Antimalarial Pyrido[1,2-a]benzimidazoles Exert Strong Parasiticidal Effects by Achieving High Cellular Uptake and Suppressing Heme Detoxification.

Pyrido[1,2-a]benzimidazoles (PBIs) are synthetic antiplasmodium agents with potent activity and are structurally differentiated from benchmark antimalarials. To study the cellular uptake of PBIs and understand the underlying phenotype of their antiplasmodium activity, their antiparasitic activities were examined in chloroquine (CQ)-susceptible and CQ-resistant Plasmodium falciparumin vitro. Moreover, drug uptake and heme detoxification suppression were examined in Plasmodium berghei-infected mice. The in vitro potency of PBIs is comparable to most 4-aminoquinolines. They have a speed of action in vitro that is superior to that of atovaquone and an ability to kill rings and trophozoites. The antiparasitic effects observed for the PBIs in cell culture and in infected mice are similar in terms of potency and efficacy and are comparable to CQ but with the added advantage of demonstrating equipotency against both CQ susceptible and resistant parasite strains. PBIs have a high rate of uptake by parasite cells and, conversely, a limited rate of uptake by host cells. The mechanism of cellular uptake of the PBIs differs from the ion-trap mechanism typically observed for 4-aminoquinolines, although they share key structural features. The high cellular uptake, attractive parasiticidal profile, and susceptibility of resistant strains to PBIs are desirable characteristics for new antimalarial agents.

Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents.

4-(Nitrophenyl)hydrazone derivatives of N-acylhydrazone were synthesized and screened for suppress lymphocyte proliferation and nitrite inhibition in macrophages. Compared to an unsubstituted N-acylhydrazone, active compounds were identified within initial series when hydroxyl, chloride and nitro substituents were employed. Structure-activity relationship was further developed by varying the position of these substituents as well as attaching structurally-related substituents. Changing substituent position revealed a more promising compound series of anti-inflammatory agents. In contrast, an N-methyl group appended to the 4-(nitrophenyl)hydrazone moiety reduced activity. Anti-inflammatory activity of compounds is achieved by modulating IL-1ß secretion and prostaglandin E2 synthesis in macrophages and by inhibiting calcineurin phosphatase activity in lymphocytes. Compound SintMed65 was advanced into an acute model of peritonitis in mice, where it inhibited the neutrophil infiltration after being orally administered. In summary, we demonstrated in great details the structural requirements and the underlying mechanism for anti-inflammatory activity of a new family of hydrazone-N-acylhydrazone, which may represent a valuable medicinal chemistry direction for the anti-inflammatory drug development in general.