Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides
| Autor: | Jinming Guan, Tanakorn Kittikool, Harriet Ling, Vanessa M. Howieson, Kevin J. Saliba, Karine Auclair, Erick T. Tjhin, Gaetan Burgio, Christina Spry, Lora Starrs, Dustin Duncan, Penghui Yang |
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| Rok vydání: | 2021 |
| Předmět: |
Erythrocytes
Plasmodium falciparum Triazole Pantothenic Acid Antimalarials Mice Structure-Activity Relationship chemistry.chemical_compound Drug Stability In vivo Amide Thiadiazoles parasitic diseases Drug Discovery Animals Humans Structure–activity relationship Plasmodium knowlesi Plasmodium berghei Malaria Falciparum Isoxazole Cell Proliferation Mice Inbred BALB C biology Chemistry Adept Biological activity Isoxazoles Triazoles biology.organism_classification Combinatorial chemistry In vitro Pantetheinase Molecular Medicine Female Caco-2 Cells Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 64:4478-4497 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The Plasmodium parasites that cause malaria are adept at developing resistance to antimalarial drugs, necessitating the search for new antiplasmodials. Although several amide analogs of pantothenate (pantothenamides) show potent antiplasmodial activity, hydrolysis by pantetheinases (or vanins) present in blood rapidly inactivates them. We report herein the facile synthesis and biological activity of a small library of pantothenamide analogs in which the labile amide group is replaced with a variety of heteroaromatic rings. Several of the new analogs display antiplasmodial activity in the nanomolar range against P. falciparum and/or P. knowlesi in the presence of pantetheinase. A previously reported triazole and an isoxazole derivative presented here 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 we show here that the two compounds fail to suppress proliferation of P. berghei in vivo, pharmacokinetic and contact time data presented provide a benchmark for the compound profile required to achieve antiplasmodial activity in mice and should facilitate lead optimization. |
| Databáze: | OpenAIRE |
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