Synthesis and in Vitro Antiprotozoal Activities of Dicationic 3,5-Diphenylisoxazoles

• Published in: Journal of medicinal chemistry Vol. 50; no. 10; pp. 2468 - 2485
• Main Authors: Patrick, Donald A, Bakunov, Stanislav A, Bakunova, Svetlana M, Kumar, E. V. K. Suresh, Lombardy, Richard J, Jones, Susan Kilgore, Bridges, Arlene S, Zhirnov, Oksana, Hall, James Edwin, Wenzler, Tanja, Brun, Reto, Tidwell, Richard R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 17-05-2007
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Benzamidines - pharmacology; Biological and medical sciences; Cations; Cell Line; Combinatorial Chemistry Techniques; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Medical sciences; Pharmacology. Drug treatments; Plasmodium falciparum; Plasmodium falciparum - drug effects; Rats; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei rhodesiense; Trypanosoma brucei rhodesiense - drug effects; Kinetoplastida; Protozoa; Apicomplexa; Isoxazole derivatives; Rat; Rodentia; Cytotoxicity; Striated muscle; In vitro; Antiprotozoal agent; Plasmodium falciparum; Vertebrata; Amidine; Mammalia; Cell line; Structure activity relation; Parasiticide; Benzenic compound; Chemical synthesis; Trypanosoma brucei; Organic dication
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0612867

3,5-Bis(4-amidinophenyl)isoxazole (3)an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazoleand 42 novel analogues were prepared by two general synthetic pathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. brucei rhodesiense) STIB900, Plasmodium falciparum (P. falciparum) K1, and rat myoblast L6 cells (for cytotoxicity) in vitro. Eleven compounds (3, 13, 16 − 18, 22, 26, 29, 31, 37, and 41) exhibited antitrypanosomal IC50 values less than 10 nM, five of which displayed cytotoxic indices (ratios of cytotoxic IC50 to antiprotozoal IC50 values) at least 10 times higher than that of furamidine. Eighteen compounds (4 − 8, 12, 14, 18 − 22, 25, 26, 28, 29, 32, and 43) were more active against P. falciparum than furamidine, with IC50 values less than 15 nM. Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher than that of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense.