2,4-Diphenyl furan diamidines as novel anti-Pneumocystis carinii pneumonia agents.
Dicationic 2,4-bis(4-amidinophenyl)furans 5-10 and 2, 4-bis(4-amidinophenyl)-3,5-dimethylfurans 14 and 15 have been synthesized. Thermal melting studies revealed high binding affinity of the compounds to poly(dA-dT) and to the duplex oligomer d(CGCGAATTCGCG)2. All of the new compounds were effective against Pneumocystis carinii pneumonia in the immunosuppressed rat model with up to 200-fold increase in activity compared to the control compound pentamidine. No toxicity was noted for 5, 7-10 at the dose of 10 micromol/kg/d; however, the isopropyl analogue 7 showed toxicity comparable to pentamidine at the dosage of 20 micromol/kg/d. Dimethylation of the parent compound on the furan ring resulted in reduced activity and increased toxicity.
Francesconi
I
I
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia 30303-3083, USA.
Wilson
W D
WD
Tanious
F A
FA
Hall
J E
JE
Bender
B C
BC
Tidwell
R R
RR
McCurdy
D
D
Boykin
D W
DW
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000737:chemistry; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D016867:Immunocompromised Host; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D051381:Rats; D013329:Structure-Activity Relationship
D000578:Amidines; D000935:Antifungal Agents; D005663:Furans; D004247:DNA