Dicationic near-linear biphenyl benzimidazole derivatives as DNA-targeted antiprotozoal agents.
A series of near-linear biphenyl benzimidazole diamidines 5a-h were synthesized from their respective diamidoximes (4a-h), through the bis-O-acetoxyamidoxime, followed by hydrogenation in glacial acetic acid/ethanol in the presence of Pd-C. Compounds 4a-h were obtained in three steps, starting with the Suzuki coupling reaction of the appropriate haloarylcarbonitriles 1a-g or 4-bromo-2-fluorobenzaldehyde with 4-formylphenylboronic acid or 4-cyanophenylboronic acid to form the anticipated 4-formylbiphenyl carbonitrile analogues 2a-h. Subsequent condensation of the formyl derivatives 2a-h with 3,4-diaminobenzonitrile in the presence of sodium bisulfite or 1,4-benzoquinone gave the desired dinitriles 3a-h, the precursors for 4a-h. All the diamidines showed strong DNA affinities, as judged by high Delta Tm values with poly(dA.dT)2) The compounds were quite active in vitro versus Trypanosoma brucei rhodesiense, giving IC50 values ranging from 3 to 37 nM. These compounds were even more active versus Plasmodium falciparum, exhibiting IC50 values ranging from 0.5 to 23 nM. The compounds showed moderate to good activity in vivo in the STIB900 model for acute African trypanosomiasis. The most active compounds 5b and e gave 3/4 cures on an IP dosage of 20 mg/kg.
Ismail
Mohamed A
MA
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA.
Batista-Parra
Adalgisa
A
Miao
Yi
Y
Wilson
W David
WD
Wenzler
Tanja
T
Brun
Reto
R
Boykin
David W
DW
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry*; D002413:Cations, Divalent / Q000737:chemistry; D016054:DNA, Protozoan / Q000235:genetics / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D013329:Structure-Activity Relationship; D013696:Temperature
D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002413:Cations, Divalent; D016054:DNA, Protozoan; C010574:biphenyl; C031000:benzimidazole