Direct, Late‐Stage Mono‐<i>N</i>‐arylation of Pentamidine: Method Development, Mechanistic Insight, and Expedient Access to Novel Antiparastitics against Diamidine‐Resistant Parasites
Bibliographic record
Abstract
A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis.
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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) | 0.001 | 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 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".