Exploration of DAPI analogues: Synthesis, antitrypanosomal activity, DNA binding and fluorescence properties.
The DAPI structure has been modified by replacing the phenyl group with substituted phenyl or heteroaryl rings. Twelve amidines were synthesized and their DNA binding, fluorescence properties, in vitro and in vivo activities were evaluated. These compounds are shown to bind in the DNA minor groove with high affinity, and exhibit superior in vitro antitrypanosomal activity to that of DAPI. Six new diamidines (5b, 5c, 5d, 5e, 5f and 5j) exhibit superior in vivo activity to that of DAPI and four of these compounds provide 100% animal cure at a low dose of 4 × 5 mg/kg i.p. in T. b. rhodesiense infected mice. Generally, the fluorescence properties of the new analogues are inferior to that of DAPI with the exception of compound 5i which shows a moderate increase in efficacy while compound 5k is comparable to DAPI.
Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: afarahat@gsu.edu.
Abdelbasset A
AA
Farahat
Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States.
Arvind
A
Kumar
Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States.
Martial
M
Say
Swiss Tropical and Public Health Institute, Basel 4002, Switzerland; University of Basel, Basel, 4003, Switzerland.
Tanja
T
Wenzler
Swiss Tropical and Public Health Institute, Basel 4002, Switzerland; University of Basel, Basel, 4003, Switzerland.
Reto
R
Brun
Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States.
Ananya
A
Paul
Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States.
W David
WD
Wilson
Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States.
David W
DW
Boykin
D000818:Animals; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D005453:Fluorescence; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
C000616834:2-(4-amidino-3-methylphenyl)-1H-indole-5-amidine; C000616833:2-(4-amidino-3-methylphenyl)-1H-indole-6-amidine; C000617095:2-(5-amidinopyridine-2-yl)-1H-indole-6-amidine; D007211:Indoles; D011725:Pyridines; D014344:Trypanocidal Agents; C007293:DAPI; D004247:DNA
Antitrypanosomal activity; DAPI; DNA minor groove binders; Diamidines; Fluorescence properties; Pinner reaction; Stille coupling