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Evaluation of Alkanediamide-Linked Bisbenzamidines as Potential Antiparasitic Agents
1 , 1 , 1 , 2 , 2 , 3 , 3 , * 1
1  College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA
2  Pace University, Haskins Laboratories, 1 pace Plaza, New York, NY 10038, USA
3  Swiss Tropical and Public Health Institute, Socinstrasse 57,CH-4002 Basel, Switzerland

Published: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

A series of 15 alkanediamide-linked bisbenzamidines and related analogs were synthesized and tested in vitro against two Trypanosoma brucei (Tb) strains: T. b. brucei (Tbb) and T. b. rhodesiense (Tbr), two Plasmodium falciparum (Pf) strains: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1), Trypanosoma cruzi (Tc), and Leishmania donovani (Ld). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency toward both strains of Tb and Pf with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1-96 nM). None of the tested derivatives was significantly active against Tc or Ld. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing 100% mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences in the minor grove as possible binding sites for these compounds. Several of the tested compounds are excellent leads for the development of improved antiparasitic agents.

Keywords: Bisbenzamidines; Alkanediamide; Trypanosoma brucei; Plasmodium falciparum; Antiparasitics
Comments on this paper
Jong H. Kim
Alkanediamide-­linked Bisbenzamidines
Interesting work regarding "drug-pathogen species" specificity and drug mechanism of action