Table I.
Biological evaluation of dicationic diaryl pyrimidines.
| Compound | ΔTm(DNA)a | Topo II G lamblia IC50 (mM)b | In vivo activity against P carinii
|
||
|---|---|---|---|---|---|
| Dosagec (mg/kg) | Toxicityc | Cystsc (%) | |||
| Pentamidine | 12.8 | NDd | 10 | 2+ | 3.3 |
| Saline | 100e | ||||
| 6 | 21.5 | 6–12 | 10.0 | 1+ | 0.9 |
| 5.0 | 0 | 4.3 | |||
| 7 | 22.7 | 3–6 | 5.0 | 1+ | 86.4 |
| 8 | >25 | 3–12 | 5.0 | 3+ | f |
| 2.5 | 0 | 31.0 | |||
| 9 | 19.1 | 6–12 | 5.0 | 1+ | 0.05 |
| 10 | 17.8 | 3–6 | 5.0 | 0 | 1.3 |
| 11 | 16.4 | 6 | 5.0 | 1+ | 4.3 |
| 15 | 0.6 | 100 | 5.0 | 1+ | 131 |
| 20 | 14.7 | 15 | 5.0 | 2+ | 0.5 |
| 21 | 18.9 | 200 | NDd | NDd | NDd |
| 22 | 13.9 | 3–6 | 5.0 | 3+ | f |
| 2.5 | 0 | 1.1 | |||
a
Thermal melting increase of poly dA.dT; see ref [26].
b
Inhibition of topoisomerase II isolated from G lamblia, see ref [27].
c
Evaluation of iv dosage of the pyrimidines against P carinii in rats as described in ref [21].
d
Not determined.
e
Mean cyst count for pooled saline controls = 3.8 × 107 cysts/g lung tissue.
f
After toxicity was noted, dosage was lowered to 2.5 mg/kg and the evaluation was continued, results for the lower dosage shown on the next line.