Trypanocidal activity of dicationic compounds related to pentamidine

• Published in: European journal of medicinal chemistry Vol. 36; no. 6; pp. 531 - 538
• Main Authors: Donkor, Isaac O, Assefa, Haregewein, Rattendi, Donna, Lane, Schennella, Vargas, Marc, Goldberg, Burt, Bacchi, Cyrus
• Format: Journal Article
• Language: English
• Published: PARIS CEDEX 15 Elsevier Masson SAS 01.06.2001; Elsevier
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; antitrypanosomal; Biological and medical sciences; Cations, Divalent - chemical synthesis; Cations, Divalent - chemistry; Cations, Divalent - pharmacology; Cations, Divalent - therapeutic use; Cattle; Chemistry, Medicinal; dicationic compounds; DNA - genetics; DNA - metabolism; Drug Design; Drug Evaluation, Preclinical; Female; Inhibitory Concentration 50; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Mice; pentamidine; Pentamidine - analogs & derivatives; Pentamidine - chemical synthesis; Pentamidine - pharmacology; Pentamidine - therapeutic use; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; Thymus Gland; trypanocidal; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanocidal Agents - therapeutic use; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei rhodesiense - drug effects; trypanosomiasis; Trypanosomiasis, African - drug therapy; antitrypanosomal; trypanosomiasis; pentamidine; dicationic compounds; trypanocidal; TRYPANOSOMA-BRUCEI-RHODESIENSE; COMPLEX; DNA-BINDING AFFINITY; ANALOGS; TOPOISOMERASE-II INHIBITION; D(CGCGAATTCGCG); PNEUMOCYSTIS-CARINII PNEUMONIA; ANTIGIARDIAL ACTIVITY; GIARDIA-LAMBLIA; MINOR-GROOVE; Imidazole derivatives; Protozoal disease; Intraperitoneal administration; Nitrogen heterocycle; Antiprotozoal agent; Structure activity relation; Parasiticid; Chemical synthesis; Trypanosoma brucei; Trypanosomiasis; Kinetoplastida; Protozoa; Aliphatic compound; Rodentia; Benzene derivatives; Pentamidine; Parasitosis; In vitro; Infection; In vivo; Vertebrata; Amidine; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Animal; Ethylenic compound
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(01)01250-8

Eight dicationic compounds related to pentamidine were studied for trypanocidal activity in seven trypanosome isolates. In vitro studies revealed that diamidines are more potent than diimidazolines. For example, 2 (a diamidine) and 4 (a diimidazoline) inhibited the growth of KETRI 243 with IC 50 values of 2.3 and 900 nM, respectively. Introduction of polar groups into the linker decreased the effectiveness of the compounds against drug-resistant trypanosomes. In compounds with a 2-butene linker between the cationic groups, trans-isomers were more potent than cis-isomers. The cis- and trans-buteneamidines cured infection caused by Trypanosoma brucei brucei (EATRO Lab 110) and protected mice against infection by Trypanosoma brucei rhodesiense isolates, some of which are resistant to diamidines and melarsoprol.