Cell-Based Progression of Spiroindoline Phenotypic Hits Leads to the Identification of Compounds with Diverging Parasitological Profiles against the Human Malaria Parasite <i>Plasmodium falciparum</i>
Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide In the search for novel chemotypes with high sp 3 character and activity against the human malaria parasite Plasmodium falciparum, a spiroindoline series was identified from a phenotypic high-throughput screening campaign. The spiroindoline hit 2 displayed good activity against both drug-sensitive and multidrug-resistant Plasmodium strains, making it an attractive starting point for hit-to-lead progression. Structure–activity relationship studies led to the identification of a novel pyridylspiroindoline frontrunner ( 50 ) with improved antiplasmodial activity, aqueous solubility, and microsomal metabolic stability. Data from additional parasitological profiling suggested that 50 likely has a mode of action differing from that of the original spiroindoline hit. Compound 50 showed excellent in vivo pharmacokinetics with efficacy being achieved in a humanized immunodeficient NSG mouse P. falciparum infection model. This provided a pharmacological proof-of-concept for this series, making it a valuable starting point for further optimization in the quest for novel antimalarial therapeutics.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".