Synthesis, antimalarial activity, and molecular modeling of new pyrrolo[1,2-a]quinoxalines, bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines.
Three pyrrolo[1,2-a]quinoxalines, 15 bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines were synthesized from various substituted nitroanilines or nitropyridines and tested for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. Bispyrrolo[1,2-a]quinoxalines showed superior antimalarial activity with respect to monopyrrolo[1,2-a]quinoxalines. The best activity was observed with bispyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine. Moreover, it was observed that the presence of a methoxy group on the pyrrolo[1,2-a]quinoxaline nucleus increased the pharmacological activity. Drug effects upon beta-hematin formation were assayed and showed similar or higher inhibitory activities than CQ. A possible mechanism of interaction implicating binding of pyrroloquinoxalines to beta-hematin was supported by molecular modeling.
Guillon
Jean
J
EA 2962-Pharmacochimie, UFR des Sciences Pharmaceutiques, Université Victor Segalen Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France.
Grellier
Philippe
P
Labaied
Mehdi
M
Sonnet
Pascal
P
Léger
Jean-Michel
JM
Déprez-Poulain
Rébecca
R
Forfar-Bares
Isabelle
I
Dallemagne
Patrick
P
Lemaître
Nicolas
N
Péhourcq
Fabienne
F
Rochette
Jacques
J
Sergheraert
Christian
C
Jarry
Christian
C
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology; D006420:Hemeproteins / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000962:Antimalarials; D006420:Hemeproteins; D011719:Pyrazines; D011725:Pyridines; D011758:Pyrroles; D011810:Quinoxalines; C020753:hemozoin