title: Synthesis and antiprotozoal activity of dicationic 2,6-diphenylpyrazines and aza-analogues.
abstract: Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8-37nM) and P. f. (10-52nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Laixing
authors.initials: L
authors.lastname: Hu
authors.forename: Alpa
authors.initials: A
authors.lastname: Patel
authors.forename: Lavanya
authors.initials: L
authors.lastname: Bondada
authors.forename: Sihyung
authors.initials: S
authors.lastname: Yang
authors.forename: Michael Zhuo
authors.initials: MZ
authors.lastname: Wang
authors.forename: Manoj
authors.initials: M
authors.lastname: Munde
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D001372:Aza Compounds / Q000737:chemistry*; D002412:Cations / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D051379:Mice; D032446:Myoblasts / Q000166:cytology; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects; D011067:Poly dA-dT / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D011719:Pyrazines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D044366:Transition Temperature; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D001372:Aza Compounds; D002412:Cations; D011355:Prodrugs; D011719:Pyrazines; D011067:Poly dA-dT; D010419:Pentamidine
keywords: 2,6-Diarylpyrazines; Antimalarial agents; Antitrypanosomal agents; Diamidines; Prodrugs