Synthesis, DNA affinity, and antiprotozoal activity of linear dications: Terphenyl diamidines and analogues.
Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium trimethylsilylamide or upon hydrogenation of bis-O-acetoxyamidoximes. Dinitriles 9a-g were prepared via Suzuki reactions between arylboronic acids and arylnitriles. Potential prodrugs 12a-f and 17 were prepared via methylation of the diamidoximes 11a-f and 16a. Significant DNA affinities for rigid-rod molecules were observed. Compounds 10a, 10b, 10d, 18a, and 18b show IC50 values of 5 nM or less against Trypanosoma brucei rhodesiense (T. b. r.) and 10a, 10b, 10e, 18a, and 18b gave similar ones against Plasmodium falciparum (P.f.). The dications, 10a, 10d, 10f, and 10g are more active than furamidine in vivo. The prodrugs are only moderately effective on oral administration. Mouse liver microsome bioconversion of the methamidoxime prodrugs is significantly reduced from that of pafuramidine and suggests that the in vivo efficacy of these prodrugs is, in part, due to poor bioconversion.
Ismail
Mohamed A
MA
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30303-3083, USA.
Arafa
Reem K
RK
Brun
Reto
R
Wenzler
Tanja
T
Miao
Yi
Y
Wilson
W David
WD
Generaux
Claudia
C
Bridges
Arlene
A
Hall
James E
JE
Boykin
David W
DW
D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D001711:Biotransformation; D002412:Cations / Q000737:chemistry; D004247:DNA / Q000187:drug effects*; D004355:Drug Stability; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013730:Terphenyl Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
D000981:Antiprotozoal Agents; D002412:Cations; D011355:Prodrugs; D013730:Terphenyl Compounds; D010419:Pentamidine; D004247:DNA