title: Synthesis and antiparasitic activity of new bis-arylimidamides: DB766 analogs modified in the terminal groups.
abstract: Fifteen novel bis-arylimidamide derivatives with various 6-membered (7a-c) and 5-membered (7d-o) heterocyclic rings replacing the terminal pyridyl rings of the lead compound DB766{(2,5-bis[2-i-propoxy-4-(2-pyridylimino)aminophenylfuran]}, were prepared and evaluated versus Trypanosoma cruzi, Leishmania amazonensis, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Compound 7a with pyrimidine replacing the pyridine rings showed good activity versus T. cruzi, T. brucei rhodesiense and P. falciparum (IC50 = 200 nM, 32 nM and 8.5 nM, respectively). Three compounds (7g, 7i, 7j) with thiazole replacing the pyridine rings gave low micromolar (0.17-0.3 μM) IC50 values versus L. amazonensis, however only 7g exhibited an acceptable selectivity index (SI = 27). Compounds 7a, 7j and 7m exhibited potent activity against T. brucei rhodesiense (IC50 = 12-60 nM). Ten of the 15 compounds with pyrimidine, pyrrole, thiazole and imidazole terminal units were highly active against P. falciparum (IC50 = 9-87 nM). Both pyrimidine and pyridine terminal groups are advantageous for anti-T. cruzi activity and several different heterocyclic terminal units are effective versus P. falciparum, both findings merit further investigation.
authors: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Zong-ying
authors: ZY
authors: Liu
authors: Swiss Tropical and Public Health Institute, Department of Medical Parasitology and Infection Biology, 4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
authors: Tanja
authors: T
authors: Wenzler
authors: Swiss Tropical and Public Health Institute, Department of Medical Parasitology and Infection Biology, 4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
authors: Reto
authors: R
authors: Brun
authors: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors: Xiaohua
authors: X
authors: Zhu
authors: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA. Electronic address: dboykin@gsu.edu.
authors: David W
authors: DW
authors: Boykin
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D007891:Leishmania / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D014345:Trypanosoma / Q000187:drug effects
chemical_list: D000577:Amides; D000977:Antiparasitic Agents
keywords: Antiparasitic agents; Bis-arylimidamides; DB766