug dilutions of compounds 8a - i, 9a - i, 10a - i, and 11a - i were prepared in groundnut oil so as to contain the required amount of the drug (1.2 mg for a dose of 96 mg/kg, 0.6 mg for a dose of 48 mg/kg, 0.3 mg for a dose of 24 mg/kg, and 0.15 mg for a dose of 12 mg/kg) in 0.1 mL and administered orally for each dose. Parasitaemia level were recorded from thin blood smears on day 4 and subsequently twice a week until day 28. The animals which did not develop patent infection until day 28 were recorded as cured. (13) Mice treated with β-arteether served as positive control.
47. 100% protection means none of the treated mice developed patent infection during the 28 days observation period and hence were recorded as cured. Similarly, 20% protection means only one out of five mice was cured.
48. 100% suppression of parasitemia means no parasites were detected in 50 oil immersion microscopic fields (parasites if at all present are below the detection limit). The parasites present below the detection limit can multiply and eventually can be detected during observation on subsequent days. In such cases, though, the drug is providing near 100% suppression of the parasitaemia on day 4 but will not provide full protection to the treated mice in the 28 day survival assay. Multidrug-resistant Plasmodium yoelii nigeriensis used in this study is resistant to chloroquine, mefloquine, and halofantrine.
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50. The fact that both the diastereomers are equipotent could be a coincidence, as in another series of structurally related amino-trioxanes we have observed, that while some of the pairs of diastereomers show similar level of activity, others show significant difference. (15)
51. Malik, H. Ph. D. Thesis. Jawaharlal Nehru University, New Delhi, 2005.