Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents.
Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed.
Fattorusso
Caterina
C
campiani@unisi.it.
Campiani
Giuseppe
G
Kukreja
Gagan
G
Persico
Marco
M
Butini
Stefania
S
Romano
Maria Pia
MP
Altarelli
Maria
M
Ros
Sindu
S
Brindisi
Margherita
M
Savini
Luisa
L
Novellino
Ettore
E
Nacci
Vito
V
Fattorusso
Ernesto
E
Parapini
Silvia
S
Basilico
Nicoletta
N
Taramelli
Donatella
D
Yardley
Vanessa
V
Croft
Simon
S
Borriello
Marianna
M
Gemma
Sandra
S
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D015195:Drug Design; D004351:Drug Resistance; D006420:Hemeproteins / Q000037:antagonists & inhibitors; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007624:KB Cells; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000166:Acridines; D000962:Antimalarials; D006420:Hemeproteins; D006835:Hydrazones; D011804:Quinolines; C020753:hemozoin; D002738:Chloroquine