BIGUANIDE AND THIOUREA DERIVATIVES OF QUINOLINE¹

Abstract

The outstanding value, as antimalarials, of Chloroquin2 and Plasmochin3 on the one hand and the exceedingly interesting properties, in experimental and clinical malaria, of Paludrine4 on the other, prompted us to attempt the synthesis of drugs carrying a biguanidyl group in place of the side chain in Chloroquin and Plasmochin. In view of the low toxicity of Paludrine and of its analogs in the phenanthrene series (1, 2), one could reasonably expect a similar property in the planned compounds.Many attempts, under varied conditions, to induce 4-amino-7-chloroquinoline to react with cyanoguanidine or isopropylcyanoguanidine failed. Moreover, we did not succeed in converting this aminoquinoline to the corresponding isothiocyanate, a potential intermediate to biguanide derivatives (1, 2). These failures may be attributed to the distinct character of the 4-amino group in the quinoline nucleus (3,4,5,6).

Thioureas

“…At this point it dropped off, probably because of water insolubility. The search for antimalarials led to the testing of many substituted thioureas and pseudothioureas (52,97,163,196). However, none of these compounds have been reported to possess antimalarial activity.…”

“…Thus, the combination of carbon disulfide and primary amine is a convenient way to prepare many 1,3-disubstituted thioureas. Arylamines with strong negative substituents may fail to undergo this reaction or give only poor yields of the desired product (107,163). Many heterocyclic amines are also reluctant to react by this method.…”