2. Academic Validation
  3. Exploration of DAPI analogues: Synthesis, antitrypanosomal activity, DNA binding and fluorescence properties

Exploration of DAPI analogues: Synthesis, antitrypanosomal activity, DNA binding and fluorescence properties

  • Eur J Med Chem. 2017 Mar 10:128:70-78. doi: 10.1016/j.ejmech.2017.01.037.
Abdelbasset A Farahat 1,  Arvind Kumar 2,  Martial Say 2,  Tanja Wenzler 3,  Reto Brun 3,  Ananya Paul 2,  W David Wilson 2,  David W Boykin 2
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States.
  • 3 Swiss Tropical and Public Health Institute, Basel 4002, Switzerland; University of Basel, Basel, 4003, Switzerland.
PMID: 28152428 DOI: 10.1016/j.ejmech.2017.01.037
Abstract

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.

Keywords

Antitrypanosomal activity; DAPI; DNA minor groove binders; Diamidines; Fluorescence properties; Pinner reaction; Stille coupling.

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