Thiazole substitution of a labile amide bond - a new option towards stable pantothenamide-mimics

2025 · doi:10.1101/2025.02.25.640258
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Researchers explored thiazole substitution as a strategy to create more stable analogs of pantoprazole, a proton pump inhibitor.

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The paper studies the problem of pantothenamide degradation in human serum caused by pantetheinase and the development of pantothenamide-mimics as antimalarials against Plasmodium falciparum. The authors synthesized 23 thiazole-substituted compounds that replace a labile amide bond and tested their antiplasmodial activity in the presence of pantetheinase, finding several with sub-micromolar in vitro potency; follow-up work confirmed CoA biosynthesis and/or utilization pathways as targets and reported no toxicity to human cells. Kinetic studies showed selected compounds were substrates of the HsPanK3 enzyme but with much lower affinity than pantothenate, and the most potent compound bound to PfPanK with 120-fold higher affinity than HsPanK, demonstrating selectivity at the enzyme and whole-cell levels, although the study focuses on in vitro/biochemical characterization rather than broader clinical evaluation. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

ABSTRACT The emergence and spread of artemisinin-resistant, malaria-causing P. falciparum provide the impetus for the development of novel antimalarials. Pantothenamides are potent inhibitors of malaria parasite proliferation, however their clinical use is hindered by pantetheinase-mediated degradation in human serum. Here we report the synthesis and biological activity of a series of pantothenamide-mimics in which the labile amide bond is replaced by a thiazole ring with various orientations. Out of 23 novel compounds generated and tested in the presence of pantetheinase, several display sub-micromolar antiplasmodial activity in vitro . A selection of compounds was studied in more detail and CoA biosynthesis and/or utilisation pathways were confirmed to be the target. Toxicity to human cells was not observed. Kinetic studies identified the selected compounds as substrates of the Hs PanK3 enzyme, but with much lower affinity compared to that of the natural substrate pantothenate. The most potent thiazole-bearing antiplasmodial compound was found to bind to Pf PanK with a 120-fold higher affinity compared to Hs PanK, highlighting excellent selectivity, not only against the key first enzyme in the CoA biosynthesis pathway, but also at the whole-cell level. In conclusion, thiazole substitution of the labile amide bond represents a promising avenue for the development of antimalarial pantothenamide-mimics.
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ABSTRACT The emergence and spread of artemisinin-resistant, malaria-causing P. falciparum provide the impetus for the development of novel antimalarials. Pantothenamides are potent inhibitors of malaria parasite proliferation, however their clinical use is hindered by pantetheinase-mediated degradation in human serum. Here we report the synthesis and biological activity of a series of pantothenamide-mimics in which the labile amide bond is replaced by a thiazole ring with various orientations. Out of 23 novel compounds generated and tested in the presence of pantetheinase, several display sub-micromolar antiplasmodial activity in vitro. A selection of compounds was studied in more detail and CoA biosynthesis and/or utilisation pathways were confirmed to be the target. Toxicity to human cells was not observed. Kinetic studies identified the selected compounds as substrates of the HsPanK3 enzyme, but with much lower affinity compared to that of the natural substrate pantothenate. The most potent thiazole-bearing antiplasmodial compound was found to bind to PfPanK with a 120-fold higher affinity compared to HsPanK, highlighting excellent selectivity, not only against the key first enzyme in the CoA biosynthesis pathway, but also at the whole-cell level. In conclusion, thiazole substitution of the labile amide bond represents a promising avenue for the development of antimalarial pantothenamide-mimics. Competing Interest Statement The authors have declared no competing interest.

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