Chemical synthesis and enzymatic late-stage diversification of novel pantothenate analogues with antiplasmodial activity
Bibliographic record
Abstract
The emergence of resistance to nearly every therapeutic agent directed against malaria-causing Plasmodium parasites emphasises the dire need for new antimalarials. Despite their high potency and low cytotoxicity in vitro, the clinical use of pantothenamides is hindered by pantetheinase-mediated hydrolysis in human serum. We herein report the chemical synthesis and biological activity of a new series of pantothenamide analogues in which the labile amide group is replaced with an isoxazole ring. In addition, we utilised, for the first time, enzymatic late-stage diversification to generate additional isoxazole-containing pantothenamide-mimics. Thirteen novel isoxazole-containing pantothenamide-mimics were generated, several of which display nanomolar antiplasmodial activity against Plasmodium falciparum and are non-toxic to human cells in vitro. Although the derivatives generated via late-stage diversification are less potent than the parent compounds, the most potent still exerted its activity via a mechanism that interferes with the pantothenate-utilising process and appears to be nontoxic to human cells. This increases the appeal of using late-stage diversification to modify pantothenamide-mimics, potentially leading to compounds with improved antiplasmodial and/or pharmacological properties.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".