Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro.

New primaquine (PQ) urea and semicarbazide derivatives 1-4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L-6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited 'head-twitch' responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine-induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the 'writhing' test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents.