p<em>K</em><sub>a</sub> modulation of a bis(2-aminoimidazoline) DNA minor groove binder that targets the kinetoplast of <em>Trypanosoma brucei</em>
Bibliographic record
Abstract
The parasite Trypanosoma brucei, ethiologic agent of human African trypanosomiasis (i.e. sleeping sickness), contains a kinetoplast with the mitochondrial DNA (kDNA) comprising of >70 % AT base pairs. Hence, DNA minor groove binding molecules have been investigated as antitrypanosomal agents. Diphenyl-based bis(2-iminoimidazolidines) are promising DNA minor groove binders that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late(CNS)-stage disease, possibly due to poor brain penetration caused by their dicationic nature. As a strategy to reduce the pKa of the basic 2-iminoimidazolidine groups, halogen atoms (R1 = Cl, F) were introduced in the structure of lead compound 1 and the pKa of the new compounds was determined . A reduction of 1–2 pKa units for the imidazolidine group linked to the substituted phenyl ring was observed. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340).1 The chloro-substituted derivative 5a, which was curative in vivo in a mouse model of stage 1 infection by T. b. rhodesiense, appeared as a new promising lead compound.2 Mechanistic studies were performed to identify the cellular target of these dicationic compounds. Altogether, our results show that 1 and 5a share the same mechanism of action against T. brucei, acting specifically on the integrity of the kinetoplast by altering the structure and replication of kDNA.2
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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".