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.
Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 20 093, Lublin, Poland.
Ewa
E
Kedzierska
Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 20 093, Lublin, Poland.
Jolanta
http://orcid.org/0000-0001-6132-6934
J
Orzelska
Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000, Zagreb, Croatia.
Ivana
I
Perković
Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000, Zagreb, Croatia.
Danijel
D
Knežević
Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 20 093, Lublin, Poland.
Sylwia
S
Fidecka
Parasite Chemotherapy, Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, 4051, Basel, Switzerland.
Marcel
M
Kaiser
Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000, Zagreb, Croatia.
Branka
B
Zorc
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D032446:Myoblasts / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D011319:Primaquine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D012663:Semicarbazides / Q000737:chemistry / Q000494:pharmacology*; D023382:Toxicity Tests, Acute; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
D000962:Antimalarials; D012663:Semicarbazides; D014508:Urea; D011319:Primaquine
antimalarial screening; behavioural tests; central nervous system activity; primaquine; semicarbazide; urea