- Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides
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Malaria-causing Plasmodium parasites are developing resistance to antimalarial drugs, providing the impetus for new antiplasmodials. Although pantothenamides show potent antiplasmodial activity, hydrolysis by pantetheinases/vanins present in blood rapidly inactivates them. We herein report the facile synthesis and biological activity of a small library of pantothenamide analogues in which the labile amide group is replaced with a heteroaromatic ring. Several of these analogues display nanomolar antiplasmodial activity against Plasmodium falciparum and/or Plasmodium knowlesi, and are stable in the presence of pantetheinase. Both a known triazole and a novel isoxazole derivative were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro. Although they fail to suppress Plasmodium berghei proliferation in vivo, the pharmacokinetic and contact time data presented provide a benchmark for the compound profile likely required to achieve antiplasmodial activity in mice and should facilitate lead optimization.
- Guan, Jinming,Spry, Christina,Tjhin, Erick T.,Yang, Penghui,Kittikool, Tanakorn,Howieson, Vanessa M.,Ling, Harriet,Starrs, Lora,Duncan, Dustin,Burgio, Gaetan,Saliba, Kevin J.,Auclair, Karine
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- OXADIAZOLE COMPOUNDS, THEIR PREPARATION AND USE
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The present invention relates to oxadiazole compounds in all their stereoisomeric and tautomeric forms and mixtures thereof in all ratios; and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs and pharmaceutically acceptable polymorphs. The invention also relates to processes for the manufacture of the oxadiazole compounds and to pharmaceutical compositions containing them. The said compounds and their pharmaceutical compositions are useful in the treatment of cancer, particularly chronic myeloid leukemia (CML). The present invention further provides a method of treatment of cancer by administering a therapeutically effective amount of said compounds or their pharmaceutical compositions, to a mammal in need thereof.
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Page/Page column 84
(2011/09/30)
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- Identification and characterization of m1 selective muscarinic receptor antagonists1
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A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential ml selective muscarinic receptor antagonists. The affinity of these compounds for the five human muscarinic receptor subtyp
- Augelli-Szafran, Corinne E.,Blankley, C. John,Jaen, Juan C.,Moreland, David W.,Nelson, Carrie B.,Penvose-Yi, Jan R.,Schwarz, Roy D.,Thomas, Anthony J.
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p. 356 - 363
(2007/10/03)
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- The Syntheses of Triazole, Sulfur-Containing Diazole and N-Phenylthiatriazole Biphenyltetrazoles as Potential Angiotensin II Receptor Antagonists
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The syntheses of triazole, sulfur-containing diazole and N-phenylthiatriazole analogs of imidazole angiotensin II antagonist, DuP 753, are reported. 5-Butyl-3-[(2-trifluoromethyl)phenyl]-2,1,3,4-1H-thiatriazole-2-one biphenyltetrazole (63) is found to hav
- Chou, Shan-Yen,Chen, Su-San,Ho, Chin-Chung,Huang, Shiang-Ling,Huang, Tsai-Mien,Pan, Ohm-Guo,Wang, Chia-Lin,Chen, Ying,Lu, Hsiao-Hwa,Liu, Shih-Hwa,Huang, Shir-Ly,Chiang, Ren-Shou
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