Pholpramool C, Ruchirawat S, Verawatnapakul V, Paovalo C, Lewin L M
Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
J Reprod Fertil. 1991 May;92(1):169-78. doi: 10.1530/jrf.0.0920169.
Sulphonamides with different chemical structures were synthesized and these 13 compounds together with 7 commercially available sulpha drugs were tested for antifertility activity by natural mating in male rats. All compounds were given daily by gastric intubation at doses of 125, 150, 250 or 450 mg/kg for 6 weeks. Sulphapyridine caused a dose-related and reversible reduction in fertility at doses between 125 and 450 mg/kg. At the high dose, fertility was reduced to 25.9% of control at 5 weeks after treatment, and complete recovery occurred by 3 weeks after drug withdrawal. This activity was abolished when the pyridine ring was substituted by other heterocyclic rings, except sulphachloropyridazine which had only weak activity. Replacement of the pyridine ring by a hydrogen atom or short aliphatic chains preserved or even enhanced the potency. Thus, sulphanilamide, N1-methylsulphanilamide or N1-diethylsulphanilamide produced a marked but reversible reduction in fertility. Removal or substitution of the N4-amino group on the benzene ring of sulphapyridine with a methyl group destroyed the activity. However, the bromo or nitro analogue (at the para- but not the meta-position of the benzene ring) still possessed some activity. N4-Acetyl derivatives of sulphapyridine, sulphanilamide, and N1-diethylsulphanilamide were as potent as their parent compounds. These results suggest that the presence of pyridine or other heterocyclic rings is not necessary for the antifertility activity of sulphonamide compounds. However, the N4-amino group is indispensable. In addition, acetylation of this amino group does not change the potency. The prototype of the antifertility sulphonamides therefore seems to be sulphanilamide.
合成了具有不同化学结构的磺胺类化合物，并通过雄性大鼠自然交配试验，对这13种化合物以及7种市售磺胺类药物的抗生育活性进行了测试。所有化合物均通过胃管给药，剂量为125、150、250或450mg/kg，每日一次，持续6周。磺胺吡啶在125至450mg/kg的剂量下可导致生育力呈剂量相关的可逆性降低。在高剂量下，治疗后5周生育力降至对照组的25.9%，停药后3周完全恢复。当吡啶环被其他杂环取代时，这种活性消失，但磺胺氯哒嗪活性较弱。用氢原子或短脂肪链取代吡啶环可保留甚至增强效力。因此，磺胺、N1-甲基磺胺或N1-二乙基磺胺可使生育力显著但可逆地降低。将磺胺吡啶苯环上的N4-氨基去除或用甲基取代会破坏活性。然而，溴代或硝基类似物（在苯环的对位而非间位）仍具有一定活性。磺胺吡啶、磺胺和N1-二乙基磺胺的N4-乙酰基衍生物与其母体化合物的效力相当。这些结果表明，吡啶或其他杂环的存在对于磺胺类化合物的抗生育活性并非必需。然而，N4-氨基是不可或缺的。此外，该氨基的乙酰化不会改变效力。因此，抗生育磺胺类化合物的原型似乎是磺胺。
