engleski

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

Primaquine urea and semicarbazide derivatives 1-4 were screened for CNS and antimalarial activity. Several behavioural tests generally accepted as basic in investigation of the central activity were performed on mice: 'head- twitch' test, nociceptive reactions, influence on body temperature, locomotor activity (spontaneous and amphetamine-induced hyperactivity), motor coordination and pentylenetetrazole-induced convulsions. 1-((4- Chlorophenyl)(phenyl)methyl)-3-(4-((6- methoxyquinolin-8-yl)amino)pentyl)urea (4) inhibited significantly L-5-hydroxy-L- tryptophan-induced 'head-twitch' responses and decreased the body temperature of normodermic mice, which suggest the enrolment of serotonergic system. In addition, compound 4 protected mice significantly against clonic seizures (pentylenetetrazole-induced convulsions) and was superior in antimalarial test performed on Plasmodium falciparum strain in vitro. Hybrid of two primaquine urea 2 showed also a strong antimalarial activity confirming previous findings of high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All compounds decreased locomotor activity of mice, but only at the dose of 0.1 ED50, which suggest their weak depressive effects on the CNS, while primaquine derivatives 1 and 2 increased the hyperactivity caused by administration of amphetamine. In addition, all tested compounds showed antinociceptive activity in the ‘writhing’ test. Compounds 3 and 4 were active at a wide range of doses up to 0.00125 ED50 and their antinociceptive effect was reversed by naloxone. In the tail immersion test compound 3 exerted significant antinociceptive effect, which was also reversed by naloxone. None of the compounds caused coordination impairments as measured in the rota-rod and chimney tests.

primaquine ; urea ; semicarbazide ; CNS activity ; behavioural tests ; antimalarial screening

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