Amodiaquine analogues containing NO-donor substructures: Synthesis and their preliminary evaluation as potential tools in the treatment of cerebral malaria

• Published in: European journal of medicinal chemistry 2011-05, Vol.46 (5), p.1757-1767
• Main Authors: Bertinaria, Massimo, Guglielmo, Stefano, Rolando, Barbara, Giorgis, Marta, Aragno, Cristina, Fruttero, Roberta, Gasco, Alberto, Parapini, Silvia, Taramelli, Donatella, Martins, Yuri C., Carvalho, Leonardo J.M.
• Format: Article
• Language: English
• Subjects: Amodiaquine; Amodiaquine - chemical synthesis; Amodiaquine - chemistry; Amodiaquine - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Biological and medical sciences; Cerebral malaria; Chemistry, Physical; Furoxans; Malaria, Cerebral - drug therapy; Male; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Structure; Nitric oxide; Nitric Oxide Donors - chemistry; Nitrooxy derivatives; Oxadiazoles - chemistry; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Plasmodium falciparum - growth & development; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.02.029

The synthesis and physico-chemical properties of novel compounds obtained by conjugation of amodiaquine with moieties containing either furoxan or nitrooxy NO-donor substructures are described. The synthesised compounds were tested in vitro against both the chloroquine sensitive, D10 and the chloroquine resistant, W-2 strains of Plasmodium falciparum (P. falciparum). Most of the compounds showed an antiplasmodial activity comparable to that of the parent drug. By comparing the activities of simple related structures devoid of the ability to release NO, it appears that the contribution of NO to the antiplasmodial action in vitro is marginal. All the compounds were able to relax rat aorta strips with a NO-dependent mechanism, thus showing their capacity to release NO in the vessels. A preliminary in vivo study using Plasmodium berghei ANKA-infected mice showed a trend for prolonged survival of mice with cerebral malaria treated with compound 40, which is potent and fast amodiaquine-derived NO-donor, when compared with amodiaquine alone or with compound 31, a milder NO-donor. The two compounds showed in vivo antiplasmodial activity similar to that of amodiaquine. Amodiaquine NO-donor antimalarials were synthesised and evaluated in vitro and in vivo in a cerebral malaria model. [Display omitted] ► We synthesised and evaluated amodiaquine NO-donors as antimalarial agents. ► Nitrooxy derivatives and furoxans were used as NO-donors. ► Compounds showed antiplasmodial activity in vitro. ► Amodiaquine-furoxan showed a trend to prolong survival of mice with cerebral malaria.