engleski

Antimalarial screening of primaquine derivatives against erythrocytic stage of P. falciparum

World malaria report 2016 of the World Health Organization tracks a dramatic decline in the global malaria burden over last 15 years, primarily due to more efficient drugs and better mosquito control. Despite the remarkable progress in fighting malaria, updated estimates indicate that there were still 212 million cases of malaria in 2015 alone, leading to 429 000 deaths.[1] Primaquine (PQ), an 8- aminoquinoline antimalarial drug, is active against all species of parasite causing human malaria, including multi-resistant Plasmodium falciparum strains. In order to overcome PQ drawbacks and drug resistance, various PQ derivatives have been synthesized and evaluated. Here we report the results of antimalarial screening of six groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a, b, acylsemicarbazides 4a-k, bis-ureas 5a-v and ureidoamides 6a-g synthesized by our research group[2-8]. Antimalarial evaluation was performed in vitro against erythrocytic stage of drug sensitive P. falciparum NF54 strain and compared with the standard antimalarial drugs. The cytotoxicity of the compounds was tested on a cell line derived from rat skeletal myoblasts (L-6). PQ amide derivatives 1d and 1e with two or three methoxy substituents on cinnamic acid residue, urea derivatives 2i and 2j with chlorobenzhydryl or trityl substituent and urea 2k with two PQ residues, PQ-cinnamic acid semicarbazide 4e with three methoxy groups, and trityl bis-urea 5r showed the highest activity and the lowest cytotoxicity. Practically all ureidoamides 6a-g excerted high selectivity index (cytotoxicity/activity ratio), but the best results showed 6e, a benzhydryl derivative of p-chlorophenylglycine. Due to their high activity and low cytotoxicity compounds 6e and 5r may be considered as potential scaffolds for development of more effective and safer drugs for malaria treatment.

primaquine derivatives ; antimalarial activity ; erythrocytic stage ; P. falciparum

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