Background
Diaveridine is a dihydrofolate reductase (DHFR) inhibitor (Ki = 11.5 nM for the P. falciparum enzyme) with antimicrobial activity.1,2,3,4 It is active against P. vulgaris, S. aureus, and S. pyogenes in vitro (MICs = 4, 1, and 2 μg/ml, respectively).2 Diaveridine has anticoccidial activity when administered alone or in combination with sulfaquinoxaline.3,4
1.Sirichaiwat, C., Intraraudom, C., Kamchonwongpaisan, S., et al.Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: Their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparumJ. Med. Chem.47(2)345-354(2004)
2.Roth, B., Falco, E.A., Hitchings, G.H., et al.5-Benzyl-2,4-diaminopyrimidines as antibacterial agents. I. Synthesis and antibacterial activity in vitroJ. Med. Chem.5(6)1103-1123(1962)
3.Ryley, J.F., and Betts, M.J.Chemotherapy of chicken coccidiosisAdvances in Pharmacology11221-293(1973)
4.Wang, J., Sun, F., Tang, S., et al.Acute, mutagenicity, teratogenicity and subchronic oral toxicity studies of diaveridine in rodentsEnviron. Toxicol. Pharmacol.40(2)660-670(2015)
Protocol
Cell experiment: | Cells are cultured at 37°C in a humidified atmosphere of 5% CO2 in air. The growth medium is Eagle’s MEM supplemented with 10% fetal bovine serum. In the experiment without metabolic activation, the cells are treated for 24 or 48 h continuously without a medium change. In the experiment with metabolic activation, the cells are pulse treated with test compounds (including Diaveridine) at varying doses for 6 h and incubated for 18 h in fresh culture medium. Breakage type chromatid aberrations, exchange type chromatid aberrations, breakage type chromosome aberrations, and exchange type chromosome aberrations are scored. Gaps are also counted. Mitotic index is determined from scoring 2000 cells[2]. |
Animal experiment: | 3]Fifty male ICR mice, weighing 25 to 35 g, are assigned to five groups randomly with 10 mice in each group. Mice in the experiment groups receive Diaveridine (DVD) via IG at ed 128 mg/kg (low doses), 256 mg/kg (medium doses), and 512 mg/kg (high doses) body weight for 5 consecutive days, respectively. Mice in negative and positive control groups receive IG 1% CMC-Na solvent and 40 mg/kg body weight of cyclophosphamide, respectively. The testing groups are administered 0.2 mL/10 g Diaveridine (mixed with 1% of CMC-Na, to obtain the concentration of 2 mg/mL.) body weight, once a day, for 5 days. The behavioral changes are recorded on the daily basis[3]. |
参考文献: [1]. Sirichaiwat C et al. Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum. J Med Chem 47:345-54 (2004).
[2]. Ono T, et al. The genotoxicity of diaveridine and trimethoprim. Environ Toxicol Pharmacol. 1997 Sep;3(4):297-306.
[3]. Wang J, et al. Acute, mutagenicity, teratogenicity and subchronic oral toxicity studies of diaveridine in rodents. Environ Toxicol Pharmacol. 2015 Sep;40(2):660-70. |
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